Pyridinone and pyridinethione derivatives having hiv inhibiting properties

[0001] The present invention is concerned with pyridinone and pyridinethione derivatives having Human Immunodeficiency Virus (HIV) replication inhibiting properties. It further relates to processes for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection.

[0002] Compounds structurally related to the present compounds are disclosed in the prior art.

[0003]

Naturforsch. B, Anorg. Chem., Org. Chem
., 1983, 38 B (3), 398-403 discloses iodine, nitrogen and sulfurylides of 2-pyridones.

[0004]

Pol. J. Chem
., 1979, 53 (11), 2349-2354 discloses N-(tetrahalo-4-pyridyl) aminobenzoic acid derivatives and their use as herbicides.

[0005]

J. Med. Chem
., 1983, 26 (9), 1329-1333 discloses the synthesis of aza analogs of lucanthone useful as antitumor and bactericidal agents.

[0006] WO 86/01815 discloses the synthesis of monoazodyes and their use as dyestuffs.

[0007]

Can. J. Chem
., 1980, 58 (5), 501-526 discloses the chemistry of aurodox and related antibiotics.

[0008] WO 97/05113 discloses 4-aryl-thio-pyridin-2(1H)-ones and their use for treating HIV related diseases.

[0009] WO 99/55676 discloses 3-(amino- or aminoalkyl)pyridinone or pyridinethione derivatives and their use for the treatment of HIV related diseases.

[0010] However their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains. The most active thiopyridinones disclosed in WO 97/05113 have a 50% inhibitory concentration of virus multiplication (IC50) for nevirapine resistant strains of about 260 nM, whereas the free amino or aminoalkyl pyridinone and pyridinone derivatives disclosed in WO 99/55676 have a 50% inhibitory concentration of virus multiplication for nevirapine resistant strains of more than 10 000 nM.

[0011] The Inventors have found a new family of pyridinones and pyridinethiones derivatives which show better HIV inhibitory properties.

[0012] The present invention is concerned with compounds of formula

[0013] the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein

[0014] Y is O or S;

[0015] Q is hydrogen; halo; C1-6alkyl; di(C1-4alkyl)amino; C1-6alkyloxy, C1-6alkyloxyC1-6alkyl; C1-6alkylthio; C1-6alkylthioC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl-S(═O)—; C1-6alkyl-S(═O)2—; hydroxyC1-6alkyl; polyhaloC1-6alkyl; C1-6akyloxycarbonylC1-6alkyl; C1-6alkyloxycarbonylC1-6alkylthio; aminocarbonyl6C1-6alkylthio; C1-6alkyloxyC1-6alkyloxycarbonyl, C2-6alkenyl optionally substituted with halo, hydroxy, cyano, formyl, —COOH, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C3-6cycloalkyl optionally substituted with C1-4alkyl; cyano; carboxyl; formyl; R5R6N—C(═O)—; R5R6N—C(═O)—C1-6alkyl; N-hydroxy-imino; N—C1-4alkyloxy-imino; aryl; aryloxy, arylthio; arylC1-6alkyl; arylcarbonyl; arylC1-6alkyloxycarbonyl; C1-6alkyl substituted with hydroxy or aryl; Het1; Het1oxy, Het1thio; Het1C1-6alkyl; Het1carbonyl; Het1C1-6alkyloxycarbonyl; C1-6alkyl-P(OR15)2═O or C1-6alkyl-P(O—C1-6alkyl-O)═O;

[0016] X is a bivalent radical of formula

—(CH2)p— (a-1)

—(CH2)q—Z—(CH2)r— (a-2);

[0017] wherein p is an integer of value 1 to 5;

[0018] q is an integer of value 0 to 5;

[0019] r is an integer of value 0 to 5;

[0020] Z is O, S, NR7, C(═O), S(═O), S(═O)2, CHOR13, CH═CH,

[0021] CH(NR7R8) or CF2;

[0022] and wherein each hydrogen atom may be replaced by C1-4alkyl or hydroxyC1-4alkyl;

[0023] R1 is C1-6alkyl, C3-6cycloalkyl, C1-6alkenyl, C1-6alkoxy, aryl or a monocyclic or bicyclic heterocycle selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or a radical of formula

[0024] with n being an integer of 1 or 2, said monocyclic or bicyclic heterocycle or said radical of formula (b-1) or (b-2) optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, polyhaloC1-4alkyl or phenyl;

[0025] or Q and X—R1 may be taken together with the pyridinone to form a tricyclic heterocycle of formula

[0026] with R16 and R17 being C1-6alkyl or forming together ═O.

[0027] R2 and R3 each independently are selected from hydrogen; halo; formyl; cyano; azido; hydroxy, oxiranyl; amino; mono- or di(C1-4alkyl)amino; formylamino; mercapto(C1-6)alkyl; hydrazino; R5aR6aN—C(═O)—; R9—N═C(R10)—; C2-6alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, di(C1-4alkyl)carbamoyl, [di(C1-4alkyl)amino(C1-6alkyl)](C1-4alkyl)carbamoyl, [di(C1-4alkyl)amino(C1-6alkyl)](arylC1-4alkyl)carbamoyl, di(C1-4alkyloxy) (C1-4alkyl)carbamoyl, (cyanoC1-6alkyl)(C1-6alkyl)aminoC1-6alkyl, N-hydroxy-imino, aryl, Het2, Het2carboxamido, Het2(C1-6alkyl)carbamoyl; C2-6alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, aryl or Het2; C1-6alkyloxy, hydroxyC1-6alkyloxy, aminoC1-6alkyloxy, mono- or di(C1-4alkyl)aminoC1-6alkyloxy; C1-6alkylcarbonyl; arylcarbonyl; Het2carbonyl; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy, aryl; aryloxy; arylC1-6allyloxy, arylthio; arylC1-6alkylthio; mono- or di(aryl)amino; Het2; Het2oxy, Het2thio; Het2C1-6alkyloxy; Het2C1-6alkylthio; Het2SO2; Het2SO; mono- or di(Het2)amino; C3-6cycloalkyl; C3-6cycloalkyloxy, C3-6cycloalkylthio; C1-6alkylthio; hydroxyC1-6alkylthio; aminoC1-6alkylthio; mono- or di(C1-4alkyl)aminoC1-6alkylthio; C1-6alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, carboxyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkylsulfonyl, C1-6alkycarbamoylC1-4alkylthio, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxyC1-6alkylthio C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C1-4alkyl)aminocarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-6alkyloxy, C1-6alkyloxycarbonylC1-6alkylthio, aryl, Het2, aryloxy, arylthio, arylC1-6alkyloxy, arylC1-6alkylthio, Het2C1-6alkyloxy, Het2C1-6alkylthio, C1-6alkyl-S(═O)2-oxy, amino, mono- or di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkylthio, [di(C1-6alkyl)amino(C1-6alkyl)](C1-6alkyl)amino, di(cyanoC1-6alkyl)amino, C1-6alkyloxycarbonylamino, C1-6alkyloxyC1-6alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC1-4alkyl)amino, mono- or di(C1-4alkyloxyC1-4alkyl)amino, mono- or di(C1-4alkylthioC1-4alkyl)amino, mono- or di(Het2C1-4alkyl)amino, (Het2C1-4alkyl)(C1-4alkyl)amino, (cyanoC1-6alkyl)(C1-6alkyl)amino, C3-6cycloalkylthio, R11—(C═O)—NH—, R12—NH—(C═O)—NH—, R14—S(═O)2—NH—, C1-6alkyl-P(O—R15)2═O, C1-6alkyl-P(O—C1-6alkyl-O)═O or a radical of formula

[0028] with A1 being CH or N, and A2 being CH2, NR13, S or O, provided that when A1 is CH then A2 is other than CH2, said radical (c-1), (c-2) and (c-3) being optionally substituted with one or two substituents each independently selected from H, C1-6alkyl, C1-6alkyloxy, hydroxy C1-4alkyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-4alkyl, aminoC1-6alkyl, C1-4alkylcarbonyl, arylcarbonyl, aryl, Het1, Het1-C═O)—, hydroxy, cyano, C1-4alkylcyano, CONR16R17 with R16 and R17 being independently H or alkyl, mono or di(C1-4alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4phenyl;

[0029] or R2 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2—A3—CH2— (d-1)

—CH═CH—CH═CH— (d-2)

[0030] with t being an integer of 0, 1 or 2 and A3 being CH2, O, S, NR7a or N[C(═O)R8a] and wherein each hydrogen in said formula (d-1) or (d-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;

[0031] R4 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C2-6alkenyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-6alkyl or aryl;

[0032] or R4 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2—A4—CH2— (e-1)

—CH═CH—CH═CH— (e-2)

[0033] with t being an integer of 0, 1 or 2 and A4 being CH2, O, S, NR7b or N[C(═O)R8b] and wherein each hydrogen in said formula (e-1) or (e-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;

[0034] or X—R1 and R2 may be taken together to form a tricyclic heterocycle of formula

[0035] with R16 and R17 being C1-6alkyl or forming together ═O.

[0036] R5 and R6 each independently are hydrogen, C1-4alkyl or C1-4alkyloxy;

[0037] R5a and R6a each independently are hydrogen; C1-4alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkylthio, amino, mono-or di(C1-4alkyl)amino or a radical of formula

[0038] with A5 and A6 each independently being CH2, NR13 or O;

[0039] R7, R7a and R7b each independently are hydrogen, formyl or C1-4alkyl;

[0040] R8, R8a and R8b each independently are hydrogen or C1-4alkyl;

[0041] R9 is hydrogen, hydroxy, C1-4alkyloxy, carboxylC1-4alkyloxy, C1-4alkyloxycarbonyl-C1-4alkyloxy, C2-4alkenyloxy, C2-4alkynyloxy or arylC1-4alkyloxy;

[0042] R10 is hydrogen, carboxyl or C1-4alkyl;

[0043] R11 is hydrogen; C1-4alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-S(═O)2—, aryl or Het3; C1-4alkyloxy; C2-4alkenyl; arylC2-4alkenyl; Het3C2-4alkenyl; C2-4alkynyl; Het3C2-4alkynyl, arylC2-4alkynyl; C3-6cycloalkyl; aryl; naphthyl or Het3;

[0044] R12 is C1-4alkyl, arylC1-4alkyl, aryl, arylcarbonyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl or C1-4alkyloxycarbonylC1-4alkyl;

[0045] R13 is hydrogen, C1-4alkyl or C1-4alkylcarbonyl;

[0046] R14 is C1-4alkyl optionally substituted with aryl or Het4; polyhaloC1-4alkyl or C2-4alkenyl optionally substituted with aryl or Het4;

[0047] R15 is C1-4 alkyl;

[0048] Het1 and Het2 each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrmidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrimidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexabydropyridazinyl, morpholinyl, thiomorpholinyl triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, benzodioxanyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, imidazopyridinyl, dihydropyrrolyl or dihydroisoxazolyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from O, S, halo, formyl, amino, hydroxy, cyano, C1-4alkyl, hydroxyC1-4alkyl, carboxyC1-4alkyl, carbamoylC1-4alkyl, carbamoylC1-4alkoxy, C1-4alkyloxy, C1-4alkylcarbonyl, C1-4alkyloxyC1-4alkyl, cyanoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl, —OCONH2, C1-4alkoxyC1-4alkyl, aryl, Het2C1-4alkyl, polyhaloC1-4alkyl, C3-6cycloalkyl or arylC2-6alkenyl,

[0049] Het3 is a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl or a radical of formula

[0050] with A7 or A8 each independently being selected from CH2 or O; each of said monocyclic or bicyclic heterocycles may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy,C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;

[0051] Het4 is a monocyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;

[0052] Het5 is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, piperidinyl, morpholinyl or pyrrolidinyl;

[0053] aryl is phenyl optionally substituted with one, two or three substituents each independently selected from halo; hydroxy, carboxyl; cyano; formyl; acetyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; mono- or di(C1-4alkyl)aminocarbonylamino; C1-4alkyl-S(═O)2—NH—; Het5(═S)—S—C1-4alkyl; C1-6alkyloxy; sulfamoyl; (C1-4alkyl)sulfamoyl; arylsulfamoyl; Het2sulfamoyl; O—P═OR15; C1-6alkyl optionally substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C2-6alkenyloxy, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonylthio, N-hydroxyimino, phenyl or Het5; C2-6alkenyl optionally substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; phenyl; phenyloxy, phenyl(C1-4alkyl)thioC1-4alkyl; (C3-6)cyclohexylthioC1-4alkyl or isoxazolinyl optionally substituted by C1-4alkyloxycarbonyl or morpholinylC1-4alkyl

[0054] provided that

[0055] 5,6,7,8-tetrahydro-3-iodo-4-phenoxy-1-phenyl-2(1H)quinolinone;

[0056] 3-iodo-6-methyl-4phenoxy-2(1H)-pyridinone;

[0057] 2-[(3,5,6-trifluoro-1,2-dihydro-2-oxo-4-pyridinyl)amino]benzoic acid;

[0058] 1,2-dihydro-6-hydroxy-2-oxo-4-(2-phenylethyl)-3-pyridinecarbonitrile;

[0059] 1,2-dihydro-6-hydroxy-2-oxo-4-(4-pyridinylmethyl)-3-pyridinecarbonitrile;

[0060] 4-[(4-bromophenyl)methoxy]-3,5-diodo-1-methyl-2(1H)-pyridinone;

[0061] 4-[(4-bromophenyl)methoxy]-1,2-dihydro-1-methyl-2-oxo-3-pyridinecarboxylic acid; 1,2-dihydro-6-methyl-2-oxo-4-(phenylthio)-3-pyridinecarboxylic acid and the alkyl-4-arylthio-1,2-dihydro-5-methyl-6-methyl-2-oxo-3-pyridine carboxylate 3-bromo-4-[[[2-(3,4-dimethoxyphenyl)ethyl]amino]methyl-2(1H)quinolinone;

[0062] 3-iodo-7-methoxy-1-methyl-4-phenoxy-2(1H)quinolinone;

[0063] 1-ethyl-3-iodo-7-methoxy-4-phenoxy-2(1H)quinolinone;

[0064] 3-iodo-7-methoxy-4-(4-methoxyphenoxy)-1-methyl-2(1H)quinolinone;

[0065] 1-ethyl-3-iodo-7-methoxy-4-(4-methoxyphenoxy)-1-methyl-2(1H)quinolinone;

[0066] 3-iodo-7-methoxy-4-(3-methoxyphenoxy)-1-methyl-2(1H)quinolinone;

[0067] 1-ethyl-3-iodo-7-methoxy-4-(3-methoxyphenoxy)-1-methyl-2(1H)quinolinone;

[0068] 3-iodo-7-methoxy-4-phenoxy-2(1H)quinolinone;

[0069] 4-(3-chloro-4-methoxyphenoxy)-3-iodo-7-methoxy-2(1H)quinolinone;

[0070] 3-iodo-4-phenoxy-2(1H)quinolinone;

[0071] 3-iodo-4-phenoxy-1-phenyl-2(1H)quinolinone;

[0072] 3-iodo-4-(4-methylphenoxy)-2(1H)quinolinone;

[0073] 3-iodo-4-(4-methoxyphenoxy)-2(1H)quinolinone;

[0074] are not included.

[0075] As used herein C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl and the like; C1-6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C1-4alkyl and pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like; C2-4alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing a double bond such as ethenyl, propenyl, butenyl and the like; C2-6alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing at least one double bond such as the groups defined for C2-4alkenyl and pentenyl, hexenyl, 2,4-hexadienyl, 1,3-butadienyl, 3-methylbutenyl and the like; C2-4alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing one triple bond such as ethynyl, propynyl, butynyl and the like; C2-6alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing one triple bond such as the groups defined such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, 3-methylbutynyl and the like; C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0076] As used hereinbefore, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, a sulfonyl moiety when two of said terms are attached to a sulfur atom, a phosphonate when attached to a phosphorus atom.

[0077] The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloC1-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1-6alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC1-6alkyl, they may be the same or different.

[0078] The R1 or Het1, Het2, Het3, Het4 or Het5 radical as described above for the compounds of formula (I) may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. For example, when Het1 is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl.

[0079] Lines drawn into ring systems indicate that the bond may be attached to any suitable ring atom.

[0080] When any variable (e.g. aryl) occurs more than one time in any constituent, each definition is independent.

[0081] It will be appreciated that some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.

[0082] The term “stereochemically isomeric forms” as used herein before defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates, quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

[0083] For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.

[0084] The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic) malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzensulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

[0085] Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0086] The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the lie, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, thiehylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

[0087] Conversely the salt forms can be converted by treatment with acid into the free acid form.

[0088] The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.

[0089] The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen.

[0090] Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

[0091] Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

[0092] Whenever used hereinafter, the term “compounds of formula (I)” or “compounds of formula (I-a)” is meant to include also the N-oxides, the addition salts, the quaternary amines and all stereoisomeric forms.

[0093] A special group of compound contains those compounds of formula (I) wherein

[0094] Q is halo; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxyC1-6alkyl; C1-6alkylthio; C1-6alkylthioC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl C1-6alkyl-S(═O)—; C1-6alkyl-S(═O)2—; hydroxyC1-6alkyl; polyhaloC1-6alkyl; C1-6alkyloxycarbonylC1-6alkyl; C1-6alkyloxyC1-6alkyloxycarbonyl; C2-6alkenyl optionally substituted with halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino or aryl; C3-6cycloalkyl optionally substituted with C1-4alkyl; cyano; carboxyl; formyl; R5R6N—C(═O)—; R5R6N—C(═O)—C1-6alkyl; N-hydroxy-imino; N—C1-4alkyloxy-imino; aryl; aryloxy; arylthio; arylC1-6alkyl; arylcarbonyl; arylC1-6alkyloxycarbonyl; C1-6alkyl substituted with both hydroxy and aryl; Het1; Het1oxy; Het1thio; Het1C1-6alkyl; Het1carbonyl; Het1C1-6alkyloxycarbonyl; C1-6alkyl-P(OR15)2═O or C1-6alkyl-P(O—C1-6alkyl-O)═O

[0095] X is a bivalent radical of formula

—(CH2)p— (a-1)

—(CH2)q—Z—(CH2)r— (a-2);

[0096] wherein p is an integer of value 1 to 5;

[0097] q is an integer of value 0 to 5;

[0098] r is an integer of value 0 to 5;

[0099] Z is O, S, NR7, C(═O), S(═O), S(═O)2, CHOR13, CH═CH, CH(NR7R8) or CF2;

[0100] and wherein each hydrogen atom may be replaced by C1-4alkyl or hydroxyC1-4alkyl;

[0101] R1 is C3-6cycloalkyl, aryl or a monocyclic or bicyclic heterocycle selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or a radical of formula

[0102] with n being an integer of 1 or 2, said monocyclic or bicyclic heterocycle or said radical of formula (b-1) or (b-2) optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, polyhaloC1-4alkyl or phenyl;

[0103] R2 and R3 each independently are selected from hydrogen; halo; formyl; cyano; azido; hydroxy, oxiranyl; amino; mono- or di(C1-4alkyl)amino; formylamino; R5aR6aN—C(═O)—; R9—N═C(R10)—; C2-6alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, aryl or Het2; C2-6alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, aryl or Het2; C1-6alkyloxy, hydroxyC1-6alkyloxy; aminoC1-6alkyloxy; mono- or di(C1-4alkyl)aminoC1-6alkyloxy; C1-6alkylcarbonyl; arylcarbonyl; Het2carbonyl; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy, aryl; aryloxy, arylC1-6alkyloxy, arylthio; arylC1-6alkylthio; mono- or di(aryl)amino; Het2; Het2oxy; Het2thio; Het2C1-6alkyloxy; Het2C1-6alkylthio; mono- or di(Het2)amino; C3-6cycloalkyl; C3-6cycloalkyloxy; C3-6cycloalkylthio; C1-6alkylthio; hydroxyC1-6alkylthio; aminoC1-6alkylthio; mono- or di(C1-4alkyl)aminoC1-6alkylthio; C1-6alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C1-6alkyloxy, C1-6alkylthio, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C1-4alkyl)aminocarbonyloxy, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-6alkyloxy, C1-6alkyloxy-carbonylC1-6alkylthio, aryl, Het2, aryloxy, arylthio, arylC1-6alkyloxy, arylC1-6alkylthio, Het2C1-6alkyloxy, Het2C1-6alkylthio, C1-6alkyl-S(═O)2-oxy, amino, mono- or di(C1-6alkyl)amino, C1-6alkyloxy-carbonylamino, C1-6alkyloxyC1-6alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC1-4alkyl)amino, mono- or di(C1-4alkyloxyC1-4alkyl)amino, mono- or di(C1-4alkylthioC1-4alkyl)amino, mono or di(Het2C1-4alkyl)amino, R11—(C═O)—NH—, R12—NH—(C═O)—NH—, R14—S(═O)2—NH—, C1-6alkyl-P(O—R15)2═O, C1-6alkyl-P(O—C1-6alkyl-O)═O or a radical of formula

[0104] with A1 being CH or N, and A2 being CH2, NR13, S or O, provided that when A1 is CH then A2 is other than CH2, said radical (c-1) and (c-2) being optionally substituted with one or two substituents each independently selected from H, C1-6alkyl, C1-6alkyloxy, hydroxy C1-4alkyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-4alkyl, aminoC1-6alkyl, carbonyl, hydroxy, cyano, CONR16R17 with R16 and R17 being independently H or alkyl, mono or di(C1-4alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4phenyl;

[0105] or R2 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2—A3—CH2— (d-1)

—CH═CH—CH═CH— (d-2)

[0106] with t being an integer of 0, 1 or 2 and A3 being CH2, O, S, NR7a or N[C(═O)R8a] and wherein each hydrogen in said formula (d-1) or (d-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;

[0107] R4 is hydrogen, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, C2-6alkenyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl or aryl;

[0108] or R4 and R3 may be taken together to form a bivalent radical of formula

—(CH2)t—CH2—A4—CH2— (e-1)

—CH═CH—CH═CH— (e-2)

[0109] with t being an integer of 0, 1 or 2 and A4 being CH2, O, S, NR7b or N[C(═O)R8b] and wherein each hydrogen in said formula (e1) or (e-2) may be substituted with halo, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, haloC1-4alkylcarbonyl or arylcarbonyl;

[0110] R5 and R6 each independently are hydrogen, C1-4alkyl or C1-4alkyloxy,

[0111] R5a and R6a each independently are hydrogen; C1-4alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkylthio, amino, mono- or di(C1-4alkyl)amino; or a radical of formula

[0112] with A5 and A6 each independently being CH2, NR13 or O;

[0113] R7, R7a and R7b each independently are hydrogen, formyl or C1-4alkyl;

[0114] R8, R8a and R8b each independently are hydrogen or C1-4alkyl;

[0115] R9 is hydrogen, hydroxy, C1-4alkyloxy, carboxylC1-4alkyloxy, C1-4alkyloxycarbonyl-C1-4alkyloxy, C2-4alkenyloxy, C2-4alkynyloxy or arylC1-4alkyloxy;

[0116] R10 is hydrogen, carboxyl or C1-4alkyl;

[0117] R11 is hydrogen; C1-4alkyl optionally substituted with cyano, C1-4alkyloxy, C1-4alkyl-S(═O )2—, aryl or Het3; C1-4alkyloxy, C2-4alkenyl; arylC2-4alkenyl; Het3C2-4alkenyl; C2-4alkynyl; Het3C2-4alkynyl, arylC2-4alkynyl; C3-6cycloalkyl; aryl; naphthyl or Het3;

[0118] R12 is C1-4alkyl, arylC1-4alkyl, aryl, arylcarbonyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, or C1-4alkyloxycarbonylC1-4alkyl;

[0119] R13 is hydrogen, C1-4alkyl or C1-4alkylcarbonyl;

[0120] R14 is C1-4alkyl optionally substituted with aryl or Het4; polyhaloC1-4alkyl or C2-4alkenyl optionally substituted with aryl or Het4;

[0121] R15 is C1-4alkyl;

[0122] Het1 and Het2 each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl or 2-oxo-1,2-dihydro-quinolinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;

[0123] Het3 is a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl or a radical of formula

[0124] with A7 or A8 each independently being selected from CH2 or O; each of said monocyclic or bicyclic heterocycles may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;

[0125] Het4 is a monocyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl or polyhaloC1-4alkyl;

[0126] Het5 is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl or oxazolyl;

[0127] aryl is phenyl optionally -substituted with one, two or three substituents each independently selected from halo; hydroxy, carboxyl; cyano; formyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; mono- or di(C1-4alkyl)aminocarbonylamino; C1-4alkyl-S(═O)2—NH—; C1-6alkyloxy, C1-6alkyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; C2-6alkenyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino phenyl or Het5; C2-6alkynyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C1-4alkyl)amino, C1-6alkyloxycarbonyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het5; phenyl or henyloxy,

[0128] A special group of compound contains those compounds of formula (I) wherein

[0129] Q is halo, C1-6alkyl or C2-6alkenyl;

[0130] X is (a-2) with q and r being 0 and Z being O, S or SO;

[0131] R1 is aryl;

[0132] R2 is selected from formyl; C1-6alkyloxycarbonylalkyl; Het2; Het2C1-6alkyl; C1-6alkylthio; C1-6alkyl optionally substituted with one or two substituents each independently selected from hydroxy or halo;

[0133] R3 is selected from formyl; C1-6alkyl optionally substituted with one or two C1-6alkyloxy,

[0134] R4 is hydrogen.

[0135] Particular compounds are those compounds of formula (T) wherein Q is iodo. Preferred compounds are those compounds of formula (I) wherein Q is iodo, X—R1 is a 3,5-dimethylphenylthio or a 3,5-dimethylphenyloxy and R2 is a hydroxymethyl or a N-morpholinomethyl or a 3-phenylpropyl or a furan-2-yl-methylthiomethyl. Also preferred compounds are those compounds of formula (I) wherein Q is iodo, X—R1 is a 3-(2-cyano-vinyl)-5-iodophenyloxy or 5-bromo-3-(2-cyano-vinyl) and R2 is ethyl.

[0136] Most preferred compounds are compounds no 242, 255, 43, 264, 124, 249, 298, 326, 133, 241, 253, 306,328, 46, 105, 234, 254, 256, 272, 284, 296, 319, 83, 88, 108, 109, 115, 277, 286, 299, 45, 85, 86, 231, 244, 297, 250, 257, 307, 324, 81, 92, 140, 143, 217, 221, 230, 232, 245, 309, 321, 322, 31, 218, 222, 314, 8, 99, 121, 219, 233, 280, 551,470, 375, 483,547, 606, 618, 662, 694, 700,709 and 713 of table 1.

[0137] The present invention also relates to a method of treating warm-blooded animals suffering from HIV infection. Said method comprises the administration of the therapeutically effective amount of a compound of formula (I) or any sub group thereof, a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.

[0138] The compounds of formula (I) can be prepared according to art-known procedures.

[0139] In general, compounds of formula (I) wherein X is an oxygen and R1 a 3,5-dimethylphenyl, said compound being represented by formula (I-a) can be prepared by reacting an intermediate of formula (II) with a derivative of formula (III)

[0140] In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.

[0141] The compounds of formula (I) wherein X is a sulphur, said compound being represented by formula (I-b) can be prepared by reacting an intermediate of formula (IV) with a derivative of formula (V) in an appropriate solvent such as for example methanol, ethanol, propanol, butanol, dioxane, tetrahydrofurane, 2-methoxyethylether or toluene, and the like. This reaction can be performed at a temperature comprised between 20 and 130° C.

[0142] The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.

[0143] The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

[0144] Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization of chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.

[0145] An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography using a chiral stationary phase.

[0146] Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.

[0147] The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0148] It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to be blocked by protecting groups.

[0149] Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C1-6alkyl or benzyl esters.

[0150] The protection and deprotection of functional groups may take place before or after a reaction step.

[0151] The use of protecting groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’ 2nd edition, T W Greene & P G M Wutz, Wiley Interscience (1991).

[0152] The compounds of the present invention show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).

[0153] The present compounds also show activity against HIV-1 strains that have acquired resistance to art-know non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human α-1 acid glycoprotein.

[0154] Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.

[0155] The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.

[0156] The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example,in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid sugars, kaolin, lubricants, binders, disintegrating agent and the like in the case of powders pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the list advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0157] To aid solubility of the compounds of formula (I), suitable ingredients, e.g. cyclodextrins, may be included in the compositions. Appropriate cyclodextrins are α, β, γ-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxy-ethyl; C1-6alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD).

[0158] The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.

[0159] The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.

[0160] Other suitable compositions for oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (I) and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.

[0161] Said particles consist of a solid dispersion comprising a compound of formula (I) and one or more pharmaceutically acceptable water-soluble polymers. The preferred technique for preparing solid dispersions is the melt-extrusion process comprising the following steps:

[0162] a) mixing a compound of formula (I) and an appropriate water-soluble polymer,

[0163] b) optionally blending additives with the thus obtained mixture,

[0164] c) heating the thus obtained blend until one obtains a homogenous melt,

[0165] d) forcing the thus obtained melt through one or more nozzles; and

[0166] e) cooling the melt till it solidifies.

[0167] The solid dispersion product is milled or ground to particles having a particle size of less than 1500 μm, preferably less than 400 μm, more preferably less than 250 μm and most preferably less than 125 μm.

[0168] The water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkyl-celluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are Eudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.

[0169] Also one or more cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly α, β, γ-cyclodextrins or the pharmaceutically acceptable derivatives thereof.

[0170] Substituted cyclodextrins which can be used include polyethers described in U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-6alkyl, hydroxyC1-6alkyl, carboxy-C1-6alkyl or C1-6alkyloxycarbonylC1-6alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-3alkyl, hydroxyC2-4alkyl or carboxyC1-2alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.

[0171] Of particular utility are the β-cyclodextrin ethers, e.g. dimethyl-β-cyclodextrin as described by M. Nogradi (Drugs of the Future, (1984) Vol. 9, No. 8, p. 577-578) and polyethers, e.g. hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for example be formed from the reaction between β-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.

[0172] A more novel type of substituted cyclodextrins is sulfobutylcyclodextrines.

[0173] The ratio of the compound of formula (I) over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of the compound of formula (I) over cyclodextrin range from about 1/10 to 10/1. More interesting ratios range from about 1/5 to 5/1.

[0174] It may further be convenient to formulate the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the compound of formula (I) but do not chemically bond to said compound.

[0175] Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

[0176] Yet another interesting way of formulating the compounds of formula (I) involves a pharmaceutical composition whereby the compounds of formula (I) are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.

[0177] Said beads comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and a seal-coating polymer layer.

[0178] Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

[0179] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

[0180] Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general, it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose at two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg , and in particular 5 to 200 mg of active ingredient per unit dosage form.

[0181] The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, the weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased of the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.

[0182] Also, the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3′-azido-3′-deoxythymidine; AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine; ddC) or lamivudine (3′-thia-2′-3′-dideoxycytidine; 3TC) and the like; non-nucleoside reverse transcriptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, rescriptor (BHAP derivative), dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6Hdipyrido[3,2-b: 2′,3′-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione compounds of the α-APA (α-anilino phenyl acetamide) type e.g. α-[(2-nitro-phenyl)amino]-2,6-dichloro-benzene-acetamide and the like; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g. indinavir, ritanovir, saquinovir, ABT-378 and the like; fusion inhibitors; integrase inhibitors; or immunomodulating agents, e.g. levamisole and the like. The compound of formula (I) can also be combined with another compound of formula (I).

[0183] The following examples are intended to illustrate the present invention. The numbers under the formulas correspond to the numbers in the table (I).

EXAMPLE 1

[0184] Ethyl 2-azido-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (Compound 106)

[0185] 2-chloro-4-hydroxy-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (intermediate 1) was obtained as described by J. A. Elvidge and N. A. Zaidi (J. Chem. Soc., (1968), 17, 2188) and dichloro-3,5-dimethyliodobenzene (intermediate 2) as described by H. J. Lucas, E. R. Kennedy, Org. Synth. (1955) Vol-III, 482-483.

[0186] 1.1.: Ethyl 2-chloro-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (Intermediate 3)

[0187] Intermediate 2 (0.73 g, 2.2 mmol) was suspended in 10 ml of water containing sodium carbonate (0.24 g, 2.2 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of intermediate 1 (0.44 g, 2 mmol) in 10 ml of water containing also sodium carbonate (0.22 g; 2 mmol) was added. After stirring for one hour at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in diglyme (5 ml). After heating at 100° C. for 10 min., the solvent was removed in vacuo. Purification by flash chromatography (SiO2, CH2C2/ethanol 98:2) gave the titled compound (0.6 g, 67%) as yellow microcrystals, m.p. 180-182° C.

[0188] 1.2.: Ethyl 2-azido-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (Compound 106)

[0189] Sodium azide (0.20 g, 3.12 mmol) was added to a solution of intermediate 3 (0.50 g, 1.56 mmol) in DMSO (5 ml), and the mixture was heated at 50° C. for 5 hours Reaction mixture was partitioned between water (30 ml) and ethyl acetate (40 ml). The organic layer was dried over magnesium sulfate and concentred. Flash chromatography (SiO2, CH2Cl2/ethanol 95:5) gave the desired product (0.49 g, 70%) as a white solid, m.p.=216-218° C.

EXAMPLE 2

4-[3,5-dimethylphenyl)-sulfinyl]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (Compound 108)

[0190]

[0191] 4-[3,5-dimethylphenyl)-thio]-5-ethyl-6-methyl-2(1H)-pyridinone (intermediate 4) was obtained as described by Doll{acute over (e )} et al. (J. Med. Chem., (1995), 38, 4679-4686).

[0192] 2.1.: 4-[3,5-dimethylphenyl)-thio]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (Intermediate 5)

[0193] The intermediate 4 (273 mg, 1 mmol) was dissolved in acetic acid (4 ml) and ethyl acetate (4 ml). At room temperature and in the dark N-iodosuccinimide (225 mg; 1 mmol) was added in one portion. After 4 hours under stirring at room temperature, the mixture was poured into water (15 ml) and the pH of the solution was adjusted to 7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3×30 ml) were washed with brine (10 ml), dried over magnesium sulfate and evaporated to give a gum. It was then purified by flash chromatography on silica gel column with CH2Cl2-ethanol (98:2) as the eluent to give the main fraction containing the titled compound which was recristallized from ethanol furnishing the pure intermediate 5 as yellow microcrystals (122 mg; 51%), m.p.=252° C.

[0194] 2.2.: 4[-3,5-dimethylphenyl)-sulfinyl]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (Compound 108)

[0195] m-chloroperbenzoic acid and water (70%, 123 mg; 0.5 mmol) in chloroform (15 ml) was dried over magnesium sulfate and filtered. To this solution at 0° C. was added the intermediate 5 (200 mg ; 0.5 mmol) and the mixture was kept under stirring for 1 hour. A saturated solution of sodium carbonate (5 ml) was added and the combined organic layers obtained by extraction with CH2Cl2 (3×30 ml) were dried over magnesium sulfate and evaporated. The residue obtained was then chromatographed (SiO2, CH2Cl2/ethanol 98:2) to give the titled compound (113 mg; 50%).

[0196] 1H NMR. (200 MHz, CDCl3), d: 0.66 (t, 3H, CH3-CH2, J=6.9 Hz); 2.20-2.90 (m, 11H, CH3-6,3′, 5′, CH2CH3); 7.08 (s, 1H, H-4′); 7.25 (s, 2H, H-2′,6′); 12.9 (s, 1H, NH).

EXAMPLE 3

4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxaldehyde (Compound 269)

[0197]

[0198] Ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylate (intermediate 6) was described by E. Knoevenagel and A. Fries (Ber., (1898), 31, 768).

[0199] 3.1.: Ethyl 4-hydroxy-5-hydroxymethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylate (Intermediate 7)

[0200] The mixture of intermediate 6 (1.8 g; 9.1 mmol), Na2CO3 (970 mg ; 9.1 mmol) and water (30 ml) was heated in an oil bath at 90° C. Three portions of 37% formaldehyde solution in water (1.46 ml; 18.2 mmol each) were added every 45 min. The homogeneous mixture obtained was kept at the same temperature for 30 min. further and the oil bath was removed. When the internal temperature reaches 60° C., ethyl acetate (40 ml) and acetic acid (1.8 ml) were added and after extraction with hot ethyl acetate (4×40 ml) the organic layer was evaporated under reduced pressure. The residue was then purified by flash chromatography on a silica gel column with CH2Cl2/ethanol (95:5) as the eluent to give the expected intermediate 7 (830 mg; 40%), m.p.=262-265° C.

[0201] 3.2.: Ethyl 5-formyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridine-3-carboxylate (Intermediate 8)

[0202] To a stirred solution of intermediate 7 (500 mg ; 2.2 mmol) in CH2Cl2 (80 ml) was added at reflux MnO2 (4 g; 46 mmol) and the reflux was maintained for 50 hours. The hot mixture was filtered off, the solid was washed successively with hot methanol (3×50 ml) and hot ethyl acetate (3×50 ml). The solvents were evaporated and the solid residue obtained was then purified by flash chromatography on a column of silica gel with CH2Cl2/ethanol (98:2) as the eluent to give the intermediate 8 (420 mg; 85%); m.p.=248-250° C.

[0203] 3.3.: 4-hydroxy-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxaldehyde (Intermediate 9)

[0204] To a solution of intermediate 8 (350 mg ;1.5 mmol) in 1,4-dioxane (15 ml) was added water (7.6 ml) and 1N HCl (2.4 ml) and the mixture was heated under reflux for 24 hours. The hot solution was extracted with ethyl acetate (3×30 ml) and the solvent was removed under reduced pressure furnishing the titled intermediate 9 as yellow microcrystals (110 mg; 47%); m.p.>260° C. This compound was used for the next step without any further purification.

[0205] 3.4.: 4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxaldehyde (Compound 269)

[0206] Intermediate 2 (1.31 g, 4.32 mmol) was suspended in 25 ml of water containing sodium carbonate (0.46 g, 4.32 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of intermediate 9 (0.55 g, 3.6 mmol) in 25 ml of water containing also sodium carbonate (0.38 g; 3.6 mmol) was added. After stirring for 1 hour at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in dimethylformamide (15 ml). After heating under reflux for 1 h the solvent was removed in vacuo. Purification by flash chromatography (SiO2, CH2Cl2/EtOH 95:5) gave the titled compound (1.01 g, 73%) as yellow microcrystals, m.p.>260° C.

EXAMPLE 4

4-(3,5-dimethylphenoxy)-5-(hydroxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (Compound 257)

[0207]

[0208] To a stirred solution of compound 269 (500 mg; 1.3 mmol) in methanol (50 ml) was added NaBH4 (350 mg; 9.2 mmol) in small portions for a period of 10 min. After 1 hour on stirring at room temperature, water (20 ml) and a solution 10% potassium carbonate (30 ml) were added. The mixture was extracted with ethyl acetate (3×60 ml) and the organic layer was washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure giving colorless microcrystals which correspond to the titled compound (490 mg ; 97%) m.p.=248-250° C.

EXAMPLE 5

5-(chloromethyl)-4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-2(1H)-pyridinone (Compound 125)

[0209]

[0210] The heterogeneous solution of compound 257 (450 mg; 1.2 mmol) in CH2Cl2 (30 ml) became homogeneous mixture by addition at room temperature of SOCl2 (2.6 ml). After 2 hours on stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected compound 125 in quantitative yield (470 mg); m.p.=256-258° C. This compound was used for the next step without any further purification.

EXAMPLE 6

4-(3,5-dimethylphenoxy)-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (Compound 255)

[0211]

[0212] A solution of compound 125 (60 mg; 0.15 mmol) in absolute ethanol (5 ml) and potassium carbonate (60 mg; 0.44 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, water (5 ml) was added and the mixture was extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulfate and the solvent was removed. The colorless solid residue was then purified by flash chromatography on a silica gel column with CH2Cl2/ethanol (98:2) as the eluent to give the titled compound 255 (59 mg; 95%); m.p.=234-236° C.

EXAMPLE 7

[0213] 4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (Compound 258)

[0214] This compound was prepared starting from the 5-ethyl-6-methyl-4-hydroxypyridin-2(1H)-one (intermediate 10) which was obtained as described by Dollé et al. (J. Med. Chem., (1995), 38, 4679-4686).

[0215] Intermediate 2 (3.75 g ; 12.4 mmol) was suspended in water (50 ml) containing sodium carbonate (1.31 g ; 12.4 mmol) and stirred for 30 min at room temperature. To this mixture a solution intermediate 10 (1.9 g; 12.4 mmol) in water (50 ml) containing also sodium carbonate (1.31 g ; 12.4 mmol) was added. After stirring for 1 hour at 20° C. the precipitate was filtered off, washed with water, dried under vacuum at room temperature and suspended in dimethylformamide (20 ml). The mixture was refluxed for 1 hour. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, CH2Cl2/Et OH 98:2) gave the titled compound (4.3 g; 90%) as colorless microcrystals; m.p.=240° C.

EXAMPLE 8

4-(3,5-dimethylphenoxy)-3-ethenyl-5-ethyl-6 methyl-2(1H)-pyridinone (Compound 234)

[0216]

[0217] Compound 258 (300 mg, 0.1783 mmol) and palladium tetrakistriphenylphosphine (45 mg, 5% mol) were dissolved in toluene (6 ml). Tributyl(vinyl)tin (358 mg, 0.94 mmol) was added at room temperature. The mixture was refluxed for 12 hours. Water (8 ml) was added and the aqueous layer was extracted with dichloromethane and dried over magnesium sulfate. The solvent was removed under vacuum and the residue was purified by flash chromatography (SiO2, CH2Cl2/ethanol 98:2) to give the titled compound 234 as colorless microcrystals (87 mg, 39%); m.p.=200° C.

EXAMPLE 9

4-(3,5-dimethylphenoxy)-3,5-diethyl-6-methyl-2(1H)-pyridinone (Compound 231)

[0218]

[0219] Compound 234 (90 mg, 0.318 mmol) was dissolved in absolute ethanol (10 ml). The catalyst palladium on carbon 10% (44 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. The catalyst was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography (SiO2, CH2Cl2/ethanol 98:2) to give the desired compound as colorless microcrystals (60 mg, 66%);, m.p.=180° C.

EXAMPLE 10

4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (Compound 86)

[0220]

[0221] 10.1. Ethyl 4-hydroxy-2-methyl-6-oxo-1 6-dihydro-3-pyridinecarboxylate (Intermediate 12)

[0222] This compound was prepared starting from the di-(2,4,6-trichlorophenyl)malonate (intermediate 11) which was obtained as described by Kappe, Th., (Mh. Chem. (1967), 98, 874).

[0223] A solution of ethyl 3-aminocrotonate (12.6 g, 97.5 mmol) and of intermediate 11 in diglyme (400 ml) was heated at 100° C. for 3 hours during which the product separated out. After cooling, diethylether (1.5 l) was added and the desired intermediate 12 was filtered (14.2 g, 75%). m.p. 243-245° C.

[0224] 10.2.: Ethyl 4-chloro-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (Intermediate 13)

[0225] To a solution of intermediate 12 (2 g; 10 mmol) and benzyltriethylammonium chloride (9.1 g; 40 mmol) in acetonitrile (40 ml) was added in one portion phosphorus oxychloride (2.2 ml; 24 mmol). The obtained mixture was stirred at room temperature under nitrogen atmosphere for 5 min. and heated under reflux for 2 hours. After evaporation of the solvent, cool water (40 ml) was added and the mixture was stirred for 0.5 hour. Extraction with CH2Cl2 followed by a silica gel column chromatography using CH2Cl2/ethanol (99:1) as eluent gave i) ethyl 2,4-dichloro-6-methylpyridin-5-ylcarboxylate (1.7 g; 72%) (which can be transformed into the intermediate 13 and ii) intermediate 13 (506 mg; 24%) m.p.=161-163° C.

[0226] 10.3.: Ethyl 4-[(3,5-dimethylphenyl)-thio]-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylate (Intermediate 14)

[0227] A mixture of the intermediate 13 (1.2 g ; 5.6 mmol) in ethanol (15 ml), triethylamine (1.5 ml) and 3,5-dimethylthiophenol (1.45 ml; 11 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, diethylether (50 ml) was added and the precipitate was filtered off. The intermediate 14 was obtained (1.42 g; 80%) as a colorless solid m.p.=233-235° C.

[0228] 10.4.: 4-[(3,5dimethylphenyl)-thio]-5-(hydroxymethyl)-6methyl-2(1H)-pyridinone (Intermediate 15)

[0229] Under nitrogen atmosphere, the intermediate 14 (500 mg; 1.6 mmol) was suspended in dry tetrahydrofurane (20 ml) and LiAlH4 (120 mg; 3.2 mmol) was added at 0° C. The mixture was stirred at room temperature for 18 hours and poured in ethyl acetate (50 ml) at 0° C. and a solution 10% H2SO4 (100 ml) was added dropwise. The mixture was extracted with ethyl acetate (2×100 ml) and the organic layer was removed under reduced pressure giving the intermediate 15 (310 mg; 71%) m.p.=268-270° C.

[0230] 10.5.: 4-[(3,5-dimethylphenyl)-thio]-5-(chloromethyl)-6-methyl-2(1H)-pyridinone (Intermediate 16)

[0231] A suspension of intermediate 15 (275 mg; 1 mmol) in dichloromethane (10 ml) became homogeneous by addition of SOCl2 (2.3 ml) at room temperature. After 2 hours of stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected intermediate 16 in quantitative yield (294 mg). This compound was used for the next step without further purification.

[0232] 10.6.: 4-[(3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-6-methyl-2(1H)-pyridinone (Intermediate 17)

[0233] A solution of intermediate 16 (250 mg ; 0.85 mmol) in absolute ethanol (10 ml) and triethylamine (0.24 ml) was heated at 50° C. for 18 hours. After evaporation under reduced pressure the residue was purified by flash chromatography on a silica gel column with CH2Cl2/ethanol (99:1) as the eluent to give the titled intermediate 17 (243 mg; 94%) m.p.=203-205° C.

[0234] 10.7.: 4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (Compound 86)

[0235] The intermediate 17 (100 mg ; 0.33 mmol) was dissolved in acetic acid (2 ml) and ethyl acetate (2 ml). At room temperature and in the dark N-iodosuccinimide (75 mg; 0.33 mmol) was added in one portion. After 2.5 h under stirring at room temperature, the mixture was poured into water (5 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia The combined organic layers obtained by extraction with CH2Cl2 (3×10 ml) were washed with water (15 ml), dried over magnesium sulfate and evaporated to give a solid residue. It was then chromatographed on silica gel column with CH2Cl2/ethanol (99:1) as the eluent to give the titled compound 86 as colorless microcrystals (96 mg; 68%) m.p.=220-222° C.

EXAMPLE 11

3-bromo-4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-6-methyl-2(1H)-pyridinone (Compound 85)

[0236]

[0237] The intermediate 17 (50 mg; 0.16 mmol) was dissolved in acetic acid (3 ml) and ethyl acetate (3 ml). At room temperature and in the dark N-bromosuccinimide (29 mg; 0.16 mmol) was added in one portion. After 30 min. under stirring at room temperature, the mixture was poured into water (10 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia The combined organic layers obtained by extraction with ethyl acetate (3×15 ml) were dried over magnesium sulfate and evaporated to give a solid residue. It was then purified by flash chromatography on silica gel column with CH2Cl2/ethanol (99:1) as the eluent to give the titled compound 85 as colorless microcrystals (48 mg; 76%) m.p.=183-184° C.

EXAMPLE 12

Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxylate (Compound 71)

[0238]

[0239] 12.1.: Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-2-methyl-1-6-oxo-3-pyridinecarboxylate (Intermediate 18)

[0240] 3,5-dimethylthiophenol (0.69 ml ; 5.1 mmol) was added to a mixture of intermediate 13 (1 g ; 4.6 mmol) in triethylamine (1 ml) and ethanol (10 ml). The mixture was stirred and refluxed then brought to room temperature and poured out into water. The precipitate was filtered. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield (1.2 g; 80%) of intermediate 18; m.p.=230° C.

[0241] 12.2.: Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxylate (Compound 71)

[0242] N-iodosuccinimide (0.085 g ; 0.4 mmol) was added at room temperature to a solution of intermediate 18 (0.1. g ; 0.3 mmol) in ethyl acetate (0.3 ml) and acetic acid (0.3 ml) under nitrogen. The mixture was stirred 48 hours in darkness. The solvent was evaporated. The residue was purified by column chromatography over Kromasil® (CH2Cl2; 100). Two fractions were collected and the solvent was evaporated to give 0.052 g of a compound which was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield (32 mg; 23%) of compound 71; m.p.=210° C.

EXAMPLE 13

4-[3,5-dimethylphenyl)-thio]-5-(hydroxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (Compound 61)

[0243]

[0244] Diisobutylaluminium hydride (20 wt. % solution in toluene) (0.75 ml; 0.9 mmol) was added at −70° C. to a mixture of compound 71 (0.1 g ; 0.2 mmol) in toluene (10 ml). The mixture was stirred at 0° C. for 1 hour, poured out into water and extracted with ethyl acetate. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield (56 mg; 70%) of compound 61; m.p.=240° C.

EXAMPLE 14

5-(chloromethyl)-4-[-3,5-dimethylphenyl)-thio]-3-iodo-6-methyl-2(1H)-pyridinone (Compound 60)

[0245]

[0246] SOCl2 (0.9 ml; 12.3 mmol) was added dropwise at 0° C. to a solution of compound 61 (0.8 g; 1.9 mmol) in CH2Cl2 (90 ml). The mixture was stirred at room temperature overnight and evaporated till dryness. The residue was taken up in CH2Cl2 and evaporated (3 times) to yield 0.7 g (89%) m.p.=218° C. The product was used without further purification in the next reaction step.

EXAMPLE 15

4-[3.5-dimethylphenyl)-thio]-5-[(ethylthio)methyl]-3-iodo-6-methyl-2(1H)-pyridinone (Compound 45)

[0247]

[0248] A mixture of compound 60 (0.1 g; 0.2 mmol) and ethanethiol (0.0361 ml; 0.5 mmol) in triethylamine (0.1 ml) and ethanol (2 ml) was stirred and refluxed for 4 hours. The solvent was evaporated. The residue (0.06 g) was purified by column chromatography over silica gel (eluent : CH2Cl2/CH3OH/NH4OH; 95/5/0. 1). The pure fractions were collected and the solvent was evaporated. The residue (0.02 g) was crystallized from diisopropylether. The precipitate was filtered off and driedto yield 0.018 g (17%); m.p.=210° C.

EXAMPLE 16

4-[(3,5-dimethylphenyl)-thio]-3-iodo-6-methyl-5-morpholinomethyl-1H-pyridin-2-one (Compound 43)

[0249]

[0250] A mixture of compound 60 (0.05 g ; 0.1 mmol), morpholine (0.02 ml; 0.0002 mol) and K2CO3 (0.082 g; 0.6 mmol) in acetonitrile (2 ml; 0.6 mmol) was stirred at 50° C. in a sealed tube for 2 hours, poured out into water and extracted with ethylacetate. The solvent was evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. The residue (0.057 g) was crystallized from isopropanol. The precipitate was filtered off and dried to yield 0.041 g (73%), m.p.=230° C.

EXAMPLE 17

6-(diethoxymethyl)-4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-2(1H)-pyridinone (Compound 134)

[0251]

[0252] 17.1.: 6-(diethoxymethyl)-5-ethyl-4-hydroxy-2H-pyran-2-one (Intermediate 19)

[0253] A solution of sodium hydride (60% dispersion in mineral oil) in tetrahydrofurane (500 ml) was cooled at 0° C. under nitrogen. 3-oxo-hexanoic-acid ethyl ester (25 g; 158 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. Butyllithium 1.6 M (99 ml; 158 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 hour. Diethoxy-acetic acid ethyl ester (27.8 g; 0.178 mol) was added drop wise and the mixture was stirred at 0° C. for 1 hour. Hydrochloric acid 12 N (50 ml) was added and the mixture was stirred at room temperature for 1 hour and extracted with diethyl ether to yield 20 g (53%) of intermediate 19. The product was used without further purification in the next reaction step.

[0254] 17.2.: 6-(diethoxymethyl)-5-ethyl-4-hydroxy-2(1H)-pyridinone (Intermediate 20)

[0255] A mixture of intermediate 19 (20 g; 82 mmol) in CH3OH/NH3 (150 ml) was stirred at 60° C. for 4 hours, evaporated till dryness and taken up in diisopropyl ether. The precipitate was filtered to yield 1.5 g of intermediate 20 (7.5%). The product was used without further purification in the next reaction step.

[0256] 17.3.: [6-diethoxymethyl-5-ethyl-4-hydroxy-2-oxo-3-pyridinyl]-3,5-dimethylphenyl)-iodonium,hydroxide,inner salt (Intermediate 21)

[0257] A mixture of intermediate 20 (3.4 g; 14 mmol) and Na2CO3 (3 g ; 28 mmol) in water (50 ml) was stirred at room temperature for 15 min to give residue 1. A mixture of intermediate 2 (4.66 g; 15.4 mmol) and Na2CO3 (3 g; 28 mmol) in water (50 ml) was stirred at room temperature for 15 min to give residue 2. Residue 1 and residue 2 were combined and then stirred at room temperature for 2 hours. The precipitate was filtered off, washed with water and dried. Yield 8 g of intermediate 21; m.p.=125° C.).

[0258] 17.4.: 6-(diethoxymethyl)-4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-2(1H)-pyridinone (Compound 134)

[0259] A mixture of intermediate 21 (6 g; 12.7 mmol) in DMF (20 ml) was stirred at 120° C. for 1 hour. The solvent was evaporated till dryness to yield 5 g of compound 134 (83%). The residue was used immediately without further purification.

EXAMPLE 18

4-(3,5-dimethylphenoxy)-3-ethyl-1,6-dihydro-5-iodo-6-oxo-2-pyridinecarboxaldehyde (Compound 159)

[0260]

[0261] A mixture of compound 134 (5 g; 10 mmol) in HCl 3N (30 ml) and tetrahydrofurane (5 ml) was stirred at 100° C. for 30 min. and then extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (5 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield 3.5 g of titled compound 159 (83%), m.p.=158° C. The residue was used without further purification.

EXAMPLE 19

4-(3,5-dimethylphenoxy)-5-ethyl-6-(hydroxymethyl)-3-iodo-2(1H)-pyridinone (Compound 133)

[0262]

[0263] NaBH4 (0.047 g; 1.3 mmol) was added to a mixture of compound 159 (0.5 g; 0.013 mol) in methanol (3 ml). The mixture was stirred at room temperature for 1 hour. Water was added. The precipitate was filtered off, taken up in diisopropyl ether and dried to yield 0.26 g (52%), m.p.=70° C.).

EXAMPLE 20

[3-(5-ethyl-3-iodo-6-methyl-2-oxo-1,2-dihydro-pyridin-4-yloxy)-5-iodo-phenyl]-acetonitrile (Compound n° 426)

[0264]

[0265] A mixture of compound 81 (0.1 g; 0.001 mol) and potassium cyanide (0.024 g; 0.0003 mol) in ethanol (2 ml) was stirred at 80° C. in a celled tube overnight. H2O was added. The mixture was extracted with CH2Cl2. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.03 g) was crystallized from DIPE. The precipitate was filtered off and dried to yield 0.21 g (21%), m.p.=220° C.

EXAMPLE 21

4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-[2-methylthiazol-4-ylmethylsulfanylmethyl)-1H-pyridin-2-one (Compound n° 483)

[0266] 21.1: 4-(3,5-dimethylphenoxy)-3-iodo-5-mercaptomethyl-6-methyl-1H-pyridin-2-one (Compound n° 451)

[0267] A mixture of compound 125 (1.5 g; 0.0037 mol) and thiourea (0.31 g; 0.00408 mol) in DMSO (30 ml) was stirred at room temperature for 1 hour. NaOH 3N was added. The mixture was stirred for 15 minutes, acidified with HCl 3N and extracted with ethylacetate (EtOAc). The organic layer was separated, dried on magnesium sulfate (MgSO4), filtered and the solvent was evaporated. The residue was taken up in DIPE and filtered. The precipitate (1.2 g) was purified by column chromatography over silica gel (eluent: EtOAc 100%; 35-70 μm) and dried to yield 0.3 g (20%).

[0268] 21.2: 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-[2-methylthiazol-4-ylmethyl-sulfanylmethyl)-1H-pyridin-2-one (Compound n° 483)

[0269] A mixture of compound 451 (0.07 g; 0.0001 mol) and 4-chloromethyl-2-methylthiazole (0.16 g, 0.0008 mol) in ethanol (3 ml) and triethylamine (0.2 ml) was stirred at 80° C. for 1 hour. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.04 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was evaporated and dried to yield 0.018 g.

EXAMPLE 22

4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (Compound 547)

[0270] 22.1: 2-(1-amino-ethylidene)-5-phenyl-pentanoic acid ethyl ester (Intermediate 23)

[0271] Ammonium nitrate (3.1 g; 0.039 mol) was added to a solution of intermediate 22 (2-acethyl-5-phenyl-pentanoic acid ethyl ester) (8.8 0.0354 mol) in tetrahydrofuran (90 ml). Ammoniac was bubbled. The mixture was stirred and refluxed for 6 hours, then stirred at room temperature for 12 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried on magnesium sulfate (MgSO4), filtered and the solvent was evaporated and dried to yield 8.3 g.

[0272] 22.2: Ethyl 4-hydroxy-6-methyl-2-oxo-5-(3-phenyl-propyl)-1,2dihydro-pyridine-3-carboxylic acid ethyl ester (Intermediate 24)

[0273] Sodium ethoxide in ethanol (27.5 ml; 0.0738 mol) was stirred and refluxed. Malonic acid diethyl ester (11.8 ml; 0.0738 mol) was added dropwise. A solution of intermediate 23 (8.3 g; 0.0335 mol) in ethanol (30 ml) was added dropwise. The mixture was stirred and refluxed for 15 hours. Three-quarters of EtOH were evaporated. The mixture was poured out in ice, acidified with HCl 3N and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated The residue (19.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/NH4OH 96/4/0.1; 15-35 μm). Two fractions were collected and the solvent was evaporated and dried to yield 0.43 g (4%).

[0274] 22.3: 4-hydroxy-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (Intermediate 25)

[0275] A mixture of intermediate 24 (0.1 g; 0.003 mol) and sodium hydroxide (0.038 g; 0.0009 mol) in H2O (1.5 ml) was stirred and refluxed for 15 hours, then cooled to 5° C. with HCl 3N. The precipitate was filtered, washed with H2O, then with isopropanol and dried to yield 0.07 g (91%).

[0276] 22.4: 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (Compound 547)

[0277] A mixture of dichloro-3,5-dimethyliodobenzene (0.096 g; 0.0003 mol) and sodium carbonate (0.12 g; 0.0005 mol) in dimethylformamide (1 ml; 0.5 ml) was stirred at room temperature for 30 minutes. A solution of intermediate 25 (0.07 g; 0.0002 mol) and sodium carbonate (0.6 g; 0.0005 mol) in H2O (0.5 ml) was added. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with H2O, then with DIPE and dried. The residue (0.12 g) was taken up in DMF and stirred at 100° C. for 30 minutes. The solvent was evaporated till dryness. The residue (0.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0 to 95/5/0.1; 35-70 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.07 g) was taken up in iPrOH. The precipitate was filtered off and dried to yield 0.06 g (44%), m.p.=220° C.

EXAMPLE 23

6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-acrylonitrilephenoxy]pyridin-2(1H)-one (Compound 470)

[0278]

[0279] 23.1. 3-Bromo-5-iodobenzaldehyde dichloride (Intermediate 26)

[0280] 3-Bromo-5-iodobenzaldehyde dichloride (intermediate 26) was obtained as described by H. J. Lucas and E. R. Kennedy, Org. Synth. (1955), III, 482-483.

[0281] 23.2. 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-formylphenoxy]pyridin-2(1H)-one (Compound 469)

[0282] Intermediate 26 (311 mg, 1 mmol) was suspended in 10 ml of water containing sodium carbonate (106 mg, 1 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of 5-ethyl-6-methyl-4-hydroxypyridin-2(1H)-one (153 mg, 1 mmol) in 10 ml of water containing also Na2CO3 (106 mg, 1 mmol) was added. After stirring for 1 h at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in dimethylformamide (5 mL). After heating at 120° C. for 10 min., the solvent was removed. Purification by flash chromatography (SiO2, CH2Cl2/EtOH 98:2) gave the titled compound (205 mg, 44%) as yellow microcrystals, m.p.>260° C.

[0283] 23.3. 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-acrylonitrilephenoxy]pyridin-2(1H)-one (Compound 470)

[0284] To a 0° C. magnetically stirred solution of diethyl(cyanomethyl)-phosphonate (113 μL, 0.68 mmol) in anhydrous THF (3 mL), NaH (28 mg; 0.68 mmol) was added (60% in mineral water). After stirring at room temperature for 1 h, compound 469 (80 mg; 0.17 mmol) was added and the reaction mixture was stirred 18 h at room temperature and poured into water (5 ml). The resulting solution was extracted with AcOEt, dried over MgSO4 and evaporated. The oily residue obtained was then crystallized from Et2O to give the pure titled compound (65 mg; 77%), m.p.>260° C. Table 1 lists intermediates and compounds of formula (I) which were made analogous to one of the above examples.

No =YQX-R1R2R3R4mp. ° C./[MH+]1OI

MeH245Chemistry 5Chemistry 62OI

MeH>250Chemistry 11Chemistry 123OI

MeH>250Chemistry 17Chemistry 184OI

H210Chemistry 23Chem 251OI

MeH245Chemistry 5Chemistry 62OI

MeH>250Chemsitry 11Chemistry 123OI

MeH>250Chemistry 17Chemistry 184OI

H210Chemistry 23Chem 255OI

MeH>250Chemistry 29Chemistry 306OI

MeH[520]Chemistry 35Chemistry 367Oi-Pr

EtMeH260-262Chemistry 418OI

MeH230Chemistry 47Chemistry 489OI

H125Chemistry 53Chem 5510OI

MeH[639]Chemistry 59Chemistry 6011OI

MeH[569]Chemistry 65Chemistry 6612OI

MeH[593]Chemistry 71Chemistry 7213OI

MeH[539]Chemistry 77Chemistry 7814OI

MeH[543]Chemistry 83Chemistry 8415OI

MeH[551]Chemistry 89Chemistry 9016OI

MeH[539]Chemistry 95Chemistry 9617OI

MeH[531]Chemistry 101Chemistry 10218OI

MeH[477]Chemistry 107Chemistry 10819OI

MeH[463]Chemistry 113Chemistry 11420OI

MeH[531]Chemistry 119Chemistry 12021O

IMeH240-244Chem 124Chemistry 12522O

HMeH192-194Chem 130Chemistry 13123OI

EtMeH102-104Chemistry 13724OI

EtMeH170-172Chemistry 14325OI

EtMeH225-226Chemistry 14926OI

EtMeH236-238Chemistry 15527OI

EtMeH260-262Chemistry 16128OI

H118Chemistry 167Chem 16929OI

100

101

H184Chemistry 173Chem 17530OI

102

103

MeH160Chemistry 179Chemistry 18031OI

104

105

MeH165Chemistry 185Chemistry 18632OI

106

107

MeH>250Chemistry 191C═NOH33OI

108

109

MeH150Chemistry 197Chemistry 19834OI

110

111

MeH>250Chemistry 203Chemistry 20435OI

112

113

MeH>250Chemistry 209Chemistry 21036OI

114

115

MeH200Chemistry 215Chemistry 21637OI

116

117

H[519]Chemistry 221Chem22338OI

118

119

H—Chemistry 227Chem 22939OI

120

121

MeH210Chemistry 233Chemistry 23440OI

122

123

H210Chemistry 239Chem 24141OI

124

125

H>250Chemistry 245C═NOH42OI

126

127

MeH>250Chemistry 251Chemistry 25243OI

128

129

MeH230Chemistry 257Chemistry 25844OI

130

131

MeH120Chemistry 263Chemistry 26445OI

132

133

MeH210Chemistry 269Chemistry 27046OI

134

135

MeH250Chemistry 275Chemistry 27647OI

136

137

MeH>250Chemistry 281Chemistry 28248OI

138

139

H218Chemistry 287Chem28949OI

140

141

MeH>250Chemistry 293Chemistry 29450OI

142

143

H226Chemistry 299Chem 30151OI

144

145

MeH236Chemistry 305Chemistry 30652OI

146

147

MeH>250Chemistry 311Chemistry 31253OI

148

149

MeH>250Chemistry 317Chemistry 31854OI

150

151

MeH150Chemistry 323Chemistry 32455OI

152

153

MeH>250Chemistry 329CN56OH

154

155

MeH>250Chemistry 335CN57OI

156

157

MeH>250Chemistry 341Formyl58OI

158

159

H182Chemistry 347Chem 34959OI

160

161

MeH245Chemistry 353CH2NMe260OI

162

163

MeH218Chemistry 369CH2Cl61OI

164

165

MeH240Chemistry 365CH2OH62OI

166

167

H165Chemistry 371Chem 37363OI

168

169

H235Chemistry 377Chem 37964OI

170

171

MeH>250Chemistry 383Chemistry 38465OI

172

173

MeH>250Chemistry 389CO2H66OI

174

175

H240Chemistry 395CH2CN67OI

176

177

H[502]Chemistry 401Chem 40368OMe

178

EtMeH207-209Chemistry 40769OH

179

EtMeH—Chemistry 41370OI

180

181

H224Chemistry 419Chem 42171OI

182

183

MeH210Chemistry 425CO2Et72OH

184

185

MeH230Chemistry 431CO2Et73OI

186

187

H181Chemistry 437Chem 43974OI

188

189

H170Chemistry 443Chem 44576OI

190

191

H 95Chemistry 449Chem 45176OI

192

193

MeH112Chemistry 455Chemistry 45677OH

194

CO2Et

195

H216-218Chemistry 461Azido78OI

196

PhHH230-232Chemistry 46779OI

197

EtMeH138-139Chemistry 47380OI

198

EtMeH178-179Chemistry 47981OI

199

EtMeH248-250Chemistry 48582OI

200

EtMeH202-204Chemistry 49183OI

201

EtMeH258-260Chemistry 49784OH

202

203

MeH205-207Chemistry 503Chemistry 50485OBr

204

205

MeH183-184Chemistry 509Chemistry 51086OI

206

207

MeH220-222Chemistry 515Chemistry 51687OCO2Et

208

EtMeH188-191Chemistry 52188OI

209

EtMeH—Chemistry 52789OH

210

EtMeH229-231Chemistry 58390OI

211

EtMeH288-290Chemistry 53991OI

212

213

MeH238Chemistry 546CH2NMe292OI

214

215

MeH220Chemistry 551Chemistry 55293OI

216

217

H160Chemistry 557Chem 55994OI

218

219

MeH218Chemistry 563Chemistry 56495OI

220

221

H214Chemistry 569Chem 57196OI

222

223

H190Chemistry 575Chem 57797OI

224

225

MeH>250Chemistry 581Chemistry 58298OI

226

227

H240Chemistry 587Chem 58999OI

228

229

MeH180Chemistry 593Chemistry 594100OI

230

231

MeH>250Chemistry 599Ac

[0285]

232

No =
Y
Q
X-R1
R2
R3
R4
mp. ° C./[MH+]

1
O
I

233

234

Me
H
245

101
O
I

235

236

237

210

Chemistry 605

(CH2)3

102
O
I

238

239

H
170

Chemistry 611

Chem613

103
O
I

240

241

H
170

Chemistry 617

Chem 619

104
O
I

242

243

H
200

Chemistry 623

Chem 625

105
O
I

244

245

H
>250

Chemistry 629

Chemistry 631

106
O
I

246

CO2Et

247

H
216-218

Chemistry 635

Azido

107
O
I

248

Et Me
H
263-265

Chemistry 641

108
O
I

249

Et
Me
H
—

Chemistry 647

109
O
Br

250

Et
Me
H
187-189

Chemistry 653

110
O
I

251

252

Me
H
240

Chemistry 659
Chemistry 660

111
O
CO2Et

253

Et
Me
H
202-204

Chemistry 665

112
O
H

254

CN
NH2
H
282-283

CHemistry 671

113
O
I

255

CN
NH2
H
283-285

Chemistry 677

114
O
H

256

Et
Me
H
166-168

3-Methylbenzyl

115
O
I

257

Et
Me
H
229-231

Chemistry 695

116
O
Br

258

Et
CH2Br
H
[430]

Chemistry 701

117
O
H

259

Et
Me
H
—

Chemistry 707

118
O
I

260

Et
Me
H
—

Chemistry 713

119
O
I

261

Et
Me
H
266-267

Chemistry 719

120
O
I

262

Et
Me
H
186-187

Chemistry 725

121
O
I

263

Et
Me
H
225-226

Chemistry 731

122
O
I

264

265

H
225-227

Chemistry 737

Azido

123
O
I

266

267

Me
H
[539]

Chemistry 743
Chemistry 744

124
O
I

268

269

Me
H
140

Chemistry 749
Chemistry 750

125
O
I

270

CH2Cl
Me
H
256-258

Chemistry 755

126
O
I

271

272

Me
H
>250

Chemistry 761
Chemistry 762

127
O
I

273

274

Me
H
—

Chemistry 767
C═C(CN)2

128
O
I

275

276

Me
H
>240

Chemistry 773
Chemistry 774

129
O
I

277

278

Me
H
230

Chemistry 779
Chemistry 780

130
O
I

279

280

H
180

Chemistry 785

Chem787

131
O
I

281

282

H
130

Chemistry 791

CH2NMe2

132
O
I

283

Et
CH2Cl
H
>240

Chemistry 797

133
O
I

284

Et
CH2OH
H
97

Chemistry 803

134
O
I

285

286

H
—

Chemistry 809

Chem 811

135
O
I

287

288

Me
H
>250

Chemistry 815
Chemistry 816

136
O
I

289

290

Me
H
>250

Chemistry 821
Chemistry 822

137
O
I

291

292

Me
H
>250

Chemistry 827
Chemistry 828

138
O
I

293

294

Me
H
250

Chemistry 833
Chemistry 834

139
O
I

295

296

H
[442]

Chemistry 839

Chem 841

140
O
I

297

298

Me
H
>250

Chemistry 845
CH═CHCN

141
O
I

299

300

H
[508]

Chemistry 851
Chemistry 852

142
O
I

301

302

H
[491]

Chemistry 857
Chemistry 858

143
O
I

303

304

Me
H
[529]

Chemistry 863
Chemistry 864

144
O
I

305

306

Me
H
[540]

Chemistry 869
Chemistry 870

145
O
I

307

308

Me
H
[545]

Chemistry 875
Chemistry 876

146
O
I

309

310

Me
H
[543]

Chemistry 861
Chemistry 862

147
O
I

311

312

Me
H
[593]

Chemistry 887
Chemistry 888

148
O
I

313

314

Me
H
[544]

Chemistry 893
Chemistry 894

149
O
I

315

316

Me
H
[570]

Chemistry 899
Chemistry 900

150
O
I

317

318

Me
H
[516]

Chemistry 905
Chemistry 906

151
O
I

319

320

Me
H
[519]

Chemistry 911
Chemistry 912

152
O
I

321

322

Me
H
[569]

Chemistry 917
Chemistry 918

153
O
I

323

324

Me
H
[535]

Chemistry 923
Chemistry 924

154
O
I

325

326

Me
H
[572]

Chemistry 929
Chemistry 930

155
O
I

327

328

Me
H
[586]

Chemistry 935
Chemistry 936

156
O
I

329

330

Me
H
[518]

Chemistry 941
Chemistry 942

157
O
I

331

332

H
195

Chemistry 947

Chem 949

158
O
I

333

334

H
200

Chemistry 953

Chem 955

159
O
I

335

336

H
158

Chemistry 959

Formyl

160
O
I

337

338

Me
H
>250

Chemistry 965
Chemistry 966

161
O
I

339

340

Me
H
195

Chemistry 971
Chemistry 972

162
O
I

341

342

Me
H
220

Chemistry 977
Chemistry 978

163
O
I

343

344

Me
H
>240

Chemistry 983
C═CHAc

164
O
I

345

346

Me
H
>240

Chemistry 989
Chemistry 990

165
O
I

347

348

Me
H
>240

Chemistry 995
Chemistry 996

166
O
I

349

350

Me
H
>250

Chemistry 1001
Chemistry 1002

167
O
I

351

352

Me
H
242

Chemistry 1007
Chemistry 1008

168
O
I

353

354

Me
H
262

Chemistry 1013
Chemistry 1014

169
O
I

355

356

Me
H
>250

Chemistry 1019
Chemistry 1020

170
O
I

357

358

Me
H
230

Chemistry 1025
Chemistry 1026

171
O
I

359

360

Me
H
[573]

Chemistry 1031
Chemistry 1032

172
O
I

361

362

Me
H
[561]

Chemistry 1037
Chemistry 1038

173
O
I

363

364

Me
H
[593]

Chemistry 1043
Chemistry 1044

174
O
I

365

366

Me
H
[525]

Chemistry 1049
Chemistry 1050

175
O
I

367

368

Me
H
[441]

Chemistry 1055
Chemistry 1056

176
O
I

369

370

Me
H
>250

Chemistry 1061
C═NOH

177
O
H

371

Et
Me
H
—

Chemistry 1067

178
O
CO2Et

372

Et
Me
H
—

Chemistry 1073

179
O
CO2Et

373

Et
Me
H
—

Chemistry 1079

180
O
n-Pr

374

Et
Me
H
158-160

Chemistry 1085

181
O
I

375

Me
H
H
>260

Chemistry 1091

182
O

376

377

Et
Me
H
158-160

Chem1096
Chemistry 1097

183
O

378

379

Et
Me
H
159-161

Chem 1102
Chemistry 1103

184
O
I

380

381

H
261-262

Chemistry 1109

Chem 1111

185
O
I

382

383

H
263-264

Chemistry 1115

Chem 1117

186
O
I

384

385

H
265-267

Chemistry 1121

SPh

187
O
I

386

387

H
224-226

Chemistry 1127

Chem 1129

188
O
I

388

389

H
218-220

Chemistry 1133

Chem1135

189
O
I

390

391

H
235-237

Chemistry 1139

Chem 1141

190
O
I

392

393

H
242-244

Chemistry 1145

Chem 1147

191
O
I

394

Et
CH2CH2Ph
H
240

Chemistry 1151

[0286]

395

No =
Y
Q
X-R1
R2
R3

192
O
I

396

397

Me

Chemistry 1157
Chemistry 1158

193
O
I

398

399

Me

Chemistry 1163
Chemistry 1164

194
O
I

400

401

Me

Chemistry 1169
Chemistry 1170

195
O
I

402

403

404

Chemistry 1175
Chemistry 1176
Me

196
O
I

405

406

Me

Chemistry 1181
Chemistry 1182

197
O
I

407

408

Me

Chemistry 1187
Chemistry 1188

198
O
I

409

410

Me

Chemistry 1193
Chemistry 1194

199
O
I

411

412

Me

Chemistry 1199
Chemistry 1200

200
O
I

413

414

Me

Chemistry 1205
Chemistry 1206

201
O
I

415

416

Me

Chemistry 1211
Chemistry 1212

202
O
I

417

418

Me

Chemistry 1217
Chemistry 1218

203
O
I

419

420

Me

Chemistry 1223
Chemistry 1224

204
O
I

421

422

Me

Chemistry 1229
Chemistry 1230

205
O
I

423

424

Me

Chemistry 1235
Chemistry 1236

206
O
I

425

426

Me

Chemistry 1241
Chemistry 1242

207
O
I

427

428

Me

Chemistry 1247
Chemistry 1248

208
O
I

429

430

Me

Chemistry 1253
Chemistry 1254

209
O
I

431

432

Me

Chemistry 1259
Chemistry 1260

210
O
I

433

434

Me

Chemistry 1265
Chemistry 1266

211
O
I

435

436

Me

Chemistry 1271
Chemistry 1272

212
O
I

437

438

Me

Chemistry 1277
Chemistry 1278

213
O
I

439

440

Me

Chemistry 1283
Chemistry 1284

214
O
I

441

442

Me

Chemistry 1289
Chemistry 1290

215
O
I

443

444

Me

Chemistry 1295
CH′CHCO2Et

216
O
I

445

446

Chemistry 1301

Chem 1303

217
O
I

447

448

Chemistry 1307

Chem 1309

218
O
I

449

450

Me

Chemistry 1313
Chemistry 1314

219
O
I

451

452

Me

Chemistry 1319
Chemistry 1320

220
O
I

453

CH2NH2
Me

Chemistry 1325

221
O
I

454

455

Chemistry 1331
Chemistry 1332

222
O
I

456

457

Chemistry 1337
(CH2)4

223
O
I

458

459

Chemistry 1343
(CH2)3

224
O
H

460

461

Chemistry 1349
Chemistry 1350

225
O
I

462

CO2Et
Me

Chemistry 1355

226
O
I

463

Et
Cl

Chemistry 1361

227
O
I

464

465

Chemistry 1367

Chem 1369

228
O
I

466

CO2Et
Cl

Chemistry 1373

229
O
H

467

CN
Cl

Chemistry 1379

230
O

468

469

Et
Me

Chem 1384
Chemistry 1385

231
O
Et

470

Et
Me

Chemistry 1391

232
O
I

471

472

Me

Chemistry 1397
Chemistry 1398

233
O
I

473

474

Me

Chemistry 1403
Chemistry 1404

234
O
Vinyl

475

Et
Me

Chemistry 1409

235
O
H

476

477

Chemistry 1415
(CH2)3

236
O
I

478

CN
Cl

Chemistry 1421

237
O
I

479

Et
Me

Chemistry 1427

238
O
I

480

CN
Me

Chemistry 1433

239
O
I

481

482

Me

Chemistry 1439
Chemistry 1440

240
O
I

483

484

Me

Chemistry 1445
Chemistry 1446

241
O
I

485

486

Me

Chemistry 1451
Chemistry 1452

242
O
I

487

488

Me

Chemistry 1457
Chemistry 1458

243
O
I

489

490

Me

Chemistry 1463
Chemistry 1464

244
O
I

491

492

Me

Chemistry 1469
Chemistry 1470

245
O
I

493

494

Me

Chemistry 1475
Chemistry 1476

246
O

495

496

Et
Me

Chem 1480
3-Methylbenzyl

247
S
H

497

Et
Me

Chemistry 1487

248
S
I

498

Et
Me

Chemistry 1493

249
O
I

499

2-Methoxybenzyl
Me

Chemistry 1505

250
O
I

500

501

Me

Chemistry 1511
Chemistry 1512

251
O

502

503

Et
Me

Chem 1516
3-Methylbenzyl

252
O

504

505

Et
Me

Chem 1522
3-Methylbenzyl

253
O
I

506

507

Me

Chemistry 1529
Chemistry 1530

254
O
I

508

509

Me

Chemistry 1535
Chemistry 1536

255
O
I

510

511

Me

Chemistry 1541
Chemistry 1542

256
O
I

512

513

H

Chemistry 1547
Chemistry 1548

257
O
I

514

CH2OH
Me

Chemistry 1553

258
O
I

515

Et
Me

Chemistry 1559

259
O
I

516

Et
Me

Chemistry 1565

260
O
SOMe

517

Et
Me

Chemistry 1571

261
O
I

518

Et
Cl

Chemistry 1577

262
O
H

519

Me
Cl

Chemistry 1583

263
O
I

520

Me
Cl

Chemistry 1589

264
O
I

521

2-Methoxyethyl
Me

Chemistry 1595

265
O
H

522

523

3-Methylbenzoyl

Chem 1603

266
O
I

524

525

3-Methylbenzoyl

Chem 1609

267
O
H

526

Et
Cl

Chemistry 1613

268
O
CH2OH

527

H
Me

Chemistry 1619

269
O
I

528

529

Me

Chemistry 1625
Formyl

270
O

530

531

Et
Me

Chem 1630
Chemistry 1631

271
O

532

533

Et
Me

Chem 1636
Chemistry 1637

272
O
SMe

534

Et Me

Chemistry 1643

273
O

535

536

Et Me

Chem 1648
3-Methylbenzyl

274
S

537

538

Et
Me

Chem 1654
3-Methylbenzyl

275
O
CO2Me

539

Et
Me

3-Methylbenzyl

276
O
C═NOH

540

Et
Me

Chemistry 1667

277
O
OMe

541

Et
Me

Chemistry 1673

278
O

542

543

Et
Me

Chem 1678
Chemistry 1679

279
O

544

545

Et
Me

Chem 1684
Chemistry 1685

280
O
SPh

546

Et
Me

Chemistry 1691

281
O
CH(OH)Ph

547

Et Me

Chemistry 1697

282
O
CO2Et

548

Et
Me

3-Methylbenzyl

283
O
CO2H

549

Et
Me

3-Methylbenzyl

284
O
Br

550

Et
Me

Chemistry 1715

285
O
CN

551

Et
Me

Chemistry 1721

286
O
I

552

Et
Me

3-Methylbenzyl

287
O
I

553

H
Me

Chemistry 1733

288
O
CCPh

554

Et
Me

Chemistry 1739

289
O
CH═CHCO2Et

555

Et
Me

Chemistry 1745

290
O
Formyl

556

Et
Me

Chemistry 1751

291
O
3-Thiphenyl

557

Et
Me

Chemistry 1757

[0287]

558

292
O
3-Cl-phenyl

559

Et
Me
H
223

Chemistry 1763

293
O
2-Furyl

560

Et
Me
H
228

Chemistry 1769

294
O
CH2OH

561

Et
Me
H
200

Chemistry 1775

295
O
CO2H

562

Et
Me
H
221

Chemistry 1781

296
O
I

563

Et
Me
H
232-234

Chemistry 1787

297
O
I

564

Et
Me
H
248-250

Chemistry 1793

298
O
I

565

Et
Me
H
250

Chemistry 1799

299
O
I

566

Et
Me
H
265-266

Chemistry 1805

300
O
I

567

Et
Me
H
275-276

Chemistry 1811

301
O
CO2H

568

H
H
H
[290]

2,5-Dimethoxybenzyl

302
O
H

569

H
Me
H
[283]

Chemistry 1823

303
O
CO2Et

570

H
Me
H
[355]

Chemistry 1829

304
O
CO2H

571

H
Me
H
[299]

Chemistry 1835

305
O
CO2Et

572

H
Me
H
[303]

Chemistry 1841

306
O
I

573

Et
Me
H
200-202

Chemistry 1859

307
O
I

574

Et
Me
H
238-240

Chemistry 1865

308
O
H

575

Et
Me
H
212-214

3,5-Dimethylbenzyl

309
O
I

576

Et
Me
H
258-260

Chemistry 1877

310
O
I

577

Et
Me
H
—

Chemistry 1883

311
O
I

578

Et
Me
H
198-199

Chemistry 1889

312
O
I

579

Et
Me
H
182-183

Chemistry 1895

313
O
I

580

Et
Me
H
265-266

Chemistry 1901

314
O
I

581

Et
H
H
210-212

Chemistry 1907

315
O
I

582

Me
Me
H
261-262

Chemistry 1913

316
O
I

583

584

H
218-219

Chemistry 1919
Chemistry 1920

317
O
I

585

586

H
230-232

Chemistry 1925
(CH2)4

318
O
I

587

588

H
206-208

Chemistry 1931
(CH2)3

319
O
I

589

Et
Me
H
242-243

Chemistry 1937

320
O
H

590

Et
Me
H
241-242

Chemistry 1943

321
O
I

591

Et
Me
H
198-200

Chemistry 1949

322
O
I

592

Et
Me
H
—

Chemistry 1955

323
O
CO2Et

593

Et
Me
H
198

Chemistry 1961

324
O
CO2Et

594

Et
Me
H
184-185

3,5-Dimethylbenzyl

325
O
H

595

Et
Me
H
232-233

Chemistry 1973

326
O
I

596

Et
Me
H
240

Chemistry 1979

327
O
H
OPh
Et
Me
H
228-229

328
O
I
OPh
Et
Me
H
180-182

329
O
I
OPh
H
Me
H
265-266

330
O
CO2Et

597

Et
Me
H
228-229

Chemistry 2003

331
O

598

599

Et
Me
H
192-193

Chem 2008
3,5-Dimethylbenzyl

332
O
CO2H

600

Et
Me
H
—

3,5-Dimethylbenzyl

333
O
CN

601

H
n-Pr
H
132

Benzyl

334
O

602

603

Et
Me
H
207

Chem 2026
3-Methylbenzoyl

335
O

604

605

Et
Me
H
216

Chem 2032
3-Methylbenzyl

336
O
CH2NMe2

606

607

H
185

3-Methylbenzyl
(CH2)4

337
O
CH2NH2

608

609

H
—

3-Methylbenzyl
(CH2)4

610

No =
Q
X-R1
R2
R3
R4
mp. ° C./(MH+)

338

611

612

613

614

H
245

I
Chemistry 3
Chemistry 4
Me

339

615

616

617

618

H
175

I
Chemistry 8
Chemistry 9
Me

340

619

620

621

622

H
[460]

I
Chemistry 13
Chemistry 14
Me

341

623

624

625

626

H
[324, 326]

H
Chemistry 18
Et
Me

342

627

628

629

630

H
[292, 294]

Cl
Chemistry 23
Et
Me

343

631

632

633

634

H
[288]

Chemistry 27
Chemistry 28

344

635

636

637

638

H
[462]

I
Chemistry 33
Et
Me

345

639

640

641

642

H
[588]

I
Chemistry 38
Et
Me

346

643

644

645

646

H
[506]

I
Chemistry 43
Chemistry 44
Me

347

647

648

649

650

H
[304]

CH2OH
Chemistry 48
Et
Me

348

651

652

653

654

H
[827]

I
Chemistry 53
Et
Me

349

655

656

657

658

H
[610]

I
Chemistry 58
Et
Me

350

659

660

661

662

H
[616]

I
Chemistry 63
Et
Me

351

663

664

665

666

H
[604]

I
Chemistry 68
Et
Me

352

667

668

669

670

H
[615]

I
Chemistry 73
Et
Me

353

671

672

673

674

H
[579]

I
Chemistry 78
Et
Me

354

675

676

677

678

H
[596]

I
Chemistry 83
Et
Me

355

679

680

681

682

H
[640]

I
Chemistry 88
Et
Me

358

683

684

685

686

H
[614]

I
Chemistry 93
Et
Me

357

687

688

689

690

H
205

I
Chemistry 98
Chemistry 99
Me

358

691

692

693

694

H
2109

I
Chemistry 103
Chemistry 104
Me

359

695

696

697

698

H
>250

I
Chemistry 108
Chemistry 109
Me

360

699

700

701

702

H
[487]

I
Chemistry 113
Chemistry 114
Me

381

703

704

705

706

H
[570]

I
Chemistry 118
Chemistry 119
Me

362

707

708

709

710

H
[455]

I
Chemistry 123
Chemistry 124
Me

363

711

712

713

714

H
215

I
Chemistry 128
Chemistry 129
Me

364

715

716

717

718

H
205

I
Chemistry 133
Chemistry 134
Me

365

719

720

721

722

H
>250

I
Chemistry 138
Chemistry 139
Me

366

723

724

725

726

H
240

I
Chemistry 143
Chemistry 144
Me

367

727

728

729

730

H
135

I
Chemistry 148
Chemistry 149
Me

368

731

732

733

734

H
>250

I
Chemistry 153
Chemistry 154

369

735

736

737

738

H
>250

I
Chemistry 158
Chemistry 159
Me

370

739

740

741

742

H
>250

I
Chemistry 163
Chemistry 164
Me

371

743

744

745

746

H
>250

I
Chemistry 168
Chemistry 169
Me

372

747

748

749

750

H
>250

I
Chemistry 173
Chemistry 174
Me

373

751

752

753

754

H
>250

I
Chemistry 178
Chemistry 179
Me

374

755

756

757

758

H
170

I
Chemistry 183
Chemistry 184
Me

375

759

760

761

762

H
220

I
Chemistry 188
Chemistry 189
Me

376

763

764

765

766

H
>250

I
Chemistry 193
Chemistry 194
Me

377

767

768

769

770

H
>250

I
Chemistry 198
Et
Chemistry 200

378

771

772

773

774

H
>250

I
Chemistry 203
Chemistry 204
Me

379

775

776

777

778

H
[395]

I
Chemistry 208
Et
CN

380

779

780

781

782

H
[399]

I
Chemistry 213
Et
CH2NH2

381

783

784

785

786

H
230

I
Chemistry 218
Chemistry 219
Me

382

787

788

789

790

H
226

I
Chemistry 223
Chemistry 224
Me

383

791

792

793

794

H
[532]

Chemistry 227
Chemistry 228

384

795

796

797

798

H
[540]

I
Chemistry 233
Chemistry 234
Me

385

799

800

801

802

H
[512]

I
Chemistry 238
Chemistry 239
Me

386

803

804

805

806

H
[256]

Vinyl
Chemistry 243
H
Me

387

807

808

809

810

H
[258]

Et
Chemistry 248
H
Me

388

811

812

813

814

H
[384]

Et
Chemistry 253
I
Me

389

815

816

817

818

H
>250

I
Chemistry 258
Chemistry 259
Me

390

819

820

821

822

H
>250

I
Chemistry 263
Chemistry 264
Me

391

823

824

825

826

H
>250

I
Chemistry 268
CH2NH2
Me

392

827

828

829

830

H
239

I
Chemistry 273
Chemistry 274
Me

393

831

832

833

834

H
220

I
Chemistry 278
Chemistry 279
Me

394

835

836

837

838

H
[458]

I
Chemistry 283
Chemistry 284
Me

395

839

840

841

842

H
240

I
Chemistry 288
Chemistry 289
Me

396

843

844

845

846

H
190

I
Chemistry 293
Chemistry 294
Me

397

847

848

849

850

H
>240

I
Chemistry 298
Chemistry 299
Me

398

851

852

853

854

H
>250

I
Chemistry 303
Chemistry 304
Me

399

855

856

857

858

H
>250

I
Chemistry 308
Chemistry 309
Me

400

859

860

861

862

H
>250

I
Chemistry 313
Chemistry 314
Me

401

863

864

865

866

H
212

I
Chemistry 318
Chemistry 319
Me

402

867

868

869

870

H
238

I
Chemistry 323
Chemistry 324
Me

403

871

872

873

874

H
188

I
Chemistry 328
Chemistry 329
Me

[0288]

875

No =
Q
X-R1
R2
R3
R4
mp. ° C./(MH+)

404

876

877

878

879

H
104

I
Chemistry 333
Chemistry 334
Me

405

880

881

882

883

H
240

I
Chemistry 338
Chemistry 339
Me

406

884

885

886

887

H
148

I
Chemistry 343
Chemistry 344
Me

407

888

889

890

891

H
214

I
Chemistry 348
Et
Chemistry 350

408

892

893

894

895

H
[308, 310]

Cl
Chemistry 353
Et
Me

409

896

897

898

899

H
[326]

CF3
Chemistry 358
Et
Me

410

900

901

902

903

H
[541]

I
Chemistry 363
Chemistry 364
Me

411

904

905

906

907

H
[429]

I
Chemistry 368
Chemistry 369
Me

412

908

909

910

911

H
220

I
Chemistry 373
Chemistry 374
Me

413

912

913

914

915

H
>250

I
Chemistry 378
Chemistry 379
Me

414

916

917

918

919

H
[557]

I
Chemistry 383
Chemistry 384
Me

416

920

921

922

923

H
162

I
Chemistry 388
Chemistry 389
Me

416

924

925

926

927

H
><240

I
Chemistry 393
Chemistry 394
Me

417

928

929

930

931

H
[328]

Chemistry 397
Chemistry 398
Et
Me

418

932

933

934

935

H
[362, 364]

Chemistry 402
Chemistry 403
Et
Me

419

936

937

938

939

H
248

I
Chemistry 408
Chemistry 409
Me

420

940

941

942

943

H
226

I
Chemistry 413
Chemistry 414
Me

421

944

945

946

947

H
174

I
Chemistry 418
Chemistry 419
Me

422

948

949

950

951

H
[350]

H
Chemistry 423
Et
CH(OH)Ph

423

952

953

954

955

H
[476]

I
Chemistry 428
Et
CH(OH)Ph

424

956

957

958

959

H
158

IU
Chemistry 433
CXhemistry 434
Me

425

960

961

962

963

H
236

I
Chemistry 438
Chemistry 439
Me

426

964

965

966

967

H
[521]

I
Chemistry 443
Et
Me

427

968

969

970

971

H
234

I
Chemistry 448
Chemistry 449
Me

428

972

973

974

975

H
204

I
Chemistry 463
Chemistry 464
Me

429

976

977

978

979

H
[556]

I
Chemistry 458
CO2Et
Me

430

980

981

982

983

H
[674]

I
Chemistry 463
Et
Me

431

984

985

986

987

H
[410]

Chemistry 467
Chemistry 468
Et
Me

432

988

989

990

991

H
[432]

Chemistry 472
Chemistry 473
Et
Me

433

992

993

994

995

H
236

I
Chemistry 478
Chemistry 479
Me

434

996

997

998

H
>250

I
Chemistry 483
Chemistry 484
Me

435

999

1000

1001

1002

H
200

I
Chemistry 488
Chemistry 489
Me

436

1003

1004

1005

1006

H
>250

I
Chemistry 493
Chemistry 494
Me

437

1007

1008

1009

1010

H
[442]

I
Chemistry 488
Et
Chemistry 500

438

1011

1012

1013

1014

H
186

I
Chemistry 503
Et
Chemistry 505

439

1015

1016

1017

1018

H
[370]

I
Chemistry 508
Me
Me

440

1019

1020

1021

1022

H
[514]

I
Chemistry 513
CH2OH
Me

441

1023

1024

1025

1026

H
[372]

I
Chemistry 518
Me
Me

442

1027

1028

1029

1030

H
[390, 392]

IO
Chemistry 523
Me
Me

443

1031

1032

1033

1034

H
[380]

I
Chemistry 528
Me
Me

444

1035

1036

1037

1038

H
[430]

I
Chemistry 533
Me
Me

445

1039

1040

1041

1042

H
[314]

Chemistry 537
Chemistry 538
Et
Me

446

1043

1044

1045

1046

H
[356]

Chemistry 542
Chemistry 543
Et
Me

447

1047

1048

1049

1050

H
[525]

I
Chemistry 548
Et
Me

448

1051

1052

1053

1054

H
[536]

I
Chemistry 553
Et
Me

449

1055

1056

1057

1058

H
>240

I
Chemistry 558
Chemistry 559
Me

450

1059

1060

1061

1062

H
230

I
Chemistry 563
Chemistry 564
Me

451

1063

1064

1065

1066

H
230

I
Chemistry 568
Chemistry 569
Me

452

1067

1068

1069

1070

H
140

I
Chemistry 573
Chemistry 574
Me

453

1071

1072

1073

1074

H
210

I
Chemistry 578
CO2Me
CH2OMe

454

1075

1076

1077

1078

H
230

I
Chemistry 583
CH2OH
CH2OMe

456

1079

1080

1081

1082

H
[434, 436]

I
Chemistry 588
CH2Cl
CH2OMe

456

1083

1084

1085

1086

H
232

I
Chemistry 593
Chemistry 594
CH2OMe

457

1087

1088

1089

1090

H
230

I
Chemistry 588
Chemistry 589
CH2OH

458

1091

1092

1093

1094

H
188

I
Chemistry 603
Chemistry 604
Me

459

1095

1096

1097

1098

H
190

I
Chemistry 608
Chemistry 609
Me

480

1099

1100

1101

H
240

I
Chemistry 613
Chemistry 614
Me

461

1102

1103

1104

1105

H
204

I
Chemistry 618
Chemistry 619
Me

462

1106

1107

1108

1109

H
248

I
Chemistry 623
Chemistry 624
Me

463

1110

1111

1112

1113

H
220

I
Chemistry 628
Chemistry 629
Me

464

1114

1115

1116

1117

H
[583]

I
Chemistry 633
Chemistry 634
Me

465

1118

1119

1120

1121

H
[576, 578]

I
Chemistry 638
Chemistry 639
Me

468

1122

1123

1124

1125

H
[560, 562]

I
Chemistry 643
Chemistry 644
Me

467

1126

1127

1128

1129

H
[542]

I
Chemistry 648
Chemistry 649
Me

468

1130

1131

1132

1133

H
[558]

I
Chemistry 653
Chemistry 654
Me

469

1134

1135

1136

1137

H
[462, 464]

I
CHemistry 658
Et
Me

470

1138

1139

1140

1141

H
[486, 487]

I
Chemistry 663
Et
Me

471

1142

1143

1144

1145

H
[390]

Chemistry 667
Chemistry 668
Et
Me

472

1146

1147

1148

1149

H
[606]

I
Chemistry 673
Et
Me

473

1150

1151

1152

1153

H
[507]

I
Chemistry 678
Et
Me

474

1154

1155

1156

1157

H
165

H
Chemistry 683
CO2Me
CH2OMe

475

1158

1159

1160

1161

H
[306]

H
Chemistry 688
CH2OH
CH2OMe

476

1162

1163

1164

1165

H
142

I
Chemistry 683
CO2Me
CH2OMe

477

1166

1167

1168

1169

H
198

I
Chemistry 698
CH2OH
CH2OMe

478

1170

1171

1172

1173

H

I
Chemistry 703
CH2Cl
CH2OMe

479

1174

1175

1176

1177

H
115

I
Chemistry 708
Chemistry 709
CH2OMe

480

1178

1179

1180

1181

H
[487]

I
Chemistry 713
Chemistry 714
CH2OH

481

1182

1183

1184

1185

H
230

I
Chemistry 718
Chemistry 719
Me

482

1186

1187

1188

1189

H
168

I
Chemistry 723
Chemistry 724
Me

483

1190

1191

1192

1193

H
[513]

I
Chemistry 728
Chemistry 729
Me

484

1194

1195

1196

1197

H
200

I
Chemistry 733
Chemistry 734
Me

485

1198

1199

1200

1201

H
[486]

I
Chemistry 738
Chemistry 739
Me

486

1202

1203

1204

1205

H
220

I
Chemistry 743
Chemistry 744
Me

487

1206

1207

1208

1209

H
174

I
Chemistry 748
Chemistry 749
Me

488

1210

1211

1212

1213

H
204

I
Chemistry 753
Chemistry 754
Me

489

1214

1215

1216

1217

H
>250

I
Chemistry 758
Chemistry 759
Me

490

1218

1219

1220

1221

H
162

I
Chemistry 763
Chemistry 764
Me

491

1222

1223

1224

1225

H
[600]

I
Chemistry 768
Chemistry 769
Me

492

1226

1227

1228

1229

H
[600]

I
Chemistry 773
Chemistry 774
Me

493

1230

1231

1232

1233

H
164

I
Chemistry 778
Chemistry 779
Me

494

1234

1235

1236

1237

H
[513]

I
Chemistry 783
Chemistry 784
Me

495

1238

1239

1240

1241

H
206

I
Chemistry 788
Chemistry 789
Me

496

1242

1243

1244

1245

H
185

I
Chemistry 793
Chemistry 794
Me

497

1246

1247

1248

1249

H
[460]

I
Chemitsyr 798
Chemistry 799
CH2OMe

498

1250

1251

1252

1253

H
[498]

I
Chemistry 803
Chemistry 804
Me

499

1254

1255

1256

1257

H
[495]

I
Chemistry 808
Chemistry 809
Me

500

1258

1259

1260

1261

H
203

I
Chemistry 813
Chemistry 814
Me

501

1262

1263

1264

1265

H
204

I
Chemistry 818
Chemistry 819
Me

502

1266

1267

1268

1269

H
168

I
Chemistry 823
Chemistry 824
Me

503

1270

1271

1272

1273

H
217

I
Chemistry 828
Chemistry 829
Me

504

1274

1275

1276

1277

H
200

I
Chemistry 833
Chemistry 834
Me

505

1278

1279

1280

1281

H

Me
Chemistry 838
CH2Cl
Me

506

1282

1283

1284

1285

H
206

Me
Chemistry 843
Chemistry 844
Me

507

1286

1287

1288

1289

H
170

Me
Chemistry 848
CO2Et
Me

508

1290

1291

1292

1293

H
218

Me
Chemistry 853
CH2OH
Me

509

1294

1295

1296

1297

H
200

Me
Chemistry 858
Chemistry 859
Me

510

1298

1299

1300

1301

H
166

I
Chemistry 863
Chemistry 864
Me

511

1302

1303

1304

1305

H
213

I
Chemistry 868
Chemistry 869

512

1306

1307

1308

1309

H
[610]

I
Chemistry 873
Chemistry 874
Me

513

1310

1311

1312

1313

H
[761]

I
Chemistry 878
CO2Et
Me

514

1314

1315

1316

1317

H
[567]

I
Chemistry 883
Chemistry 884
Me

515

1318

1319

1320

1321

H
[418, 420]

I
Chemistry 888
Et
Me

516

1322

1323

1324

1325

H
[472]

I
Chemistry 893
Et
Me

517

1326

1327

1328

1329

H
[621]

I
Chemistry 898
Chemistry 899
Me

518

1330

1331

1332

1333

H
[416]

I
Chemistry 903
Et
Me

519

1334

1335

1336

1337

H
[556]

I
Chemistry 908
Chemistry 909
Me

520

1338

1339

1340

1341

H
[452, 454, 456]

I
Chemistry 913
Et
Me

521

1342

1343

1344

1345

H
[434, 436]

I
Chemistry 918
Et
Me

522

1346

1347

1348

1349

H
[476]

I
Chemistry 923
Et
Me

523

1350

1351

1352

1353

H
[517]

I
Chemistry 928
Chemistry 929
Me

524

1354

1355

1356

1357

H
[362]

Chemistry 932
Chemistry 933
Et
Me

525

1358

1359

1360

1361

H
[361]

Chemistry 937
Chemistry 938
Et
Me

526

1362

1363

1364

1365

H
[450]

I
Chemistry 943
Chemistry 944
Me

527

1366

1367

1368

1369

H
[399]

I
Chemistry 948
Et
Me

528

1370

1371

1372

1373

H
[381]

I
Chemistry 953
Et
Me

529

1374

1375

1376

1377

H
[282]

I
Chemistry 958
Chemistry 959
Me

530

1378

1379

1380

1381

H
210

I
Chemistry 963
Chemistry 964
Me

531

1382

1383

1384

1385

H
144

I
Chemistry 968
Chemistry 969
Me

532

1386

1387

1388

1389

H
[512]

I
Chemistry 973
CH2OH
Me

533

1390

1391

1392

1393

H
[579]

I
Chemistry 978
Chemistry 979
Me

534

1394

1395

1396

1397

H
[469]

I
Chemistry 983
Chemistry 984
Me

535

1398

1399

1400

1401

H
[485]

I
Chemistry 988
Chemistry 989
Me

536

1402

1403

1404

1405

H
[380]

I
Chemistry 993
Et
Me

537

1406

1407

1408

1409

H
[424]

I
Chemistry 998
Et
Me

538

1410

1411

1412

1413

H
[494]

I
Chemistry 1003
Chemistry 1004
Me

539

1414

1415

1416

1417

H
203

I
Chemistry 1008
Chemistry 1009
Me

540

1418

1419

1420

1421

H
230

I
Chemistry 1013
Chemistry 1014
Me

541

1422

1423

1424

1425

H
[510]

I
Chemistry 1018
Chemistry 1019
Me

542

1426

1427

1428

1429

H
206

Me
Chemistry 1023
Chemistry 1024
Me

543

1430

1431

1432

1433

H
>250

Me
Chemistry 1028
Chemistry 1029
Me

544

1434

1435

1436

1437

H
[560, 562, 564]

I
Chemistry 1033
Chemistry 1034
Me

545

1438

1439

1440

1441

H
248

I
Chemistry 1038
Chemistry 1039
Me

546

1442

1443

1444

1445

H
100

I
Chemistry 1043
Chemistry 1044
Me

547

1446

1447

1448

1449

H
220

I
Chemistry 1048
Chemistry 1049
Me

548

1450

1451

1452

1453

H
[459]

I
Chemistry 1053
Et
Me

549

1454

1455

1456

1457

H
[431]

I
Chemistry 1058
Et
Me

550

1458

1459

1460

1461

H
[398]

I
Chemistry 1063
Et
Me

551

1462

1463

1464

1465

H
[421]

I
Chemistry 1068
Et
Me

552

1466

1467

1468

1469

H
[370]

I
Chemistry 1073
Et
Me

553

1470

1471

1472

1473

H
[298]

H
Chemistry 1078
Et
Me

554

1474

1475

1476

1477

H
[424]

I
Chemistry 1083
Et
Me

555

1478

1479

1480

1481

H
[376, 378]

Br
Chemistry 1088
Et
Me

556

1482

1483

1484

1485

H
[600]

I
Chemistry 1093
Et
Me

557

1486

1487

1488

1489

H
[435]

I
Chemistry 1098
Et
Me

558

1490

1491

1492

1493

H
194

I
Chemistry 1103
Chemistry 1104
Me

559

1494

1495

1496

1497

H
146

I
Chemistry 1108
Chemistry 1109
Me

560

1498

1499

1500

1501

H
168

I
Chemistry 1113
Chemistry 1114
Me

561

1502

1503

1504

1505

H
>250

I
Chemistry 1118
Chemistry 1119
Me

562

1506

1507

1508

1509

H

I
Chemistry 1123
Chemistry 1124
Me

563

1510

1511

1512

1513

H
232

I
Chemistry 1128
Chemistry 1129
Me

564

1514

1515

1516

1517

H
>250

I
Chemistry 1133
Chemistry 1134
Me

565

1518

1519

1520

1521

H
235

H
Chemistry 1138
CO2Et
Chemistry 1140

566

1522

1523

1524

1525

H
210

I
Chemistry 1143
Chemistry 1144
Me

567

1526

1527

1528

1529

H
202

Vinyl
Chemistry 1148
Chemistry 1149
Me

568

1530

1531

1532

1533

H
[330]

H
Chemistry 1153 Chemistry 1154
Me

569

1534

1535

1536

1537

H
[302]

H
Chemistry 1158
CH2CH2CO2H
Me

570

1538

1539

1540

1541

H
[371]

H
Chemistry 1163
Chemistry 1164
Me

571

1542

1543

1544

1545

H
>250

I
Chemistry 1168
Chemistry 1169
Me

572

1546

1547

1548

1549

H
230

I
Chemistry 1173
Chemistry 1174
Me

573

1550

1551

1552

1553

H
249

I
Chemistry 1178
Chemistry 1179
Me

574

1554

1555

1556

1557

H
>250

I
Chemistry 1183
Chemistry 1184
Me

575

1558

1559

1560

1561

H
216

I
Chemistry 1188
Chemistry 1189
Me

576

1562

1563

1564

1565

H
>250

I
Chemistry 1193
Chemistry 1194
Me

577

1566

1567

1568

1569

H
[472]

I
Chemistry 1198
Et
Me

578
I

1570

1571

Me
H
[427]

Chemistry 3
Et

579
I

1572

1573

Me
H
[468]

Chemistry 8
Et

580
I

1574

1575

Me
H
[467]

Chemistry 13
Et

581
I

1576

1577

Me
H
[469]

Chemistry 18
Et

582
I

1578

1579

Me
H
[502]

Chemistry 23
Et

583
I

1580

1581

Me
H
[515]

Chemistry 28
Et

584
I

1582

1583

Me
H
[498]

Chemistry 33
Et

585
I

1584

1585

Me H
180

Chemistry 38
Chemistry 39

586
I

1586

1587

Me
H
168

Chemistry 43
Chemistry 44

587
I

1588

1589

Me
H
236

Chemistry 48
Chemistry 49

588
I

1590

1591

Me
H
228

Chemistry 53
Chemistry 54

589
I

1592

1593

Me
H
>250

Chemistry 58
Chemistry 59

590
H

1594

1595

Me
H
[399]

Chemistry 63
Chemistry 64

591
I

1596

1597

Me
H
144

Chemistry 68
Chemistry 69

592
I

1598

1599

Me
H
>250

Chemistry 73
Chemistry 74

593
I

1600

1601

Me
H
192

Chemistry 78
Chemistry 79

594
I

1602

1603

Me
H
212

Chemistry 83
Chemistry 84

595
I

1604

1605

Me
H
>250

Chemistry 88
Chemistry 89

596
I

1606

1607

Me
H
[466]

Chemistry 93
Chemistry 94

597
I

1608

1609

Me
H
>250

Chemistry 98
Chemistry 99

598
Chemistry 102

1610

1611

Me
H
[227]

Chemistry 103
H

599
Chemistry 107

1612

1613

Me
H
[255]

Chemistry 108
H

600
Chemistry 112

1614

1615

Me
H
[244]

Chemistry 113
H

601
Chemistry 117

1616

1617

Me
H
[291]

Chemistry 118
H

602
I

1618

1619

Me
H
[508]

Chemistry 123
Et

603
I

1620

1621

Me
H
[427]

Chemistry 128
Et

604
I

1622

1623

Me
H
[429]

Chemistry 133
Et

605
I

1624

1625

Me
H
178

Chemistry 138
Chemistry 139

606
I

1626

1627

Me
H
120

Chemistry 143
Chemistry 144

607
I

1628

1629

Me
H
>250

Chemistry 148
Chemistry 149

608
I

1630

1631

Me
H
[437]

Chemistry 153
Chemistry 154

609
I

1632

1633

Me
H
[439]

Chemistry 158
Chemistry 159

610
I

1634

1635

Me
H
[426]

Chemistry 163
Chemistry 164

611
I

1636

1637

Me
H
>250

Chemistry 168
Chemistry 169

[0289]

1638

No =
Q
X-R1
R2
R3
R4
mp. ° C./(MH+)

612
H

1639

1640

Me
H
[302]

Chemistry 173
CO2Et

613
Br

1641

1642

Me
H
[381]

Chemistry 178
CO2Et

614
Br

1643

1644

Me
H
[338, 340]

Chemistry 183
CH2OH

615
Br

1645

1646

Me
H

Chemistry 188
CH2Cl

616
Br

1647

1648

Me
H
>250

Chemistry 193
Chemistry 194

617
I

1649

1650

Me
H
>250

Chemistry 198
Chemistry 199

618
I

1651

1652

Me
H
[451]

Chemistry 203
Chemistry 204

619
I

1653

1654

Me
H
[513]

Chemistry 508
Chemistry 209

620
I

1655

1656

Me
H
[639]

Chemistry 213
Chemistry 214

621
I

1657

1658

Me
H
[456]

Chemistry 218
Chemistry 219

622
I

1659

1660

Me
H
[582]

Chemistry 223
Chemistry 224

623
I

1661

1662

Me
H
[428]

Chemistry 228
CH2CH2CO2H

624
I

1663

1664

e
H
[554]

Chemistry 233
CH2CH2CO2H

626
I

1665

1666

Me
H
[529]

Chemistry 238
Chemistry 239

626
I

1667

1668

Me
H
[453]

Chemistry 243
Chemistry 244

627
I

1669

1670

Me
H
[481]

Chemistry 248
Chemistry 249

628
I

1671

1672

Me
H
[541]

Chemistry 253
Chemistry 254

629
I

1673

1674

Me
H
[510]

CHemistry 258
Chemistry 259

630
I

1675

1676

Me
H
[483]

Chemistry 263
Chemistry 264

631
I

1677

1678

Me
H
[478]

Chemistry 268
Chemistry 269

632
I

1679

1680

Me
H
[492]

Chemistry 273
Chemistry 274

633
I

1681

1682

Me
H
[586]

Chemistry 278
Chemistry 279

634
I

1683

1684

Me
H
[493]

Chemistry 283
Chemistry 284

635
I

1685

1686

Me
H
[536]

Chemistry 288
Chemistry 289

636
I

1687

1688

Me
H
[511]

Chemistry 293
Chemistry 294

637
I

1689

1690

Me
H
[523]

Chemistry 298
Chemistry 299

638
I

1691

1692

Me
H
[508]

Chemistry 303
Chemistry 304

639
I

1693

1694

Me
H
[584]

Chemistry 308
Chemistry 309

640
I

1695

1696

Me
H
[571]

Chemistry 313
Chemistry 314

641
I

1697

1698

Me
H
[484]

Chemistry 318
Et

642
I

1699

1700

Me
H
[498]

Chemistry 323
Et

643
I

1701

1702

Me
H
[510]

Chemistry 328
Et

644
I

1703

1704

Me
H
[545]

Chemistry 333
Et

645
I

1705

1706

Me
H
[514]

Chemistry 338
Et

646
I

1707

1708

Me
H
[546]

Chemistry 343
Et

647
I

1709

1710

Me
H
[497]

Chemistry 348
Et

648
I

1711

1712

Me
H
[250

Chemistry 353
Chemistry 354

649
I

1713

1714

Me
H
165

Chemistry 358
Chemistry 359

650
I

1715

1716

Me
H
181

Chemistry 363
Chemistry 364

651
I

1717

1718

Me
H
[497]

Chemistry 368
Et

652
I

1719

1720

Me
H
[515]

Chemistry 373
Et

653
I

1721

1722

Me
H
[443]

Chemistry 378
NHCO2Et

654
I

1723

1724

Me
H
[371]

Chemistry 383
Et

655
H

1725

1726

Me
H
[245]

Chemistry 388
Et

656
I

1727

1728

Me
H
[386]

Chemistry 393
Et

657
I

1729

1730

Me
H
[401]

Chemistry 398
Et

658
I

1731

1732

Me
H
[386]

Chemistry 403
Et

659
I

1733

1734

Me
H
[506]

Chemistry 408
Et

660
Br

1735

1736

Me
H
>250

Chemistry 413
Chemistry 414

661
Br

1737

1738

Me
H
>250

Chemistry 418
Chemistry 419

662
I

1739

1740

Me
H
>250

Chemistry 423
Chemistry 424

663
I

1741

1742

Me
H
[552]

Chemistry 428
Chemistry 429

664
I

1743

1744

Me
H
[483]

Chemistry 433
Chemistry 434

665
I

1745

1746

Me
H
[533]

Chemistry 438
Chemistry 439

666
I

1747

1748

Me
H
[559]

Chemistry 443
Chemistry 444

667
I

1749

1750

Me
H
[516]

Chemistry 448
Chemistry 449

668
I

1751

1752

Me
H
[516]

Chemistry 453
Chemistry 454

669
I

1753

1754

Me
H
[505]

Chemistry 458
Chemistry 459

670
I

1755

1756

Me
H
[497]

Chemistry 463
Chemistry 464

671
I

1757

1758

Me
H
[513]

Chemistry 468
Chemistry 469

672
I

1759

1760

Me
H
[588]

Chemistry 473
Chemistry 474

673
I

1761

1762

Me
H
[558]

Chemistry 478
Chemistry 479

674
I

1763

1764

Me
H
[465]

CHemistry 483
Chemistry 484

675
I

1765

1766

Me
H
[559]

Chemistry 488
Chemistry 489

676
I

1767

1768

Me
H
[521]

Chemistry 493
Chemistry 494

677
I

1769

1770

Me
H
[525]

Chemistry 498
Chemistry 499

678
I

1771

1772

Me
H
>250

CHemistry 503
Chemistry 504

679
I

1773

1774

Me
H
>250

Chemistry 508
Chemistry 509

680
I

1775

1776

Me
H
>250

Chemistry 513
Chemistry 514

681
H

1777

1778

Me
H
[392]

Chemistry 518
CO2Et

682
I

1779

1780

Me
H
[440]

Chemistry 523
Et

683
I

1781

1782

Me
H
[492]

Chemistry 528
Et

684
I

1783

1784

Me
H
[486]

Chemistry 533
Et

685
I

1785

1786

Me
H
[412]

Chemistry 538
Et

686
I

1787

1788

Me
H
[414]

Chemistry 543
Et

687
I

1789

1790

Me
H
[398]

Chemistry 548
Et

688
H

1791

1792

Me
H
[272]

Chemistry 553
Et

689
CO2Et

1793

1794

Me
H
[344]

Chemistry 558
Et

690
H

1795

1796

Me
H
[272]

Chemistry 563
Et

691
I

1797

1798

Me
H
[471]

Chemistry 568
Chemistry 569

692
I

1799

1800

Me
H
[531]

Chemistry 573
Et

693
I

1801

1802

Me
H
[468]

Chemistry 578
Chemistry 579

694
I

1803

1804

Me
H
[572]

Chemistry 583
Chemistry 584

695
I

1805

1806

Me
H
[544]

Chemistry 588
Chemistry 589

696
I

1807

1808

Me
H
[531]

Chemistry 593
Chemistry 594

697
I

1809

1810

Me
H
[482]

Chemistry 598
Chemistry 599

698
I

1811

1812

Me
H
[557]

Chemistry 603
Chemistry 604

699
I

1813

1814

Me
H
[598, 600, 602]

Chemistry 608
Chemistry 609

700
I

1815

1816

Me
H
[548]

Chemistry 613
Chemistry 614

701
I

1817

1818

Me
H
[498]

Chemistry 618
Chemistry 619

702
I

1819

1820

Me
H
[532]

Chemistry 623
Chemistry 624

703
I

1821

1822

Me
H
[544]

Chemistry 628
Chemistry 629

704
I

1823

1824

Me
H
>250

Chemistry 633
Chemistry 634

705
I

1825

1826

Me
H
[530]

Chemistry 638
Chemistry 639

706
I

1827

1828

Me
H
[450]

Chemistry 643
Chemistry 644

707
I

1829

1830

Me
H
[542, 544]

Chemistry 648
Chemistry 649

708
I

1831

1832

Me
H
[514, 516]

Chemistry 653
Chemistry 654

709
I

1833

1834

Me
H
[528, 530]

Chemistry 658
Chemistry 659

710
I

1835

1836

Me
H
[513]

Chemistry 663
Chemistry 664

711
I

1837

1838

Me
H
[438]

Chemistry 668
Chemistry 669

712
I

1839

1840

Me
H
[451]

Chemistry 673
Chemistry 674

713
I

1841

1842

Me
H
[437]

Chemistry 678
Chemistry 679

714
I

1843

1844

Me
H
[465]

Chemistry 683
Chemistry 684

715
I

1845

1846

Me
H
[513]

Chemistry 688
Chemistry 689

716
I

1847

1848

Me
H
[530]

Chemistry 693
Chemistry 694

717
I

1849

1850

Me
H
[512]

Chemistry 698
Chemistry 699

718
I

1851

1852

Me
H
[450]

Chemistry 703
Chemistry 704

719
I

1853

1854

Me
H
[466]

Chemistry 708
Chemistry 709

720
I

1855

1856

Me
H
[512]

Chemistry 713
Chemistry 714

721
I

1857

1858

Me
H
[464]

Chemistry 718
Chemistry 719

722
I

1859

1860

Me
H
[478]

Chemistry 723
Chemistry 724

723
I

1861

1862

Me
H
[450]

Chemistry 728
Chemistry 729

724
I

1863

1864

Me
H
[526]

Chemistry 733
Chemistry 734

725
I

1865

1866

Me
H
[537]

Chemistry 738
Chemistry 739

726
I

1867

1868

Me
H
[537]

Chemistry 743
Chemistry 744

727
I

1869

1870

Me
H
>250

Chemistry 748
Chemistry 749

728
I

1871

1872

Me
H
164

Chemistry 753
Chemistry 754

729
H

1873

1874

Me
H
[254]

Chemistry 758
Et

730
I

1875

1876

Me
H
[464, 466]

Chemistry 763
Et

731
H

1877

1878

Me
H
[338, 340]

Chemistry 768
Et

732
H

1879

1880

Me
H
[285]

Chemistry 773
Et

733
I

1881

1882

Me
H
[450, 451]

Chemistry 778
Et

734
I

1883

1884

Me
H
[371]

Chemistry 783
NH2

735
I

1885

1886

Me
H
[475]

Chemistry 788
Chemistry 789

736
I

1887

1888

Me
H
[491]

Chemistry 793
Chemistry 794

737
I

1889

1890

Me
H
[399]

Chemistry 798
NMe2

738
CO2Et

1891

1892

Me
H
[428]

Chemistry 803
Et

739
I

1893

1894

Me
H
[461]

Chemistry 808
Chemistry 809

740
I

1895

1896

Me
H
248

Chemistry 813
Chemistry 814

741
I

1897

1898

Me
H
>250

Chemistry 818
Chemistry 819

742
I

1899

1900

Me
H
[486]

Chemistry 823
Chemistry 824

743
I

1901

1902

Me
H
[504, 506, 508]

Chemistry 828
Chemistry 829

744
I

1903

1904

Me
H
[513]

Chemistry 833
Chemistry 834

745
I

1905

1906

Me
H
[562]

Chemistry 838
Chemistry 839

746
I

1907

1908

Me
H
[563]

Chemistry 843
Chemistry 844

747
I

1909

1910

Me
H
[527]

Chemistry 848
Chemistry 849

748
I

1911

1912

Me
H
[563, 565]

Chemistry 853
Chemistry 854

749
I

1913

1914

Me
H
[486]

Chemistry 858
Chemistry 859

750
I

1915

1916

Me
H
[515]

Chemistry 863
Chemistry 864

751
I

1917

1918

Me
H
[500]

Chemistry 868
Chemistry 869

752
I

1919

1920

Me
H
[499]

Chemistry 873
Chemistry 874

753
I

1921

1922

Me
H
[514]

Chemistry 878
Chemistry 879

754
I

1923

1924

Me
H
>250

Chemistry 883
Chemistry 884

755
I

1925

1926

Me
H
[466]

Chemistry 888
Et

756
I

1927

1928

Me
H
[478]

Chemistry 893
Chemistry 894

757
I

1929

1930

Me
H
>250

Chemistry 898
Chemistry 899

758
I

1931

1932

Me
H
>250

Chemistry 903
Chemistry 904

759
I

1933

1934

Me
H
213

Chemistry 908
Chemistry 909

760
I

1935

1936

Me
H
207

Chemistry 913
Chemistry 914

761
I

1937

1938

Me
H
>250

Chemistry 918
Chemistry 919

762
I

1939

1940

Me
H
[437]

Chemistry 923
Et

763
I

1941

1942

Me
H
[458]

Chemistry 928
Et

764
Vinyl

1943

1944

Me
H
[321]

Chemistry 933
Et

765
H

1945

1946

Me
H
[286]

Chemistry 938
Et

766
I

1947

1948

Me
H
[429]

Chemistry 943
Et

767
H

1949

1950

Me
H
[284]

Chemistry 948
Et

768
CO2Et

1951

1952

Me
H
[388]

Chemistry 953
Et

769
H

1953

1954

Me
H
[316]

Chemistry 958
Et

770
I

1955

1956

Me
H
[442]

Chemistry 963
Et

771
CO2Et

1957

1958

Me
H
[380, 382]

Chemistry 968
Et

772
H

1959

1960

Me
H
[308, 310]

Chemistry 973
Et

773
I

1961

1962

Me
H
>250

Chemistry 978
Chemistry 979

774
I

1963

1964

Me
H
[481]

Chemistry 983
Chemistry 984

776
I

1965

1966

Me
H
[545]

Chemistry 988
Chemistry 989

776
I

1967

1968

Me
H
[476]

Chemistry 993
Chemistry 994

777
I

1969

1970

Me
H
[484]

Chemistry 998
Chemistry 999

778
I

1971

1972

Me
H
[588]

Chemistry 1003
Chemistry 1004

779
I

1973

1974

Me
H
[560]

Chemistry 1008
Chemistry 1009

780
I

1975

1976

Me
H
[547]

Chemistry 1013
Chemistry 1014

781
I

1977

1978

Me
H
[591]

Chemistry 1018
Chemistry 1019

782
I

1979

1980

Me
H
[580]

Chemistry 1023
Chemistry 1024

783
I

1981

1982

Me
H
[546]

Chemistry 1028
Chemistry 1029

784
I

1983

1984

Me
H
[574]

Chemistry 1033
Chemistry 1034

785
I

1985

1986

Me
H
[614, 616, 618]

Chemistry 1038
Chemistry 1039

786
I

1987

1988

Me
H
[564]

Chemistry 1043
Chemistry 1044

787
I

1989

1990

Me
H
[548]

Chemistry 1048
Chemistry 1049

788
I

1991

1992

Me
H
[552]

Chemistry 1053
Chemistry 1054

789
I

1993

1994

Me
H
[560]

Chemistry 1058
Chemistry 1059

790
I

1995

1996

Me
H
[586]

Chemistry 1063
Chemistry 1064

791
I

1997

1998

Me
H
[530, 532]

Chemistry 1068
Chemistry 1069

792
I

1999

2000

Me
H
[604]

Chemistry 1073
Chemistry 1074

793
I

2001

2002

Me
H
[580]

Chemistry 1078
Chemistry 1079

794
I

2003

2004

Me
H
[493]

Chemistry 1083
Chemistry 1084

795
H

2005

2006

Me
H
[260]

Chemistry 1088
CH2OH

796
H

2007

2008

Me
H

Chemistry 1093
CH2Cl

797
H

2009

2010

Me
H
>250

Chemistry 1098
Chemistry 1099

798
I

2011

2012

Me
H
245

Chemistry 1103
Chemistry 1104

799
I

2013

2014

Me
H
>250

Chemistry 1108
Chemistry 1109

800
I

2015

2016

Me
H
232

Chemistry 1113
Chemistry 1114

801
I

2017

2018

Me
H
224

Chemistry 1118
Chemistry 1119

802
I

2019

2020

Me
H
184

Chemistry 1123
Chemistry 1124

803
I

2021

2022

me
H
>250

Chemistry 1128
Chemistry 1129

804
I

2023

2024

Me
H
>250

Chemistry 1133
Chemistry 1134

805
I

2025

2026

Me
H
>250

Chemistry 1138
Chemistry 1139

806
I

2027

2028

Me
H
>250

Chemistry 1143
Chemistry 1144

807
I

2029

2030

Me
H
250

Chemistry 1148
Chemistry 1149

808
I

2031

2032

Me
H
198

Chemistry 1153
Chemistry 1154

809
NO2

2033

2034

Me
H
[363]

Chemistry 1158
CO2Et

810
NH2

2035

2036

Me
H
[317]

Chemistry 1163
CO2Et

811
NMe2

2037

2038

Me
H
[361]

Chemistry 1168
CO2Et

812
NMe2

2039

2040

Me
H
146

Chemistry 1173
CH2OH

813
NMe2

2041

2042

Me
H
[337]

Chemistry 1178
CH2Cl

814
NMe2

2043

2044

Me
H
178

Chemistry 1183
Chemistry 1184

815
NMe2

2045

2046

Me
H
168

Chemistry 1188
Chemistry 1189

816
I

2047

2048

Me
H
[493]

Chemistry 1193
Chemistry 1194

817
I

2049

2050

Me
H
[493]

Chemistry 1198
Chemistry 1199

818
I

2051

2052

Me
H
>250

Chemistry 1203
Chemistry 1204

819
I

2053

2054

Me
H
>250

Chemistry 1208
Chemistry 1209

820
I

2055

2056

Me
H
[509]

Chemistry 1213
Chemistry 1214

821
I

2057

2058

Me
H
>250

Chemistry 1218
Chemistry 1219

822
I

2059

2060

Me
H
>250

Chemistry 1223
Chemistry 1224

823
I

2061

2062

Me
H
>250

Chemistry 1228
Chemistry 1229

824
I

2063

2064

Me
H
>250

Chemistry 1233
Chemistry 1234

825
I

2065

2066

Me
H
>250

Chemistry 1238
Chemistry 1239

[0290] A rapid, sensitive and automated assay procedure was used for the in vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, (1985), 36, 445-451) to be highly susceptible to and permissive for HIV infection, served as the target cell line. Inhibition of the HIV-induced cytopathic effect was used as the end point. The viability of both HIV- and mock-infected cells was assessed spectrophotometrically via the in situ reduction of 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT). The 50% cytotoxic concentration (CC50 in μM) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells was calculated by the following formula:

\frac{{({OD}_{T})}_{HIV} - {({OD}_{C})}_{HIV}}{{({OD}_{C})}_{MOCK} - {({OD}_{C})}_{HIV}}

[0291] expressed in %,

[0292] whereby (ODT)HIV is the optical density measured with a given concentration of the test compound in HIV-infected cells; (ODC)HIV is the optical density measured for the control untreated HIV-infected cells; (ODC)MOCK is the optical density measured for the control untreated mock-infected cells; all optical density values were determined at 540 nm. The dose achieving 50% protection according to the above formula was defined as the 50% inhibitory concentration (IC50 in μM). The ratio of CC50 to IC50 was defined as the selectivity index (SI). The compounds of formula (I) were shown to inhibit HIV-1 effectively. Particular IC50, CC50 and SI values are listed in Table 2 hereinbelow.

7TABLE 2N°IC50(μm)cSIcCC50(μm)2420,0006>158489>1002550,0006>15849>106840,0008>125893>100430,001010000102640,0010>10000>104700,001012589134830,0010>100000>1005510,001012589131240,0013>7943>102490,0013>25119>322980,0013>7943>103260,00137943103750,0013>79433>1005890,0013>7943>106060,001315849201330,0016>6310>102410,0016>63096>1002530,0016>6310>103060,0016>19953>323280,0016>63096>1003700,0016>63096>1006620,0016>63096>1004260,00163981163460,0020>50119>1001050,0020>5012>102340,00205012102540,0020>15849>322560,0020>5012>102720,002012589252840,0020>5012>102960,002012589253190,0020>50119>1005740,0020>50119>1006180,002025119506500,0020>50119>100830,002531628880,0025>39811>1001080,002519953501090,002512589321150,0025316282770,0025>39811>1002860,0025>12589>322990,00253207130,0025>39811>100450,0032>31623>100850,0032>31623>100860,0032>31623>1002310,00323162104090,003212589402440,0040>25119>1002970,0040>7943>322500,00505012252570,0050>6310>323070,0050>6310>323240,0050631032810,0063199513920,0063>5012>321400,0063>1585>101430,0063>1585>102170,0063>1585>102210,0063>3162>202300,0063125982320,0063>5012>322450,0063>15849>1003090,00631585103210,0063>15849>1003220,0063>15849>1005470,0063>15849>100310,0079>12589>1002180,0079>1259>102220,007925127000,0079>1000>83140,0079>3981>327010,010063106380,0100>10000>100990,0100>10000>1001210,0100>10000>1002190,0100>3162>322330,0100>1000>106940,010039811632800,01002512256960,0158>2512>40

Pyridinone and pyridinethione derivatives having hiv inhibiting properties

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

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Claims

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