MXPA00009435A - Hiv inhibiting pyrimidine derivatives - Google Patents

Abstract

This invention concerns the use of the compounds of formula (I), the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein A is CH, CR4 or N;n is 0 to 4;Q is hydrogen or -NR1R2;R1 and R2 are selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)- amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each C1-12alkyl may optionally be substituted;or R1 and R2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene;R3 is hydrogen, aryl, C1-6alkylcarbonyl, optionally substituted C1-6alkyl, C1-6alkyloxycarbonyl;and R4 is hydroxy, halo, optionally subsituted C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy;R5 is hydrogen or C1-4alkyl;L is optionally substituted C1-10alkyl, C3-10alkenyl, C3-10alkynyl, C3-7cycloalkyl;or L is -X1R6 or -X2-Alk-R7 wherein R6 and R7 are optionally substituted phenyl;X1 and X2 are -NR3-, -NH-NH-, -N=N-, -O-, -S-, -S(=O)- or -S(=O)2-;Alk is C1-4alkanediyl;aryl is optionally substituted phenyl;Het is an optionally substituted aliphatic or aromatic heterocyclic radical;for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. It further relates to new compounds being a subgroup of the compounds offormula (I), their preparation and compositions comprising them.

Description

DERIVATIVES OF P1RLMIDINA HIV INFLUENZA The present invention relates to pyrimidine derivatives having replication inhibitory properties of HIV. The invention also relates to methods for their preparation and to pharmaceutical compositions containing them. The invention further relates to the use of said compounds for the manufacture of a medicament that is useful for the treatment of subjects suffering from infections caused by HIV (Human Immunodeficiency Virus). Compounds structurally related to the present compounds have been described in the prior art. Japanese patents JP-2,052,360, JP-2,308,248, JP-9,080,676 and JP-9,068,784 describe a variety of trisubstituted pyrimidines which are useful as photographic material. JP-8,199,163 discloses trisubstituted pyrimidines which are useful in an organic electroluminescent device. Japanese Patent JP-2,300,264 and British GB 1, 477,349 disclose pyrimidintriamines which are used in the dye industry. J. Indian Chem. Soc. (1975), 52 (8), 774-775 describes the synthesis of certain bis (arylamino) pyrimidines. J. Heterocycl. Chem. (1973), 10 (2), 167-171 describes the condensation of several aminopyridines with picric halides. J. Org. Chem. (1961), 26, 4433-4440 describes various triaminopyrimidines as intermediates in the synthesis of triazolo [4,5-d] pyrimidines.

WO 91/18887 describes diaminopyrimidines as inhibitors of gastric acid secretion. Unexpectedly, it has now been found that the compounds of formula (I) effectively inhibit replication of the Human Immunodeficiency Virus (HIV) and that they may therefore be useful for the treatment of HIV-infected individuals. The present invention relates to the use of the compounds of formula the N-oxides, pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein A is CH, CR4, or N; n is 0, 1, 3, or 4; Q is hydrogen or -NR1R2; R1 and R2 are each independently selected from hydrogen, hydroxy, C? -? 2 alkyl, C? -? 2 alkyloxy, C? -? 2 alkylcarbonyl, C? -? 2 alkyloxycarbonyl, aryl, amino, mono- or di ( C? -? 2) amino, mono- or di (C? -? 2 alkyl) aminocarbonyl alkyl wherein each of the C? -? 2 alkyl groups > the aforementioned can optionally be and each independently substituted with one or two substituents each independently selected from hydroxy, C?-C alquilo alkyloxy, C hidro-hydroxyalkyloxy. 6, carboxyl, C?-C alquilo alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di (C!-C a-amino) amino, aryl and Het; or R 1 and R 2 taken together can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C 1. 2 a) alkyl aminoidene C 1 -C 4; R 3 is hydrogen, aryl, alkylcarbonyl d-6, C 1-6 alkyl) C 1-6 alkyloxycarbonyl, C 1-6 alkyl substituted with C 1-6 alkyloxycarbonyl; and each R4 independently is hydroxy, halo, C? -6 alkyl, C-i-β alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy or C? -6 alkyl, substituted with cyano or aminocarbonyl; R5 is hydrogen or C- alkyl; L is C? -? Or C, C3-10 alkenyl, C3.10 alkynyl, C3-7 cycloalkyl, or C? -? Alkyl or substituted with one or two substituents independently selected from C3-7 cycloalkyl, indanyl, indolyl and phenyl , wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or when possible five substituents each independently selected from halo, hydroxy, C? -6 alkyl, C? _6 alkyloxy, cyano, aminocarbonyl, alkyloxycarbonyl C1-6, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and Ct-β alkylcarbonyl, or L is -X1-R6 or -X2-Alc-R7 where R6 and R7 are each independently phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C? -6 alkyloxy, C? -6 alkylcarbonyl, C? -6 alkanoxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy and trihalomethyl; and X1 and X2 are each independently -NR3-, -NH-NH-, N = N, -O-, -S-, -S (= 0) - or -S (= 0) 2-; Ale, is Ci-alkyldiyl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, d-β alkyl, C?-6 alkyloxy, cyano, nitro and trifluoromethyl; Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radicals may be optionally substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radicals may be optionally substituted with hydroxy; for the manufacture of a medicament for the treatment of subjects suffering an infection caused by HIV (Human Immunodeficiency Virus). The present invention also relates to a method for treating warm-blooded animals suffering from an infection caused by HIV (Human Immunodeficiency Virus). Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or any subgroup thereof, a? / -oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a carrier pharmacist. The invention also relates to compounds of formula to the / V-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein, L, Q, R3, R4, R 5 and A are as defined under formula (I), and R 4 'is halo, C 1-6 alkyl, cyano, aminocarbonyl, nitro, trihalomethyl, trihalomethyloxy or C 1-6 alkyl, substituted with cyano or aminocarbonyl; n 'is 0, 1, 2 6 3; with the proviso that Q and L are different from anilino, 2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino, 3,4-dimethoxy-anilino, 3-chloro-4-fluoro -anilino, 4-cyano-anilino, 2- (C6-alkyl) -anilino, 4- (C6-6) -anlino, 3-chloroanilino, 4-bromo-anilino, 4-nitro -anilino and 4-chloroanilino. In the form in which it is used in the foregoing definitions and then, halo defines fluorine, chlorine, bromine, and iodine: C 1-4 alkyl, as a group or part of a group embraces straight and branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl and the like; Ci-β alkyl as a group or part of a group embraces straight and branched chain saturated hydrocarbon radicals defined in C 1-4 alkyl as well as higher homologs thereof containing 5 to 6 carbon atoms, such as for example , pentyl or hexyl; C-MO alkyl as a group or part of a group embraces the straight and branched chain saturated hydrocarbon radicals as defined in C? -6 alkyl as well as also the higher homologues thereof containing 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl or dodecyl; C? -12 alkyl as a group or part of a group comprises the straight and branched chain saturated hydrocarbon radicals as defined in C-MO alkyl as well as also the higher homologs thereof containing 11 or 12 carbon atoms such as , for example, undecyl, dodecyl and the like; alkylidene C? _4 as a group or part of a group defines bivalent straight and branched chain hydrocarbons having from 1 to 4 carbon atoms such as, for example, methylene, ethylidene, propylidene, butylidene and the like; C 1-4 alkanediyl as a group or part of a group encompasses those radicals defined under C 1 -C 4 alkylidene as well as other straight and branched chain bivalent hydrocarbons having from 1 to 4 carbon atoms such as, for example, 1 , 2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, and the like; C3-7 cycloalkyl as a group or part of a group is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C3.10 alkenyl as a group or part of a group defines straight and branched chain hydrocarbon radicals containing a double bond having from 3 to 10 carbon atoms, such as, for example, 2-propenyl, 2-butenyl, 2 -pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atom attached to the pyrimidine ring is preferably an aliphatic carbon atom; C3-? alkynyl or as a group or part of a group defines straight and branched chain hydrocarbon radicals containing a triple bond and having from 3 to 10 carbon atoms, such as, for example, 2-propynyl, 2-butynyl , 2-pentinium, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 3-heptynyl, 2-octynyl, 2-noninyl, 2-decynyl and the like, whereby the carbon atom attached to the pyrimidine ring it is preferably an aliphatic carbon atom. It is necessary to understand that the three substituents [L, Q and NR3 (phenyl or optionally substituted pyridyl)] in the pyrimidine ring can be in any free position of the pyrimidine ring. Therefore, given the following pyrimidine ring numbering the three substituents may be connected to the pyrimidine ring in three different forms: 2-L, 4-Q, 6-NR3 (optionally substituted phenyl or pyridyl); or 4-L ', 2-Q, 6-NR3 (optionally substituted phenyl or pyridyl); or 6-L, 4-Q, 2-NR3 (optionally substituted phenyl or pyridyl). The positions 4 and 6 are equivalent to each other. For example, the substitution pattern 6-L, 4-Q, 2-NR3 (optionally substituted phenyl or pyridyl) which is the preferred substitution pattern, is equivalent to the substitution pattern 4-L, 6-Q, 2-NR3 (phenyl or optionally substituted pyridyl). Said subgroup of compounds is represented by the formula An interesting group of compounds consists of the compounds of formula Particularly interesting are those compounds of formula (P-1) in which L and Q are different from anilino, 2,4,6-trinitro-anilino, 4- (C 6 -alkyl) -anilino, 4-bromo -anilino, 4-nitroanilino and 4-chloroanilino; and those compounds of the formula (I-1) in which R 4 'is cyano, aminocarbonyl or C 1-6 alkyl substituted with cyano or aminocarbonyl are even more particularly interesting.

The addition salts mentioned herein comprise the therapeutically active addition salt forms which the compounds of the present invention are capable of forming with the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric acids; nitric; phosphoric and similar acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, amino-salicylic, pamoic and similar acids. The pharmaceutically acceptable addition salts mentioned above also comprise the non-toxic therapeutically active base, in particular, the metal or amine addition salt forms which the compounds of the present invention are capable of forming. Said salts can be conveniently obtained by treating the compounds of the present invention containing acidic hydrogen atoms with the appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali metal and the alkaline earth metal salts, for example. the salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example benzathine,? / - methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and Similar. Conversely, said salt forms can be converted by treatment with an appropriate base or acid, to the free acid or base form. The term "addition salts" also encompasses the hydrates and solvent addition forms that the compounds of the present invention are capable of forming. Examples of such forms are for example hydrates, alcoholates and the like. The term "stereochemically isomeric forms" of compounds of the present invention, as used above, defines all possible compounds constituted by the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, than the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that said compound may possess. Said mixture can contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form and in admixture with one another are encompassed within the scope of the present invention. Some of the compounds of the present invention may also exist in their tautomeric forms. Said forms, although not explicitly indicated in the preceding formula, are considered to be included within the scope of the present invention.

Whenever the term "compounds of the present invention" is used below, it is meant that it includes the compounds of formula (I), (l-1) > ('') > (l'-1) ° any subgroup thereof, also N-oxides, pharmaceutically acceptable addition salts and all stereoisomeric forms. Interestingly, the group containing those compounds of the present invention in which Q is NR1R2, each R4 independently is hydroxy, halo, Ci-β alkyl, C-i-β cyanoxy, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; L is C-MO alkyl, C3-10 alkenyl, C3-10 alkynyl C3-7 cycloalkyl or C-MO alkyl substituted with one or two substituents independently selected from C3-7 cycloalkyl, indolyl or indolyl substituted with one, two, three, or four substituents each independently selected from halo, C?-6 alkyl, Ci-β alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy and d-β alkylcarbonyl, phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C? -6 alkyl, C? -6 alkanoxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy and C? _6 alkylcarbonyl; or L is -X1-Rd where R6 is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C6_6 alkyl, 1-6 alkyloxy, C1-6 alkylcarbonyl, cyano, nitro and trifluoromethyl; Also interesting is the group containing those compounds of the present invention in which Q is NR1R2; each R 4 independently is hydroxy, halo, C 1-6 alkyl, C 1-6 alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; L is d.io alkyl, substituted with one or two substituents independently selected from phenyl, or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, alkyl-e, alkyloxy d-6 , cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy and C 1-6 alkylcarbonyl; or L is -X1-R6 where R6 is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C? -6 alkyl, alkyloxy d-6, alkylcarbonyl d-β, cyano, nitro and trifluoromethyl; with the proviso that the compounds (a)? 2-hydroxy -? / 2-methyl-? / 4, /? 6-diphenyl-2,4,6-pyrimidn-triamine; (b)? /,? /,? / *,? / ",? /" - hexakis (3-methylphenyl) -2,4,6-pyrimidinetriamine; (c) 4-methyl-? / 2- (2-methylphenyl) -? 4-phenyl-2,4,6-pyrimidinediamine; (d) A / 4-methyl- / V2- (2-methylphenyl) -? / 4-phenyl-6- (phenylmethyl) -2,4-pyrimidinediamine; (e)? / 4- (2-methylphenyl) -6- (phenylmethyl) -2,4-pyrimidinamine; (f)? /, A / ', / V "-tr¡s (4-methoxyphenyl) -2,4,6-pyrimidintriamina; (g) A /,? /' - b / s (4) -hexyphenyl) -6- (4-methoxyphenoxy) -2,4-pyrimidinediamine; (h)? 2,? 4-bis (4-hexylphenyl) -? and 6,? / 6-dimethyl-2,4,6 pyrimidinetriamine; (i) A /,? / *,? / "- tris (4-hexyllfl) -2,4,6-pyridintriamine; G)? / 2,? / 2-dimethy1-? / 4, / \ / 6-b1s (4-methylphenyl) -2,4,6-pyridimintriamine; (k) A /, / V ',? / "- tris (4-methoxyphenyl) -2,4,6-pyrimidintramine; (I) N, N', / V" -tr¡phenyl-2 , 4,6-pyrimidintriamamine; (m)? /,?,? / ',? /',? / ",? /" - hexakis (4-ethoxyphenyl) -2,4,6-pyrimidinetriamine; (n)? / 4,? / 6-bys (2-chlorophenyl) -2,4,6-pyrimidinetriamine; (o)? / 4,? / 6-bys (3-chlorophenyl) -2,4,6-pyrimidntriamine; (p)? 4,? / 6-bis (2-ethoxyphenyl) -2,4,6-pyridintrimamine; (q)? / 4, A / 6-b1s (2-ethoxy-phenyl) -2,4,6-pyrimidintriamine; (r)? 4 ,? 6-bis (2-methylphenyl) -2,4,6-pyrimidinetriamine; (s)? / 4,? / 6-bis (4-bromophenyl) -2,4,6-pyrimidinetriamine; (t)? 4,? / 6-bis (4-methylphenyl) -2,4,6-pyrimidinetriamine; (u) A / 2,? / 4-bis (4-methoxyphenyl) -2,4,6-pyrimidinetriamine; (v)? / 2,? 4-bis (4-methylphenyl) -2,4,6-pyrimidinetriamine; (w)? /,? / ',? / "- tr¡s (2,4,6, -trinitrofen¡l) -p¡r¡m¡d¡ntriam¡na; (x)? / 4 ,? 6-bis (4-chlorophenyl) -2,4,6-pyrimidimethylene; (y)? 4, A / 6-bis (4-methoxy-phenyl) -2,4,6-pyrimidinetriamine; z) N2, N4, / V6-trimethyl-? / 2,? / 4,? / 6-triphenyl pyrimidine-2,4,6-triyltriamine; (aa) A / 4, / V4-dimethylal? 2,? / 6-di-p-tolyl-pyrimide-2,4,6-trithyrimamine, and (bb)? / 2,? / 4-diphenyl-pyrimidine2,4,6 -tri¡lt¡amina are not included.

Conveniently, Q can also be hydrogen in the preceding two groups of interest. A special group of compounds consists of those compounds of formula (I) or (I ') in which n is at least 1 and at least one R 4 is cyano; preferably, n is 1 and R 4 is cyano substituted in para position in relation to the NR 3 portion. Another special group of compounds contains those compounds of formula (I) or (I ') which are other than (c)? / 4-methylene-2 / 2- (2-methylphenyl) -? / 4-phen L-2,4,6-pyrimidntramine; (d)? / 4-methyl-? / 2- (2-methylphenyl) -? / 4-phenyl-6- (phenylmethyl) -2,4-pyrimidinediamine; e)? / 4- (2-methylphenyl) -6- (phenylmethyl) 2,4-pyrimidinediamine; the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof. An interesting group of compounds are those compounds of the present invention in which the portion NR3 (phenyl or substituted pyridyl) is in position 4 or 6 of the pyrimidine ring. Another interesting group consists of those compounds of the present invention in which each R 4 is independently hydroxy, halo, Ci-β alkyloxy, cyano aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; R6 is phenyl or phenyl substituted with one, two, or three, four or five substituents each independently selected from halo, C6_6alkyloxy, C6_6alkylcarbonyl, cyano, nitro and trifluoromethyl; and aryl is phenyl substituted with one, two, three, four or five substituents each independently selected from halo, alkyloxy, C6-6, cyano, nitro and trifluoromethyl. Conveniently, Q is -NR1R2; where R1 is hydrogen, hydroxy, C? -? 2 alkyl, C1-12 alkyloxy, alkylcarbonyl d-? 2? C 1. 2 alkyloxycarbonyl, aryl, amino, mono- or di (C 1 a 2) amino, mono- or di (d 2 alkyl) aminocarbonyl; and R2 is hydroxy, C? -12 alkyl, C1.12 alkyloxy, C-? 12 alkylcarbonyl; C 1 -12 alkyloxycarbonyl, aryl, amino, mono- or di (mono- or di (d 2 alkyl) aminocarbonyl alkyl, wherein each of the aforementioned C 1, β 2 alkyl groups may optionally be and each independently substituted with one or two substituents each independently selected from hydroxy, alkyloxy d-6, hydroxyalkyloxy d) carboxyl, alkyloxycarbonyl d-6, cyano, amino, phenyl, aminocarbonyl, aminocarbonylamino, mono- or di (alkyl d- 6) amino, aryl and Het; or R 1 and R 2 taken together can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C 1. 2 alkyl) amino C 1-4 alkylidene Conveniently, L is C 0 alkyl, substituted with one or two independently selected substituents of C3-7 cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or when possible five substituents each independently selected from halo, hydroxy, C1-6alkyl, C 1-6 alkyloxy, cyano, aminocarbonyl, alkyloxycarbonyl d-β, formyl, nitro, arrimo, trihalomethyl, trihalomethyloxy and alkylcarbonyl d-6; or L is -X1-R6 or -X2-Alc-R7 and when X1 is NR3, then R6 is phenyl substituted with one, two, three, four or five substituents each independently selected from C?-6alkyloxycarbonyl, formyl , nitro and trihalomethyloxy. Conveniently R 4 or R 4 'is nitro, trihalomethyloxy or C 1-6 alkyl substituted with cyano or aminocarbonyl. Conveniently, R6 is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, alkyl d.6, alkyloxy d-β, alkyloxycarbonyl d-6, formyl, cyano, aminocarbonyl , nitro, amino, trihalomethyloxy and trihalomethyl. Conveniently, both Q and R5 are hydrogen. Conveniently, L is C 1-10 alkyl, substituted with one or two substituents independently selected from C 3-7 cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or when possible five substituents each independently selected from halo, hydroxy, d-6 alkyl, d-6alkyloxy, cyano, aminocarbonyl, C 1-6 alkyloxycarbonyl, formyl, nitro, amino trihalomethyl, trihalomethyloxy, and C? -6 alkylcarbonyl; or L is -X1-R6 or X2-Alc-R7; and R5 is hydrogen. The groups of compounds in which one or more of the following conditions are given are very particular: (i) n is 0, 1, or 3; (ii) Q is hydrogen; (iii) Q is NR1R2 where R1 and R2 are each independently selected from hydrogen, hydroxy, C? -? 2 alkyl, C1.12 alkyloxy, C1-12 alkylcarbonyl, C1.12 alkyloxycarbonyl, cyano where C1-12 alkyl groups mentioned above may optionally be and each individually substituted with one or two substituents each independently selected from hydroxy, cyano, C 1-6 alkyloxy, hydroxyalkyloxy d 6, aryl and Het; or R 1 and R 2 taken together can form mono- or di (C 1 -C 2 alkyl) amino C 1 -4 alkylidene; (iv) R3 is hydrogen or C6-alkyl; (v) R 4 is cyano, aminocarbonyl, amino, nitro, hydroxy, halo, C 1-6 alkyl, or cyanoalkyl d-β; (vi) R4 is cyano, aminocarbonyl, halo, alkyl d-6, or cyano alkyl d-6, (vii) R5 is hydrogen or methyl; (viii) L is d.io alkyl, substituted with phenyl substituted with one or two halogens; or L is -X1-R6 where R6 is phenyl substituted with one, two or three substituents selected from C? -6 alkyl, trifluoromethyl, trifluoromethoxy, cyano and halogen, and X1 is -S-, -O- or -NR3-; or L is -X2-Alc-R7 wherein R7 is phenyl substituted with one, two or three substituents selected from C6-cyano and halogen alkyl and X2 is NH. Other particular compounds are those compounds of the present invention in which L contains phenyl, 2,6-disubstituted phenyl, 2,4,6-trisubstituted phenyl, or 2,3,4,5-tetrasubstituted phenyl; especially, L contains phenyl, 2,4,6-trihalo-phenyl, 2,4,6-tri-alkyl d-4-phenyl, 2,3,4,5-tetrahalo-phenyl, 2,4-dihalo-6 -alkyl C? -4 phenyl, 2,6-dihalo-4-alkyl C ^ phenyl, 2,6-dihalo-4-cyano-phenyl, 2,6-dihalo-4-trifluoromethoxy-phenyl, 2,6-dihalo -4-trifluoromethyl-phenol, 2,6-di-C-4-halo-phenyl-alkyl, 2,6-dialkyl Ci-cyano-phenyl, 2,6-dihalo-phenyl or 2,6-dialkyl d -4-phenyl; more preferably, L contains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro -phenyl, 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1 -yl-phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, , 6-dimethyl-4- (1,1-dimethylethyl) -phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluor phenyl, 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, or 4-cyano-2,6-dimethyl-phenyl. More particular compounds are the compounds of the present invention in which L is 2,6-dichlorobenzyl, or L is -X 1 -R 6 where X 1 is -NR 3 -, -S- or -O- and R 6 is 2,4,6 -trichlorophenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl , 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano -phenyl, 2,6-dichloro-4-trifluoromethoxy-phenol, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4- (1, 1- dimethylethyl) phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl- phenyl, 4-chloro-2,6-dimethyl-phenyl, 4-cyano-2,6-dimethyl-phenyl; or L is -X2-Alc-R7 wherein -X2-Alc is -NH-CH2- and R7 is phenyl. Other particular compounds are those compounds of formula (I) in which R3 is hydrogen, A is CH, n is 1, and R4 is halo, methyl or cyano and is located at the 4-position of the phenyl ring. Preferred compounds are those compounds of the present invention in which L is 2,6-dichlorobenzyl and the NR 3 portion (phenyl or optionally substituted pyridyl) represents p-cyano-anilino and is in the 2-position of the pyrimidine ring. Other preferred compounds are those compounds of the present invention in which Q is hydrogen, L is -X1-R6 where X1 is -NH- and R6 is 2,4,6-trimethyl-phenyl or 4-cyano-2,6- dimethylphenyl, the NR3 portion (phenyl or optionally substituted pyridyl) represents p-cyano-anilino and is in the 2-position of the pyrimidine ring. Other preferred compounds are those compounds of the present invention in which L is -X2-Alc-R7 where X2 is -NH-, Ale is methylene and R7 is phenyl, 2,6-dichlorophenyl, 2,4,6-trimethyl- phenyl or 4-cyano-2,6-dimethylphenyl. More preferred are compounds of formula (1"-1) in which R4 is halo, cyano, aminocarbonyl or cyano C? -6 alkyl?; n is zero, A is CH, R3 is hydrogen; R5 is hydrogen or methyl; Q is hydrogen or NHR1; and L contains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl , 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl -phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6 -dimethyl-4- (1,1-dimethylethyl) -phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl , 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, or 4-cyano-2,6-dimethyl-phenyl. Even more preferred are 4 - [[4-amino-6 - [(2,6-dichlorophenol) methyl] -2-pyrimidinyl] amino] benzonitrile; 6 - [(2,6-dichlorophenyl) methyl] -? 2- (4-fluorophenyl) -2,4-pyrimidinediamine; 4 - [[4 - [(2,4-dichlorophenyl) methyl] -6 - [(4-hydroxybutyl) amino] -2-pyrimidinyljaminojbenzonitrile; 4 - [[4- [2,6-dichlorophenyl) methyl] -6 - [(3-hydroxypropyl) amino] -2-pyrimidinyl] amino] benzonitrile; ? / - [2 - [(4-cyanophenyl) amino] -6 - [(2,6-dichlorophenyl) methyl] -4-pyrimidinyl] -acetamide; ? / - [2 - [(4-cyanophenyl) amino] -6 - [(2,6-dichlorophenol) methyl] -4-pyrimidinyl] -butanamide; 4 - [[2-amino-6- (2,6-dichlorophenoxy) -4-pyridyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [(2-hydroxy-2-phenylethyl) amino] -2-pyrimidinyl]] amino] benzon thresh 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [[3- (2-oxo-1-pyrrolidinyl) propyl] amino] -2-pyridomethyl] amino ] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [[2- (2-hydroxyethoxy) -ethyl] amino] -2-pyramidyl] amino] benzonyl monohydrochloride thresh 4 - [[4 - [(2,6-dichlorophenol) methyl] -6 - [(2,3-dihydroxypropyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4- (2,6-dichlorophenyl) methyl] -6- (hydroxyamino) -2-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [(2-cyanoethyl) amino] -6 - [(2,6-dichlorophenyl) methyl] -2-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [[2- (1-pyrrolidinyl) etl] amino] -2-pyrimidinylj-aminojbenzonitrile; 4 - [[4-amino-6 - [(2,6-dichlorophenyl) methyl] -5-methyl-2-pyrimidinyl] -aminojbenzonitrile; ? / 2- (4-bromophenyl) -6 - [(2,6-dichlorophenyl) methyl] -5-methyl-2,4-pyrimidindiamine; 4 - [[4 - [(2,4,6-Tr.methyl) phenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[2 - [(2,4,6-trimethylphenyl] amino] -4-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dimethyphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4- (2,4,6-trimethylphenoxy) -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) th]] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [[2,6-d, bromo-4- (1-methylethyl) phenyl] amino] -2-pyrimidinyl] amino] -benzonitrile; 4 - [[4 - [[2,6-d.chloro-4- (trifluoromethyl) phenyl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4-dichloro-6-methylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[2 - [(cyanophenol) amino] -4-pyrimidinyl] amino] -3,5-dimethylbenzonitrile; 4 - [[4 - [(2,4-dibromo-6-fluorophenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4-amino-6 - [(2,6-dichlorophenyl) methyl] -5-methyl-2-pyrimidinyl] amino] benzoacetonitrile; 4 - [[4- [methyl (2,4,6-trimethylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trichlorophenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trimethylphenyl) thio] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trimethylphenyl) amino-2-pyrimidinyl] amino] benzonitrile; 4 - [[4-amino-6 - [(2,4,6-trimethylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[2-amino-6 - [(2,4,6-trimethylphenyl) amino] -4-pyrimidinyl] amino] benzonitrile; 4 - [[4- (2-bromo-4-chloro-6-methylphenoxy) -2-pyrimidinyl] amino] benzonitrile; 4 - [[4- (4-chloro-2,6-dimethylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 3,5-dichloro-4 - [[2 - [(4-cyanophenyl) amino] -4-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [[2,6-dichloro-4- (trifluoromethoxy) phenyl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4-dibromo-3,6-dichlorophenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dibromo-4-propylphenyl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trimethylphenyl) amino] ] -2-pyrimidinyl] amino] benzamide; 4 - [[4 - [(4- (1,1-dimethylethyl) -2,6-dimethylphenyl] amino] -2-pyrim Dinyl] -aminojbenzonitrile; 4 - [[2 - [(4-cyanophenyl) amino] -4-pyrimidinyl] oxy] -3,5-dimethylbenzontrile; 4 - [[4 - [(4-chloro- 2,6-dimethylphenyl) amino] -5-methyl-2-pyrimidinyl] amino] benzonitrile; 4 - [[2 - [(4-cyanophenyl) amino] -5-methyl-4-pyrimidinyl] amino- 3,5-dimethylbenzonitrile; 44 - [[4 - [[4- (1, 1-dimethylethyl) -2,6-dimethylphenyl] amino] -5-methyl-2-pyrimidinyl] amino] benzonitrile; - [[4 - [(4-bromo-2,6-dimethylphenyl) amino] -5-methyl-2-pyrimidinyl] amino] benzonitrile; 4 - [[5-methylene] 4 - [(2,4,6-Trimethylphenyl) thio] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dibromo-4-propylphenyl) amino] ] -5-methyl-2-pyrimidol] amino] benzonitrile N3-oxide of 4 - [[4- (2,4,6-trimethylene] amino] -2-pyrimidinyl ] amino] benzamide;? / 2- (4-chlorophenyl) -N4- (2,4,6-trimethylphenyl) -2,4-pyrimidinediamine; 4 - [[4 - [[2,6-dib] rom-4- (1-methylethyl) phenyl] amino] -5-methyl-2-pyrimidinyl] amino] benzonitrile; 4 - [[2 - [(4-cyanophenyl) amino] -5-methyl-4-pyrimidinyl] amino] -3,5-dimethylbenzonitrile; 4 - [[4 - [(phenylmethyl) amino] -2-pyrimidinyl] amino] benzonitrile; the? / - oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof. The compounds of formula (I) can be prepared according to procedures known in the art. In particular, the compounds of formula (I ') can be prepared generally by the reaction of an intermediate of formula (IA) wherein W1 is an appropriate leaving group such as, for example, a halogen, with an amine derivative of formula III) optionally in a solvent such as, for example, water, 2-propanol, diethyl ether, 1-methyl-2-pyrrolidinone and the like, and optionally in the presence of an acid, such as, for example, 1 N hydrochloric acid in ether diethyl It may be convenient to carry out the reaction under an atmosphere inert to the reaction such as, for example, nitrogen or oxygen free argon. (ll-A) (III) (0 In this and in the following preparations, the reaction products can be isolated from the reaction medium, and if necessary, can be further purified according to methodologies generally known in the art such as , for example, extraction, crystallization, distillation, trituration and chromatography In a manner analogous to the reaction procedure described above, H-NR1R2 (VI) can also react with an intermediate of formula (11-B).

(II-B) (VI) C) Suitable solvents for the foregoing reaction include, for example, 2-propanol or 1,4-dioxane. In the case where Q is NR1R2 and R2 contains a hydroxy portion, it may be convenient to carry out the foregoing reaction with a form of protected intermediate (VI) by which the hydroxy portion carries the appropriate protecting group P, which is , for example, a benzyl, and subsequently removing the protecting group according to methodologies known in the art, such as, for example, reaction with BBr3 in dichloromethane under nitrogen atmosphere. It is also possible to react H-X1-R6 with an intermediate of formula (ll-C) in an appropriate solvent such as, for example, 1,4-dioxane, thereby obtaining the compounds of formula (I ') in the which L is -X1-R6, said compounds being represented by the formula (l'-C). (ll-C) (r-c) Depending on the nature of X1 an appropriate base or acid may be used to improve the rate of the reaction. For example, in case X1 is -O-, sodium hydride can be used as the appropriate base; or in the case that X1 is NR3, HCl can be used as the appropriate acid. The compounds of formula (I ') can be further prepared by conversion of the compounds of formula (I') to each other according to group transformation reactions known in the art.

For example, the compounds of formula (I ') in which Q is NR1R2 and R1 and R2 are taken together to form mono- or di (alkyl d.i2) aminoalideneide CM, said compounds represented by the formula ( I '-a), can be prepared by reacting a compound of formula (I') wherein R1 and R2 are hydrogen, with an intermediate of formula (IV) or a functional derivative thereof.

(Na) Likewise, the compounds of formula (I ') in which Q in NR1R2 and R1 and R2 are hydrogen can further react with an acyl halide or an alkyl chloroformate in a reaction-inert solvent such as, for example, , dichloromethane, in the presence of an appropriate base such as, for example, pyridine, to form the corresponding amide, respectively, the carbamate derivative. Some of the compounds of the formula (I ') and some of the intermediates in the present invention may contain an asymmetric carbon atom. The stereochemically pure isomeric forms of said compounds and said intermediates can be obtained by the application of methods known in the art. For example, the diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, for example distribution or countercurrent, liquid chromatography and similar methods. The enantiomers can be obtained by racemic mixtures, first converting said racemic mixtures with appropriate resolving agents such as, for example, chiral acids, to mixtures or compounds of diastereomeric salts; then said mixtures of diastereomeric salts or compounds are physically separated by, for example, selective crystallization techniques or chromatographic techniques, for example, liquid chromatography and similar methods; and finally said salts or separated diastereomeric compounds are converted into the corresponding enantiomers. Stereochemically pure isomeric forms can also be obtained from stereochemically pure isomeric forms of the appropriate intermediates and starting materials, with the proviso that intervening reactions occur stereospecifically. An alternative way of separating the enantiomeric forms of the compounds of the formula (I ') and the intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. The preceding reaction processes specified for the preparation of the compounds of the formula (I ') or the subgroups thereof can also be applied for the preparation of the compounds of the formula (I'). Some of the intermediates and starting materials are known compounds and can be commercially obtainable or can be prepared according to procedures known in the art. The intermediates of the formula (I IA) where Q in NR1R2, and which are represented by the formula (ll-A-1), can be prepared by the reaction of a pyrimidine derivative of formula (V) wherein W2 is an appropriate leaving group such as, for example, a halogen, with HNR1R2 (VI) in a reaction-inert solvent such as, for example, 1,4-dioxane, 2-propanol or the like. Different regio-specific isomers can be formed and can be separated from one another using appropriate separation techniques such as, for example, chromatography.

The intermediates of the formula (11-B) can be prepared analogously to the preparation of the compounds of the formula (I ') from the intermediates (ll-A) and (III).

(V) ("(ll-B) A particular subgroup of the intermediates of the formula (ll-B) is represented by the formula The particular intermediates of the formula (ll'-B) are those in which W1 is a halogen, in particular a chlorine atom. The intermediates of formula (V) in which Q is NR1R2 and L is L-CH2 and which are adhered in the 2-position of the pyrimidine ring and W2 is chlorine, said intermediates being represented by the formula (Va), may be prepared by the reaction of an imidamide of formula (VII) with a propanedioic acid ether of formula (VIII) in a solvent such as, for example, ethanol, and in the presence of, for example, sodium and subsequently the intermediate thus formed is reacted of formula (IX) with an appropriate reagent such as, for example, phosphoryl chloride.

V- C (VII) (VIII) (IX) (V-a) The intermediates of formula (V) in which Q is NR1R2 and L is L-CH2 and are attached in the 4 or 6 position of the pyrimidine ring and W2 is chlorine, said intermediates being represented by the formula (Vb), may be prepared by reacting an intermediate of formula (X) with urea or with a functional derivative thereof, in a solvent such as, for example ethanol, and in the presence of, for example, sodium, and subsequently the intermediate thus formed is reacted of formula (XI) with an appropriate reagent such as for example phosphoryl chloride.

L'- C (X) (XD (V-b) The intermediates of the formula (V) wherein Q is NR1R2 and L is L'-CH2 and are attached to any part of the pyrimidine ring, said intermediates being represented by the formula (Vc), can be prepared by the reaction of an intermediate of formula (XII-1), for Q is NR1R2 and formula (XII-2) for Q is hydrogen, where W2 is an appropriate leaving group such as, for example, a halogen, with an intermediate of formula (XIII) where W3 is a appropriate leaving group such as, for example, a halogen, according to the procedure of a Grignard reaction.

The intermediates of formula (V) in which Q is NR1R2 and L is -O-R6 or -NH-R6 and is adhered in the 4 or 6 position of the pyrimidine ring, said intermediate being represented by the formula (Vd), can prepared by the reaction of an intermediate of formula (XIV) with an intermediate of formula (XII) wherein W2 is an appropriate leaving group, such as, for example, a halogen, is a solvent inert to the reaction such as, for example , tetrahydrofuran or 1,4-dioxane, and in the presence of an appropriate base such as, for example, potassium hydroxide or diisopropyl ethanamine, or sodium hydride.

The intermediates of formula (V-a) to (V-d) can be prepared analogously to the compounds of formula (I ') wherein Q is hydrogen. For this purpose, there is a leaving group W2 less in the pyrimidine ring of the respective starting material. The compounds of the formula (I ') and some of the intermediates can have one or more stereogenic centers in their structure, present in an R or S configuration. The compounds of the formula (I') prepared in the previously described processes can be synthesized as mixtures of stereoisomeric forms in particular in racemic mixtures forms of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) can be converted to the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated with alkali. An alternative way of separating the enantiomeric forms of the compounds of the formula (I) involves liquid chromatography using a chiral stationary phase. Said stereochemically pure isomeric forms can also be derived from the corresponding stereochemically pure isomeric forms of the appropriate starting materials, with the proviso that the reaction occurs stereospecifically. Preferably if it is desired to obtain a specific stereoisomer, said compound will be synthesized by stereospecific preparation methods. These methods advantageously employ enantiomerically pure starting materials. The compounds of the present invention and the intermediates of the formula (11'-B) show antiretroviral properties, in particular against the Human Immunodeficiency Virus (HIV), which is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. 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 amount of T-4 cells that decreases permanently, and also behave abnormally. Therefore, the immune defense system is unable to fight infections and neoplasms and the subject infected with HIV usually dies from opportunistic diseases such as pneumonia or cancer. Other conditions that are associated with infection caused by HIV include thrombocytopenia, Kaposi's sarcoma, and central nervous system infection characterized by progressive demyelination, which results in dementia and symptoms such as progressive dysarthria, ataxia, and disorientation. Infection caused by HIV has also been associated with peripheral neuropathies, generalized progressive lymphodenopathies (PGL), and AIDS-related complex (ARC). The present compounds also show activity against strains of HIV-1 having acquired resistance to the non-nucleoside reverse transcriptase inhibitors known in the art. They also have little or no adhesion affinity with the alpha-i-human glycoprotein. Due to the antiretroviral properties, particularly its anti-HIV properties, especially its anti-HIV-1 activity, the compounds of the present invention are useful in the treatment of individuals who have been infected with HIV and for the prophylaxis of these individuals In general, the compounds of the present invention can be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends on, the reverse transcriptase enzyme. Conditions that can be avoided or treated with the compounds of the present invention, especially conditions that are related to HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), generalized progressive lymphodenopathies (PGL), as well as also chronic CNS diseases caused by retroviruses, such as, for example, dementia and multiple sclerosis mediated by HIV. The compounds of the present invention or any subgroup thereof may therefore be used as medicaments against the previously mentioned conditions. Said use as a medicament or method of treatment comprises the systematic administration to individuals infected with HIV, of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1. The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As suitable compositions, all the compositions that are usually used to administer drugs systematically can be cited. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of an addition salt, as an active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier can have a wide variety of forms depending on of the desired preparation form for administration. These pharmaceutical compositions are conveniently administered in unit dosage form particularly for oral administration, rectal, percutaneous or by parenteral injection. For example, to prepare compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be employed in the case of oral liquid preparations, such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous form of oral dosage unit, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to aid in solubility. For example, injectable solutions can be prepared in which the carrier comprises a saline solution, a glucose solution or a mixture of saline and glucose. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like will be employed. Also included are preparations in solid form that are intended to be converted, shortly before use, into liquid form preparations. In which are suitable for percutaneous administration compositions, the carrier optionally comprises an agent to improve penetration and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions additives, which additives do not introduce a significant deleterious effect on the skin . It is especially advantageous to formulate the aforementioned pharmaceutical compositions in a unit dosage form to facilitate administration and uniformity of dosages. A dosage unit 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, seals, injectable solutions or suspensions and the like and segregated multiples thereof. Experts in the treatment of the infection caused by HIV were able to determine the effective daily amount from the test results presented here. In general it has been 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 in the form of two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses can be formulated as unit dosage forms, for example, those containing 1 to 1000 mg and in particular 5 to 200 mg of active ingredient per unit dosage form. The exact dose 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, weight and general physical condition of the patient. particular patient as well as other medication that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount can be decreased or increased depending on the response of the subject being treated and / or the evaluation of the physician prescribing the compounds of the present invention. The ranges of effective daily amounts mentioned above are therefore only guidelines and are in no way intended to limit the scope or use of the invention. Likewise the combination of an antiretroviral compound and a compound of the present invention can be used as a medicament. Therefore, the present invention also relates to a product containing (a) a compound of the present invention and (b) another antiretroviral compound, in the form of a combined preparation for simultaneous, separate or sequential use in an anti-HIV treatment . The different drugs can be combined in a single preparation in conjunction with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors for example zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (dedeoxi inosine; ddl), zalcitabine (dideoxycytidine, ddC) or lamivudine (S'-thia ^ '- S'-dideoxycytidine, 3TC) and the like; non-nucleoside reverse transcriptase inhibitors such as suramin, foscamet-sodium (trisodium phosphonoformate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6 / - / - d-pyro [3] , 2-b: 2 ', 3', - e] [1,4] diazepin-6-one), sustiva (efavirenz), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO type (tetrahydro-imidazo [4,5 1-jk] [1,4] -benzodiazepine-2 (1H) -one and thione) for example (S) -8-chloro-4,5,6,7 -tetrahydro-5-methyl-6- (3-methyl-2-butenyl) imidazo- [4,5,1-jk] [1,4] benzodiazepine-2 (1 / - /) -thione; compound of the type to APA (α-anilino phenyl acetamide) for example a - [(2-nitro-phenyl) amino] -2,6-dichloro-benzene-acetamide and the like; TAT inhibitors, for example RO-5-3335 and the like; protease inhibitors for example indinavir, ritanovir, saquinovir and the like; NMDA receptor inhibitors for example pentamidine; a-glycosidase inhibitors, for example castanospermine and the like; Rnase H inhibitor e.g. dextran (dextran sulfate) and the like; or immunomodulatory agents, for example levamisole, thymopentin and the like. The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART A. Intermediary compounds EXAMPLE A1 a) A solution of 2,6-dichlorobenzyl chloride (0.102 mol) in 1,1-diethyl ether (60 ml) was added dropwise to magnesium (0.102 mol) in 1,1-diethyl ether (60 ml). The reaction was initiated by the addition of two drops of 1,2-dibromoethane. After most of the magnesium disappeared, 2,4,6-trichloropyrimidine (0.051 mol) was added in 1,1-diethyl ether (30 ml). The mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by evaporative column chromatography on silica gel (eluent: CH2Cl2 / hexane 1/2). The desired fractions were collected and the solvent was evaporated, yielding 3.3 g of (21%) 2,4-dichloro-6 - [(2,6-dichlorophenyl) methyl] pyrimidine (intermediate 1; mp 106-107 ° C ). b) The intermediate (1) (0.0081 mol) in 2-propanol (100 ml) was heated until complete dissolution. Then the solution was transferred to a pressure tube, and NH3 gas was bubbled therein, for 20 minutes. The mixture was then heated at 80 ° C for 16 hours. The solvent was evaporated, obtaining a residue of two compounds: 2-chloro-6 - [(2,6-di-chloro-phenyl) methyl] -4-pyrimidinamine (intermediate 2) and 4-chloro-6 - [(2,6-dichloro-phenyl) methyl] -2-pyrimidinamine (intermediate 3).

EXAMPLE A2 a) Urea (0.03 mol) was added to a mixture of ethyl (+) 2,6-dichlorophenyl-phenyl-a-methyl-β-oxobutanoate (0.02 mol) in NaOC2Hs in ethanol, (1M, 0.040 mol, 40 mol) ). The reaction mixture was stirred and refluxed overnight. The solvent was evaporated, water was added and the mixture was neutralized with 0.3 N HOAc. The precipitate was separated by filtration and further triturated with ether and then with H20 and separated by filtration and dried to obtain 2.2 g (39%). ) of 6 - [(2,6-dichloro-phenyl) methyl] -5-methyl-2,4 (1 / - /, 3H) -pyrimidinadione (intermediate 4). b) A mixture of intermediate (4) (0.0095 mol) in phosphoryl chloride (50 ml) was stirred and refluxed overnight. Then the excess phosphoryl was evaporated. Ice water was added to the residue. A white precipitate formed, separated by filtration and dried. The residue was purified by evaporative column chromatography on silica gel (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated, yielding 2.06 g (67%) of 2,4-dichloro-6 - [(2) 6-dichloro-phenyl) methyl] -5-methyl-pyrimidine (intermediate 5). ). c) 4-Chloro-6 - [(2,6-dichloro-pheny!) methyl] -5-methyl-2-pyrimidinamine (intermediate 6) and 2-chloro-6 - [(2,6-dichlorophenol) methyl] -5-methyl-4-pyrimidinamine (intermediate 7) were prepared at starting from intermediate 5 following the procedures described in example A1 b.

EXAMPLE A3 a) To the stirred solution of HCl of 2,6-dichlorobenzene-imidamide (1: 1), (0.0042 mol) in ethanol (20 ml), a solution of sodium (0.013 mol) in ethanol (10 ml) was added, by drip first and then diethyl ether of propanedioic acid (0.0109 moles) was added. The reaction mixture was stirred and refluxed for four hours and then stirred at room temperature overnight. After adding another equivalent of propanodioic acid diethyl ester (stirring and refluxing overnight), the solvent was evaporated and the residue was dissolved in water and acidified with 1 N HCl. The solid was filtered off, washed with water and dried, yielding 0.87 g (76.4%) of 2 - [(2,6-dichloro-phenyl) methyl] -4,6-pyrimidinediol (intermediate 8). b) 6-Chloro-2 - [(2,6-dichloro-phenyl) methyl] -4-pyrimidinamine (intermediate 9) was prepared from intermediate 8 according to the procedures described in Example A1.b, A2. b & A2.c.

EXAMPLE A4 4-Amino-1-butanol (1.57 ml) was added to a solution of intermediate (1) (0.008 mol) in 1,4-dioxane (20 ml) under an argon atmosphere. The reaction mixture was stirred for two hours at room temperature. The solvent was evaporated. The residue was purified by evaporative column chromatography over silica gel (gradient of the eluent: CH 2 Cl 2 / CH 3 OH: from 100/0 to 98/2). The pure fractions were collected and the solvent was evaporated, yielding 2.05 g of a mixture of 4 - [[2-chloro-6 - [(2,6-dichloro-phenyl) methyl] -4-pyrimidinyl] -amino] -1-butanol (intermediate 10) and 4 - [[4-chloro-6 - [(2,6-dichloro-phenyl) methyl] -2-pyrimidinyl] amino] -1-butanol (intermediate 11).

EXAMPLE A5 a) Potassium hydroxide / ethanol (10%, 0.035 mol) was added to a solution of 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). The mixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added. The mixture was stirred overnight at 60 ° C. The reaction was quenched with NaOH in a 1 N solution. The aqueous layers were extracted with EtOAc several times and then the organic layers were combined and washed with NaOH3N and saturated NaCl, removed and concentrated. The residue was recrystallized from CH2Cl2 / hexane. The precipitate was separated by filtration and dried, yielding 5.98 g of 2,4-dichloro-6- (2,6-dichlorophenoxy) pyrimidine (55%) (intermediate 12). b) Reaction under argon atmosphere. 2,4-6-trimethylaniline (0.0678 moles) was added to 2,4-dichloropyrimidine (0.0664 moles) in 1.4 dioxane (100 ml). Added / V,? / - di (1-methylethyl) -etanamine (0.0830 moles). The reaction mixture was stirred and refluxed for four days and then the solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated solution of NaHCO3, and then dried (Na2S4), filtered and the solvent was evaporated to give 17.1 g of solid residue. This solid was dissolved in CH2Cl2: hexane (1: 1, 150 mL) and the resulting solution was concentrated to 100 mL and then filtered. The residue was purified by column chromatography over KP-Sil (eluent - CH2Cl2). The desired fractions were collected and the solvent was evaporated. The less polar fraction was stirred in CH2Cl2 for three hours and filtered to obtain 0.44 g of 4-chloro -? / - (2,4,6-trimethylphenyl) -2-pyrimidineamine (intermediate 48). A second fraction was recrystallized from acetonitrile, separated by filtration and dried, yielding 2-chloro-β / - (2,4,6-trimethyl-phenyl) -4-pyrimidinamine (intermediate 49).

EXAMPLE A6 Pyridine (1 mL) was added to a mixture of 4 - [[4-amino-6 - [(2,6-dichloro-phenyl) -methyl] -2-pyrimidinyl] amino] benzonitrile (0.00135 mol) in CH 2 Cl 2 (19). my). To a solution of chloroethanoyl chloride (0.001375 mol) in CH2Cl2 (0.5 ml) was added dropwise in an ice bath. The mixture was stirred at room temperature for two hours. Additional chloroethanoyl chloride (0.00625 moles) in CH2Cl2 (0.5 ml) was added. The mixture was kept in the refrigerator overnight. The solvent was evaporated. The residue was treated with a saturated solution of NaC 3 and the mixture was extracted with CH 2 Cl 2. The separated organic layer was dried, filtered and concentrated. The residue was purified by evaporative column chromatography on silica gel (eluent: CH2Cl2 / CH3? H / NH4OH 99/1 / 0.1). The desired fractions were collected and the solvent was evaporated, yielding 0.22 g (36.5%) of 2-chloro -? - [6 - [(2,6-dichloro-phenol) meth] -2- [ (4-cyano-phenyl) amino] -4-pyrimidinyl] acetamide (intermediate13).

EXAMPLE A7 A mixture of 4 - [(4-chloro-2-pyrimidinyl) amino] benzonitrile (0.005 mol) and nitrile tetrafluoroborate (0.0025 mol) in acetonitrile (5 ml) was stirred at room temperature for four hours. The material was quenched with saturated bicarbonate (50 ml) in crushed ice. The mixture was allowed to come to room temperature, and the yellow solid was removed by filtration. The solid was absorbed on silica and purified by column chromatography (eluent: 30%, 50%, 60%, 70% CH2Cl2 in hexanes). The solvent of the desired fraction was evaporated and the residue dried to obtain 0.89 g (64%) of 3-nitro-4 - [(4-chloro-2-pyrimidinyl) amino] benzonitrile (intermediate 51).

EXAMPLE A8 A mixture of 2,6-dichloro- / V- (2,4,6-tritymethyl) -4-pyrimidineamine (0.00376 moles) in a 2.0 M solution of NH3 in 2-propanol (25 ml) and a 0.5M solution of NH3 in dioxane (25 ml) was heated in a pressure sample at 110-115 ° C for 24 hours. The solvent was evaporated and the residue was chromatographed on Biotage (eluent: 1: 1 CH2CI2 hexane). The desired fractions were collected and the solvent was evaporated, obtaining a mixture of 0.523 g of 2-chloro-A / 4- (2,4,6-trimethyphenyl) -4,6-pyrimidine diamine (intermediate 53) and 0.101 g of 6-chloro- / V4- (2,4,6-trimethylphenyl) -2,4-pyrmidinediamine (intermediate 50). Tables 1 and 2 list the intermediaries that were prepared analogously to one of the preceding examples: TABLE 1A TABLE 1B B. Compounds of formula (V) EXAMPLE B1 A mixture of intermediate (42) and intermediate (19) (0.004 moles) in 4-amino-benzonitrile (0.0084 moles) were combined in a sealed tube and heated for 16 hours at 160 ° C under argon atmosphere. The reaction mixture was allowed to cool to room temperature and was dissolved in CH 2 Cl 2 / CH 3 OH 90/10 (20 mL) and 5 g of silica gel was added. After evaporating the solvent, the residue was purified by evaporative column chromatography over silica gel (eluent gradient: CH 2 Cl 2 / CH 3 OH: from 100/0 to 97/3). The desired fraction was collected and the solvent was evaporated, yielding 0.31 g (18.1%) of 4 - [[4 - [(2,6-dichloro-phenyl) methyl] -6- [3-hydroxypropyl] amine ] -2-pyrimidinyl] amino] benzonitrile (compound 3).

EXAMPLE B2 Intermediates (47) and (22) (0.00399 moles) and 4-aminobenzonitrile (0.0012 moles) in 1-methyl-2-pyrrolidinone (3 ml) were stirred for 16 hours at 130 ° C under argon atmosphere. The reaction mixture was cooled to room temperature and quenched with H20 (200 mL). A precipitate formed, which was stirred for 16 hours and filtered off over Celite. The residue was dissolved in CH3OH / CH2Cl2 (10%, 200 mL), dried over K2CO3, filtered, and evaporated. This resulting material was further purified by evaporative column chromatography on silica gel (eluent gradient: CH 2 Cl 2 / CH 3 OH: from 100/0 to 95/5). The desired fraction was collected and the solvent was evaporated, yielding 0.43 g (21.7%) of 4 - [[6 - [(2,6-dichloro-phenyl) methyl] -2 - [[3- (2-oxo-1 -pyrrolidinyl) propyl] -amino] -4-pyrimidinyl] amino] benzonitrile (compound 39; 104-114 ° C).

EXAMPLE B3 HCl / diethyl ether (1 N, 2.77 ml) was stirred in a solution of intermediate (33) (0.00277 moles) in 1-methyl-2-pyrrolidinone (4 ml) under N2 atmosphere. The reaction mixture was heated for five minutes. Then 4-aminobenzonitrile (0.0061 mol) was added and the reaction was heated at 100 ° C for 16 hours. Then, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 mL). The organic layer was washed with NaOH (1 N; 2 x 100 mL), H20 (2 x 100 mL), brine (50 mL), respectively, dried, filtered and the filtrate was evaporated. The crude material was purified by evaporative chromatography (eluent: 2.5-7.5% CH3OH containing 10% NH4OH in CH2Cl2). The desired fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.160 g (12.0%) of 4 - [[4 - [(2> 6-dichloro-phenol) methyl] -6 - [[2- (1-pyrrolidone)]. nyl) etl] amino] -2-pyrimidinyl] amino] benzonitrile (compound 13, mp 80-85 ° C).

EXAMPLE B4 A suspension of intermediate (14) (0.005 mole) in CH2Cl2 (150 ml) was stirred rapidly and cooled to 0 ° C under a nitrogen atmosphere. It was introduced by means of a BBr syringe (0.015 moles). The reaction mixture was stirred rapidly for two hours. The reaction mixture was again cooled to 0 ° C and quenched with NaOH (1 N ac, 25 mL). The partial biphasic mixture quenched provided a precipitate that was separated by filtration and dried, obtaining 2.5 g (91%) of 4 - [[4 - [(2,6-dichloro-phenyl) methyl] -6- (hydroxyamino) dibromhydrate pentahydrate 2-pyrimidinyl] amino] benzonitrile (compound 15, mp 240-244 ° C).

EXAMPLE B5 1,1-dimethoxy-α /, γ / -dimethylmethanamine (0.152 mol) was added to 4 - [[4-amino-6 - [(2,6-dichlorophenyl) methyl] -2-pyrimidinyl] amino] benzonitrile (0.0008 mol). The mixture was stirred at room temperature for two days and then concentrated. The crude product was purified by evaporative chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH: 99/1). The desired fraction was collected and the solvent was evaporated. The resulting residue was triturated with hexane, yielding 0.15 g (42%) of / V- [2 - [(4-cyano-phenyl) amino] -6 - [(2,6-dichlorophenyl) methyl] -4-p, rimidinyl] -? /,? / - dimethyl-methanumiddam (compound 26, mp 175-180 ° C).

EXAMPLE B6 Piperidine (0.12 ml) was added to a mixture of intermediate (13) (0.00047 mol) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 4 hours. More piperidine (0.14 ml) was added. The mixture was stirred for two more hours. The solvent was evaporated. The residue was purified by evaporative column chromatography on silica gel (CH2Cl2 / CH3OH / NH4OH 99/1 / 0.1). The desired fractions were collected and the solvent was evaporated, obtaining 0.05 g (21.5%) of N- [6 - [(2,6-dichloro-phenyl) methyl] -2 - [(4-cyano-phen L) amino] -4-pyrimidinyl] -1-pyridine-acetamide (compound 25, mp 175-180 ° C).

EXAMPLE B7 Pyridine (0.014 mol) was added to a mixture of 4 - [[4-amino-6- [(2,6-dichlorophenol) -methyl] -2-pyrimidinyl] amino] benzonitr (0.0013 moles) in CH2Cl2. A solution of octanoyl chloride (1.5 equiv.) In CH2Cl2 (0.5 ml) was added dropwise. The mixture was stirred at room temperature for two hours. Additional octanoyl chloride (3.5 equiv) in CH2Cl2 was added dropwise. The mixture was stirred. Then the solvent was evaporated. The residue was treated with a saturated aqueous solution of NaHCO 3 and the mixture was extracted with CH 2 Cl 2. The separated organic layer was dried, filtered and the solvent was evaporated to give the crude product. The residue was recrystallized from CHCl3 and hexane, yielding 0.443 g (68.6%) of N- [6 - [(2,6-dichloro-phenyl) methyl] -2 - [(4-cyano-phenyl) amino] - 4-pyrimidinyl] octanamide (compound) 17; p.f. 135-137 ° C).

EXAMPLE B8 a) A mixture of intermediate 49 (0.082 mol) and 5.4 N HCl in 2-propanol (0.086 mol) in water (300 ml) was stirred and heated at 40-45 ° C for 30 minutes. 4-Amino-benzonitrile (0.242 mol) was added at 40-45 ° C. The reaction mixture was stirred and refluxed for 4.5 hours and then cooled to room temperature. The mixture was made alkaline by dropwise addition of NaHC 3. This mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried, filtered and the solvent was evaporated. This fraction was stirred in ethanol p.a. (100 ml), separated by filtration, washed with ethanol (50 ml), then dried, yielding 23.1 g (86%) 4 - [[4 - [(2,4,6-trimethylphenyl) -amino] - 2-pyrimidinyl] amino] benzonitrile (compound 52). b) A mixture of 4 - [(4-chloro-2-pyrimidinyl) amino] benzonitrile (0.021 mol) and HCl in 2-propanol (0.0095 mol) in water (30 ml) was stirred for one hour at 45 °. C. 4-Amino-3,5-dimethyl-benzonitrile (0.025 mol) was added and the reaction mixture was stirred and refluxed overnight. The mixture was cooled to room temperature and then neutralized with NaHC 3. This mixture was extracted with ethyl acetate. The separated organic layer was washed with brine, dried, filtered and the solvent was evaporated. The residue was crystallized from CH 3 CN, separated by filtration and dried. The residue was stirred in boiling CH2Cl2, then separated by filtration and dried. The residue was crystallized from methyl isobutyl ketone, filtered off and dried, yielding 0.3 g of 4 - [[2 - [(cyanophenyl) amino] -4-pyrimidinyl] amino] -3,5-dimethylbenzonitrile (compound 69).

EXAMPLE B9 a) 4 - [(4-chloro-2-pyrimidinyl) amino] benzonitrile (0.003 mol), 2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1M HCl in diethyl ether were combined ( 4.5 ml) in 1,4-dioxane (10 ml) in a tube and heated under Ar until all the diethyl ether was evaporated. The tube was sealed and heated at 170 ° C for 2.5 days. Silica gel was added and the solvent evaporated. The residue was purified by evaporative column chromatography on silica gel (eluent gradient: (CH 2 Cl 2 / CH 3 OH: NH 4 OH 100: 0: 0 to 99: 0.9: 0.1) The desired fractions were collected and the solvent was evaporated. recrystallized from acetonyl, it was separated by filtration and dried, obtaining 0.22 g (15.9%) of 4 - [[4 - [(2,6-dibromo-4-methylphenyl) amino] -2-pyrimidinyljaminojbenzonitrile (compound 61). b) 4 - [[4 - [(4-chloro-5-methyl-2-pyrimidinyl] amino] benzonitrile (0.01541 mol), 4-amino-3,5-dimethyl-benzonitrile were combined (0.00219 moles), 1-methyl-2-pyrrolidone (4 ml), 1-4-dioxane (15 ml) and diisopropylethylamine (0.0154 mol) in a flask under a stream of argon and heated to 160-230 ° C during 16 hours. CH 2 Cl 2 and 1 N NaOH were added and the mixture was stirred for 1 hour and filtered to give a tan solid (*). The CH2Cl2 filtrate was separated and evaporated and purified by evaporative column chromatography (eluent: 2% CH3? H / CH2CI2). The desired fractions were combined, evaporated and the residue was stirred in CH2Cl2. The solid precipitate was separated by filtration, combined with the tan solid (*) and recrystallized from CH3CN. The precipitate was separated by filtration and dried, yielding 1.57 g (29%) of 4 - [[2 - [(4-cyanophenyl) amino] -5-methyl-4-pyrimidinyl] amino] -3.5- dimethylbenzonitrile (compound 89). c) 2 - [(4-Cyanophenyl) amino] -4-pyrimidinyltrifluoromethanesulfonate (0.0022 moles) and 2,6-dichloro-4- (trifluoromethyl) -benzenamine (0.0044 moles) in 1,4-dioxane (2.5 ml) were combined. and they were heated in a sealed tube under Ar at 170 ° C for 40 hours. The reaction mixture was allowed to cool to room temperature. Silica gel was added and the solvent evaporated. The residue was purified by evaporative column chromatography on silica gel (eluent gradient. (CH2Cl2 / CH3OH: NH4OH 100: 0: 0 to 97: 2.7: 0.3) The desired fractions were collected and the solvent was evaporated. recrystallized from CH 3 CN, separated by filtration and dried, yielding 0.86 g (9.2%) of 4 - [[4 - [(2,6-dichloro-4-trifluoromethyl) -phenylJamino] -2-p. rimidinyl] amino] benzonitrile (compound 66).

EXAMPLE B10 To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml), 2,4,6-trimethylphenol (0.006 mol) was added. The mixture was stirred for 15 minutes at room temperature, and a clear solution formed. 4 - [(4-Chloro-2-pyrimidinyl) amino] benzonitrile (0.004 mole) was added, and the reaction mixture was heated to reflux under argon for 15 hours. The reaction mixture was allowed to cool to room temperature, 0.5 ml of water was added followed by 4 g of silica gel, and the solvent was evaporated. The residue was purified by evaporative column chromatography over silica gel (eluent gradient: (CH2Cl2: CH3? H 100: 0: 0 to 97: 3) .The pure fractions were collected and the solvent was evaporated, yielding 1.18 g (89.4 g. %) of 4 - [[4- (2,4,6-trimethylphenoxy) -2-pyrimidinyl] amino] benzonitrile (compound 58).

EXAMPLE B11 Compound (52) (0.0015 mol) was stirred in boiling ethanol (8 mL). 6 M HCl in 2-propanol (0.0015 mol) was added and the salt allowed to crystallize overnight at room temperature. The precipitate was separated by filtration, washed with 2-propanol and dried, yielding 0.47 g (86%) of 4 - [[4 - [(2,4,6-trimethyl-phenyl) ammonium hydrochloride. ] -2-pyrimidinyl] amino] benzonitrile (1: 1) (compound 53).

EXAMPLE B12 A mixture of compound (52) (0.00303 mol) and NaBO34H2O (0.00911 mol) in CH3OH (30 ml) and H20 (10 ml) was stirred and refluxed for four days. The reaction mixture was cooled. The precipitate was separated by filtration and the precipitate (*) was purified by evaporative column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH gradient from 100/0 to 95/5). The desired fractions were collected and the solvent was evaporated, yielding 0.586 g (56%) of 4 - [[4 - [(2,4,6-trimethylphenyl) amino] -2-pyrimidinyl] -aminoj-benzamide (compound 100). The filtrate (*) was purified by reverse phase HPLC (eluent gradient: ((0.5% ammonium acetate in H20 / CH3CN 90/10) / CH3OH / CH3CN (0 minutes) 75/25/0, (44 minutes ) 0/50/50, (57 minutes) 0/0/100, (61.1-70 minutes) 75/25/0) Three groups of desired fractions were collected and their solvent was evaporated, obtaining 0.18g? / 3- 4 - [[4 - [(2,4,6-trimethylphenyl) amino] -2-pyrimidinyl] amino] benzamide oxide, (compound 106) and 0.030 g of 4 - [[4 - [(2 , 4,6-trimethylphenyl) amino] -2-pyrimidinyl] -amino] -benzamide (compound 107). Tables 3, 4, 5 and 6 list the compounds of formula (I) which were prepared according to one of the preceding examples.

TABLE 3 TABLE 4 TABLE 5 TABLE 6 PHARMACOLOGICAL EXAMPLE EXAMPLE C.1 A rapid, sensitive and automated test procedure was used for the in vitro evaluation of anti-HIV agents. A T4 cell line transformed with HIV-1, MT-4, which was previously demonstrated (Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985) that was highly susceptible and permissive for HIV infection. HIV, served as the target cell line. The inhibition of the cytopathic effect induced by HIV was used as the final point. The viability of the HIV infected cells and the cells of simulated infection was verified spectrophotometrically through an in situ reduction of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT). The 50% cytotoxic concentration (CC 0 in μM) was defined as the concentration of compound that reduced the absorbance of the simulated infection control sample (MOCK) by 50%. The percentage of protection achieved by the compound of the HIV-infected cells was calculated by the following formula: Expressed in %. where (ODT) HIV is the optical density measured with a determined concentration of the test compound in HIV infected cells; (ODC) IH is the measured optical density for untreated HIV infected control cells (ODC) MOCK is the measured optical density for untreated simulated infection control cells; all optical density values were determined at 540 nm. The dose that achieved a 50% protection according to the preceding formula was defined as a 50% inhibitory concentration (Cl50 in μM). The ratio of CC50 to Cl50 was defined as the selectivity index (IS). The compounds of formula (I) were shown to inhibit HIV-1 effectively. The particular values of CI5o, CC50 and IS are listed in Table 7 below.

TABLE 7 D. Composition Examples The following formulations exemplify typical pharmaceutical compositions suitable for systemic administration for animal and human subjects according to the present invention. "Active ingredient" (I.A.) as used throughout these examples refers to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

EXAMPLE D.1 Film-coated tablets Preparation of the core for tablets A mixture of 100 g of IA 579 g of lactose and 00 g of starch was mixed well, and then wetted with a solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone in approximately 200 ml of Water. The wet powder mixture was screened, dried and sieved again. Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added. The whole was mixed well and compressed into tablets, obtaining 10,000 tablets, each comprising 10 mg of the active ingredient.

Coating To a solution of 10 mg of methylcellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. 10 g of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated color suspension were added and the whole was homogenized. The tablet cores were coated with the mixture thus obtained by means of an apparatus capable of effecting the coating.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. - Use of a compound of formula an N -oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein A is CH, CR4 or N; n is 0, 1, 2, 3, or 4; Q is hydrogen or -NR1R2; R1 and R2 are each independently selected from hydrogen, hydroxy, C? -? 2 alkyl, C1-12 alkyloxy, C? _2 alkylcarbonyl, C? .12 alkyloxycarbonyl, aryl, amino, mono- or di (C? -? 2) amino, mono- or di (alkyl) where each of the aforementioned C1-12 alkyl groups may be optionally and each independently substituted with one or two substituents each independently selected from hydroxy, C-? - alkyloxy 6, C6-6 hydroxyalkyloxy, carboxyl, C6-6 alkyloxycarbonyl, cyano, amino, methyl, aminocarbonyl, aminocarbonylamino, mono- or di (C6-6) amino, aryl and Het; or R1 and R2 taken together they can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C? -? 2 alkyl) amino alkylidene Ci ^;

R 3 is hydrogen, aryl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, substituted with alkyloxycarbonyl and each R 4 independently is hydroxy, halo, C 1-6 alkyl, C 1-6 alkyloxy, cyano , aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy or C? -6 alkyl, substituted with cyano or aminocarbonyl; R5 is hydrogen or C1-4 alkyl; L is C 0 alkyl, C 3-10 alkenyl, C 3-10 alkynyl, C 3-7 cycloalkyl or C 1 -C 8 alkyl substituted with one or two substituents independently selected from C 3-7 cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, Ndanyl and indolyl can be substituted with one, two, three, four or when possible five substituents each independently selected from halo, hydroxy, C? -6 alkyl, C1-6 alkyloxy, cyano, aminocarbonyl, C? -6 alkyloxycarbonyl? , formyl, nitro, amino, trihalomethyl, trihalomethyloxy and Ci-β alkylcarbonyl, or L is -X1-R6 or -X2-Alc-R7 where R6 and R7 are each independently phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C6-6alkyl, C1-6alkyloxy, C6-6alkylcarbonyl, C6-6alkyloxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy and trihalomethyl; and X1 and X2 are each independently -NR3-, -NH-NH-, N = N, -O-, -S-, -S (= 0) - or -S (= 0) 2-; Ale, is alkanediyl d ^; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C? -6 alkyl, C? -6 alkyloxy) cyano, nitro and trifluoromethyl; Het is an aliphatic or aromatic heterocyclic radical, said aliphatic heterocyclic radical being selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radicals may be optionally substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radicals may be optionally substituted with hydroxy; for the manufacture of a medicament for the treatment of subjects suffering an infection caused by HIV (Human Immunodeficiency Virus). 2. The use of a compound according to claim 1, wherein n is at least 1 and at least one R4 is cyano.

3. The use of a compound according to claim 1 or 2, wherein the compound has the formula

4. - The use of a compound as claimed in any of claims 1 to 3, wherein the compound has the formula

5. - A compound of formula an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein L, Q, R3, R4, R5 and A are as defined under formula (I) and R4 is halo, C? _6 alkyl, cyano, aminocarbonyl, nitro, trihalomethyl, trihalomethyloxy or C? -6 alkyl substituted with cyano or aminocarbonyl; n 'is 0, 1, 2 or 3; with the proviso that Q and L are different from anilino, 2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino, 3,4-dimethoxy-anilino, 3-chloro-4-fluorine -anilino, 4-cyano-anilino, 2- (C6-alkyl) -anilino, 4- (Ci-β-anilino, 3-chloroanilino, 4-bromo-anilino, 4-nitro-anilino and -chloro-aniline

6. A compound according to claim 5, wherein the compound has the formula:

7. The compound according to claim 6, wherein L and Q are different from anilino, 2,4,6-trinitro-anilino, 4- (C? -6) -anilino, 4-bromo-anilino , 4-nitro-anilino and 4-chloroanilino.

8. The compound according to claim 6 or 7, wherein R4 is cyano, aminocarbonyl or C-? 6 alkyl substituted with cyano or amiocarbonyl.

9. The compound according to any of claims 5 to 8, wherein L is 2,6-dichlorobenzyl, or L is -X1-R6 where X1 is NR3, -S- or -O- and R6 is 2 , 4,6-tichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro -6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methylphenyl, 2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro -4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4- (1, 1-dimethylethyl) -phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6 -dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, 4-cyano-2,6-dimethyl-phenyl; or L is X2-Alc-R7 where -X2-Alk- is -NH-CH2- and R7 is phenyl.

10. The compound according to any of claims 5 to 9, wherein Q is hydrogen, L is -X1-R6 where X1 is -NH- and R6 is 2,4,6-trimethyl-phenyl or 4- cyano-2,6-dimethylphenol, the NR3 portion (phenyl or optionally substituted pyridyl) represents p-cyano-anilino and is in the 2-position of the pyrimidine ring.

11. The compound as claimed in claims 5 to 10, wherein R4 is halo, cyano, aminocarbonyl or cyanoalkyl C2; n is zero, A is CH, R3 is hydrogen; R5 is hydrogen or methyl; Q is hydrogen or NHR1; and L contains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl , 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl -phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6 -dimethyl-4- (1,1-dimethylethyl) -phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl , 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl or 4-cyano-2,6-dimethyl-phenyl.

12. The compound according to claim 5 wherein the compound is 4 - [[4-amino-6 [(2,6-dichlorophenyl) methyl] -2-pyrimidinyl] amino] benzonitrile; 6 - [(2,6-dichlorophenyl) methyl] -? 2- (4-fluorophenyl) -2,4-pyrimidine diamine; 4 - [[4 - [(2,4-dichlorophenyl) methyl] -6 - [(4-hydroxybutyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [(3-hydroxypropyl) amino] -2-pyrimidinyl] amino] benzonitrile; ? - [2 - [(4-cyanophenyl) amino] -6 - [(2,6-dichlorophenol) methyl] -4-pyrimidinyl] -acetamide; ? - [2 - [(4-cyanophenyl) amino] -6 - [(2,6-dichlorophenyl) methyl] -4-pyrimidinyl] -butanamide; 4 - [[2-amino-6- (2,6-dichlorophenoxy) -4-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [(2-hydroxy-2-phenylethyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [[3- (2-oxo-1-pyrrolidinyl) propyl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [[2- (2-hydroxyethoxy) etl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [(2,3-dihydroxypropyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6- (hydroxyamino) -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2-cyanoethyl) amino] -6 - [(2,6-dichlorophenyl) methyl] 2-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) methyl] -6 - [[2- (1-pyrrolidinyl) ethyl] amino] -2-pyrimidinyl] -amino] benzonitrile; 4 - [[4-amino-6 - [(2,6-dichlorophenol) methyl] -5-methyl-2-pyrimidinyl] -amino] benzonitrile; 2- (4-bromophenyl) -6 - [(2,6-dichlorophenyl) methyl] -5-methyl-2,4-pyrimidinediamine; 4 - [[4 - [(2,4,6-trimethyphenyl) amino] -2-pyrimidinyl] -amino] benzonitrile; 4 - [[2 - [(2,4,6-trimethylphenyl) amino] -4-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dimethylphenyl] amino) -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trimethyphenoxy) -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,6-dichlorophenyl) thio] -2-pyrimidinyl] amino] bezonitrile; 4 - [[4 - [[2,6-dibromo-4- (1-methylethyl) pheny] amino] -2-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [[2,6-dichloro-4- (trifluoromethyl) phenyl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4-dichloro-6-methylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[2 - [(cyanophenyl) amino] -4-pyrimidinyl] amino] -3,5-dimethylbenzonitrile; 4 - [[4 - [(2,4-dibromo-6-fluorophenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 [[4- [amino-6 - [(2,6-dichlorophenyl) methyl] -5-methyl-2-pyrimidinyl] amino] benzoacetonitrile; 4 - [[4- [methyl (2,4,6-trimethylphenyl) amino] -2-pyrimidinyljaminojbenzonitrile; 4 -__ 4 - [(2,4,6-trichlorophenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trimethylphenyl) thio] -2-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [(2,4,6-Trimethylphenyl) amino-2-pyrimidinyl] amino] benzonitrile; 4 - [[2-amino-6 - [(2,4,6-trimethylphenyl) amino] -4-pyrimidinyl] amino] benzonitrile; 4 - [[4- (2-bromo-4-chloro-6-methylphenoxy) -2-pyrimidinyl] amino] benzonitrile; 4 - [[4- (4-chloro-2,6-dimethylphenyl] amino] -2- pyrimidinyl] amino] benzonitrile; 3,5-dichloro-4 - [[2 - [(4-cyanophenyl) amino] -4-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [[2,6-dichloro-4- (trifluoromethoxy) phenyl] amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4-dibromo-3,6-dichlorophenyl) amino] -2-pyrimidinyljaminojbenzonitrile; 4 - [[4 - [(2,6-dibromo-4-propylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[4 - [(2,4,6-trimethylphenyl) amino] -2-pyrimidinyl] amino] benzamide; 4 - [[4 - [(4- (1,1-dimethylethyl) -2,6-dimethylphenyl) amino] -2-pyrimidinyl] amino] benzonitrile; 4 - [[2 - [(4-cyanophenyl) amino] -4-pyrimidinyl] oxy] -3,5-dimethylbenzonitrile; 4 - [[4 - [(4-chloro-2,6-dimethyphenyl) amino] -5-methyl-2-pyrimidinyljaminojbenzonitrile; 4 - [[- 2 - [(4-cyanophenyl) amino] -5-methyl-4-pyrimidinyl] amino-3,5-dimethylbenzonitrile; 4 - [[4 - [[4- (1, 1-dimethylethyl) -2,6-dimethyl] amino] -5-methyl-2-pyrimidinyl] amino] -benzonitrile; 4 - [[4 - [(4-bromo-2,6-dimethylphenyl) amino] -5-methyl-2-pyrimidinyl] amino] benzonitrile; 4 - [[5-methyl-4 - [(2,4,6-trimethylphenyl) thio] -2-pyrimidinyl] amino] -benzonitrile; 4 - [[4 - [(2,6-dibromo-4-propylphenyl) amino] -5-methyl-2-pyrimidinyl] amino] benzonitrile; ? / 4-oxide 4 - [[4 - [(2,4,6-trimethylphenyl) amino] -2-pyrimidinyl] amino] benzamide; ? / 2- (4-chlorophenyl) -N 4 - (2,4,6-trimethylphenyl) -2,4-pyrimidineadimamine; 4 - [[4 - [[2,6-dibromo-4- (1-methylethyl) pheny] amino] -5-methylene-2-pyrimidinyl] amino] benzonitride the; 4 - [[2 - [(4-cyanophenyl) amino] -5-methyl-4-pyrimidinyl] amino] -3,5-dimethylbenzonitrile; 4 - [[4- [(phenylmethyl) amino] -2-pyrimidinyl] amino] benzonitrile; a? / -oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of a compound as defined in any of claims 5 to 12.

14. A process for preparing a pharmaceutical composition as defined in claim 13 characterized in that a therapeutically effective amount of a compound as defined in any of claims 5 to 12 is intimately mixed with a pharmaceutically acceptable carrier.

15. A process for preparing a compound as defined in claim 5, characterized by a) reacting an intermediate of formula (I IA) in which W1 is an appropriate leaving group with an amino derivative of formula (III) ) optionally in a solvent under an atmosphere inert to the reaction, and optionally in the presence of an acid (ll-A) (III) (! ') where Q, R3, R4, R4, R5, A, n' and L are as defined in claim 5; b) an intermediate of formula (II-B) is reacted in which W1 in an appropriate leaving group with an amino derivative of formula (VI) is optionally a solvent under an atmosphere inert to the reaction, and optionally in the presence of an acid (ll-B) (vi) (r) c) reacting an intermediate HX-R6 with an intermediate of formula (ll-C) in an appropriate solvent optionally in the presence of an appropriate acid or base; thereby obtaining the compounds of formula (I ') in which L is -X 1 -R 6, said compound being represented by the formula (1-c). (ll-C) (r-c) or if desired, converting the compounds of formula (I ') to one another following transformations known in the art, and further, if desired, converting the compounds of formula (I') to a non-toxic acid addition salt, Therapeutically active by treatment with an acid, or in a non-toxic therapeutically active base addition salt by treatment with a base, or conversely, converting the acid addition salt form to the free base by treatment with an alkali, or converting the base addition salt in the free acid by acid treatment; and if desired, preparing the stereochemically isomeric forms thereof or the? / - oxides thereof.

16. The use of a compound of formula (I) as defined in claim 1, in combination with another antiretroviral compound for the manufacture of a medicament for an anti-VI H treatment in patients.

17. The use of a compound of formula (I ') as defined in claim 5, in combination with another antiretroviral compound for the manufacture of a medicament for an anti-HIV treatment in patients.

18. A product containing (a) a compound of formula (I) as defined in claim 1, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in an anti-retroviral treatment. HIV

19. A product containing (a) a compound of formula (I ') as defined in claim 5, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in an anti-retroviral treatment. -VIH.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I) as defined in claim 1, and (b) another antiretroviral compound.

21. The pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I ') as defined in claim 5, and (b) another antiretroviral compound.

22. A compound of formula (ll'-B) wherein R3, R4, R4, n 'A and L are as defined in claim 5 and W1 in a halogen. SUMMARY OF THE INVENTION This invention relates to the use of the compounds of the formula: the ? -oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein A is CH, CR4 or N; n is 0 to 4; Q is hydrogen or -NR1R2; R1 and R2 are selected from hydrogen, hydroxy, C1-12 alkyl, C1-12 alkyloxy, C2 alkylcarbonyl, C2-? 2 alkyloxycarbonyl, aryl, amino, mono- or di (C? -? 2 alkyl) amino , mono- or di (C? -? 2 alkyl) aminocarbonyl wherein each of the C? -? 2 alkyl groups may be optionally substituted; or R 1 and R 2 taken together can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di (C 1 -C 2 alkyl) amino alkylidene C 1 -; R3 is hydrogen, aryl, C-uß alkylcarbonyl, optionally substituted C6-6 alkyl, C6-6 alkyloxycarbonyl; and R 4 is hydroxy, halo, optionally substituted C 1-6 alkyl, Ci-β alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy; R5 is hydrogen or C? -4 alkyl; L is optionally substituted C-MO alkyl, C3-? Alkenyl, or C3-? 0 alkynyl; or L is X1-R6 or -X2-Alc-R7 where R6 and R7 are optionally substituted phenyl; X1 and X2 are -NR3-, -NH-NH-, N = N, -O-, -S-, S (= 0) - or -S (= 0) 2-; Ale is C ^ alkanediyl; aryl is optionally substituted phenyl; Het is an optionally substituted aliphatic or aromatic heterocyclic radical; for the manufacture of a medication to stop the treatment of subjects suffering from HIV infection (Human Immunodeficiency Virus); it also relates to new compounds that consist of a sub-group of the compounds of the formula (I), their preparation and the compositions comprising them. JANSSEN / pbg * jtc * igp * rcp * ogm * ald * osu * mmr * kra * avc * P00 / 1001F