3-(Amino-or aminoalkyl) pyridinone derivatives and their use for the treatment of HIV related diseases

Abstract

3-(amino- or aminoalkyl) pyridinone derivatives having the formula (1) 1

Description

[0001] The present invention is concerned with 3-(amino- or aminoalkyl) pyridinone derivatives which inhibit the reverse transcriptase of the Human Immunodeficiency Virus (HIV).

[0002] It relates moreover to the use of such compounds for treating HIV-related diseases.

[0003] Furthermore it relates to a process for the preparation of these compounds.

[0004] It is known that some pyrimidinone and pyridinone derivatives inhibit HIV reverse transcriptase.

[0005] In particular, derivatives from 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) are well known for their HIV1 reverse transcriptase inhibitory properties.

[0006] European Patent Application EP-0 462 800 (Merck and Company Inc.) discloses pyridinones being substituted on position 3 with an aryl or heterocyclic group, linked to the pyridinone ring through a chain.

[0007] Unfortunately, strains resistant to these compounds appeared Thus, their use in therapeutical treatments is questionable.

[0008] 4-aryl-thio-pyridinones have been more recently disclosed by DOLLE et al. (1995, J. Med. Chem., 38, 4679-4686), and in the corresponding PCT Patent Application WO 97/05 113.

[0009] However, their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains.

[0010] The most active thio pyridinones disclosed therein have a 50% inhibitory concentration of virus multiplication (IC50 ) for nevirapine resistant strains of about 260 nM.

[0011] The inventors have found a new pyridinone derivative family which show better HIV inhibitory properties.

[0012] They have moreover found a new process for obtaining these compounds.

[0013] The present invention relates to compounds having the following general formula I. 2

[0014] wherein

[0015] Q represents —NR1R2 or —R0NR1R2 wherein:

[0016] R0 represents C1-6 alkanediyl;

[0017] R1 and R2 each independently represent C1-6alkyl or C3-6alkenyl; said C1-6alkyl and C3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C1-4alkyloxy, C1-4alkylthio, aryloxy, arylthio, amino, mono- or di(C1-4alkyl)amino and aryl; or

[0018] R1 and R2 taken together may form a bivalent radical —R1-R2— wherein —R1-R2— represents —(CH2)2—O—(CH2)2—, —(CH2)2—NR7—(CH2)2, —(CH2)2—CH(NHR7)—(CH2)2— or —(CH2)n, wherein R7 represents hydrogen or C1-4alkyl and n represents 2, 3, 4, 5 or 6;

[0019] R3 represents aryl or a monocyclic or bicyclic heterocycle selected from pyridinyl, pyrimidinyl, thiazolinyl, furanyl, thienyl, imidazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl; said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from hydroxy, C1-4-alkyl, C1-4alkoxy, halo, trifluoromethyl, dimethylenoxy or phenyl,

[0020] R4 and R5 each independently represent hydrogen, C1-6alkyl, C3-6alkenyl, C1-4alkoxy, C1-4alkyloxy, C1-4alkyl, amino, mono- or di(C1-4alkyl) amino, formyl, C1-4alkylcarbonyl, carboxyl, C1-4 alkyloxycarbonyl, or C1-4alkylaminocarbonyl; wherein C1-6alkyl and C3-6alkenyl may be substituted with one, two or three substituents selected from hydroxy, C1-4alkyloxy, C1-4alkyl thio, aryloxy, arylthio, amino, mono- or di(C1-4alkyl)amino and aryl; or

[0021] R4 and R5 taken together form a bivalent radical of formula —R4-R5— wherein —R4-R5— represents —CH═CH—CH═CH— or —(CH2)t—, wherein t represents 3 or 4;

[0022] R6 represents hydrogen, hydroxy, C1-4alkyloxy, C1-6alkyl, C3-6alkenyl, aryl, C1-4alkyl, amino, mono- or di(C1-4alkyl)amino or alkylaryl;

[0023] Y represents O or S;

[0024] X represents a radical of formula:

—(CH2)p—

—(CH2)q—Z—(CH2)r—

[0025] or

—CO—

[0026] wherein p represents 1, 2, 3, 4 or 5;

[0027] q represents 0, 1, 2, 3, 4 or 5;

[0028] r represents 0, 1, 2 or 3;

[0029] Z represents NR8, C(═O), CHOH, CHNR8R9; CF2, O, S or CH═CH; wherein R8 and R9 each independently represent hydrogen or C1-4 alkyl;

[0030] or N-oxides, stereochemically isomeric forms or a pharmaceutically acceptable addition salts thereof.

[0031] As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-4-alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof containing 5 to 6 carbon atoms such as, for example, pentyl, hexyl or the like; C3-6alkenyl defines straight and branched chain hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C3-6alkenyl being connected to a nitrogen atom preferably is saturated; C1-6-alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The term <<C(═O)>> refers to a carbonyl group. Aryl is phenyl or phenyl substituted with one, two or three substituents selected from C1-4alkyl, C1-4alkyloxy, halo and trifluoromethyl,

[0032] Preferred compounds according to the present invention are those in which X represents —CH2— or C (═O) and R3 represents a phenyl group, substituted with two methyl groups, and the most preferred of them are those wherein R3 represents a phenyl group substituted, in each meta position, with two methyl groups.

[0033] Preferably, in the compounds according to the present invention, R1 and R2 represent each a methyl group, R4 represents an ethyl group, R5 represents a methyl group and/or R6 represents a hydrogen atom.

[0034] The most preferred compound of this invention is the 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.

[0035] The compounds in which X is —CH2—, R3 represents a phenyl group optionally substituted, Y represents O and R6 represents a hydrogen atom can be obtained by the general process represented on FIG. 1.

[0036] This first process comprises the following steps:

[0037] a) reacting a pyridine (2), substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C1-C6 alkyllithium, resulting in a lithiated derivate (3) of the said pyridine.

[0038] b) transforming the lithiated derivate (3) into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide.

[0039] c) obtaining the pyridinone (4) by reacting the organocopper reagent with optionally substituted benzyl halide.

[0040] d) hydrolysing the protected pyridinone (4) and obtaining the deprotected pyridinone (5).

[0041] e) substituting the 3-amine group of the pyridinone (5) and obtaining the pyridinone (6).

[0042] This first process is summarized in the reaction Scheme I hereinafter: 3

[0043] In this process R10 and R11 represent independently C1-C6 alkyl. In a preferred embodiment, R10 is a methyl group and R11 is a tert-butyl group.

[0044] The C1-C6 alkyllithium, reacted with the pyridine(2) can be a n-butyllithium.

[0045] The optionally substituted benzyl halide used in the step c) is preferably benzyl bromide.

[0046] The hydrolysis of the protected pyridinone(4), resulting in its deprotection, is advantageously obtained by adding hydrochloric acid to the pyridinone(4) and refluxing the mixture.

[0047] In a preferred embodiment, the amino group in position 3 of the pyridinone ring, deprotected during the step (d) is substituted by alkylation, by the Eschweiler-Clarke reaction.

[0048] Compounds wherein X represents —(CH2)q—Z—(CH2)r—, Y represents O, R3 is an optionally substituted phenyl group and R6 is an hydrogen atom can be obtained by a similar process.

[0049] Compounds wherein X represents C (═O), or —CH2—, Y represents O, R3 is an optionally substituted phenyl group and R6 is an hydrogen atom can be obtained by a second process.

[0050] In this second process, the lithiated derivative (3) is reacted with an optionally substituted benzaldehyde, resulting in the intermediates of formula (7).

[0051] The intermediate (7) is oxidized to intermediate (8).

[0052] The intermediate (8) is thereafter deprotected by hydrolysis, as in the first process, resulting in the pyridinone (9) of general formula I.

[0053] This second process is summarized in the reaction scheme II hereinafter. 4

[0054] Preferably the oxidation of the intermediate (7) is performed in the presence of manganese dioxide.

[0055] The intermediate (7) can also be transformed into corresponding ester (10) wherein R12 represents a C1-C4 alkyl group whose hydrogenolysis provides pyridinone(4) in better yields. Preferably, the ester (10) wherein R12 is CH3 is prepared by treatment of intermediate (7) with acetic anhydride. Subsequently hydrogenolysis is performed under hydrogen atmosphere and in the presence of a catalyst, especially 30% paladized charcoal. This process is summarized in the reaction scheme III 5

[0056] Other compounds of general formula I, and wherein X is (CH2)p or (CH2)q—Z—(CH2)r or C(═O), and R3 is other than phenyl and R6 is other than hydrogen can be obtained by these processes, appropriately adapted by the man skilled in the art.

[0057] The compounds according to the present invention, in which X is S can be obtained by the process described in the article of DOLLE et al. (1995, previously cited) or in the corresponding patent application WO 97/05 113, the contents of which are included in the present application.

[0058] The compounds can also be obtained by other processes known by the man skilled in the art.

[0059] The present invention relates moreover to the intermediates of the processes hereabove disclosed. In particular it relates to the lithiated derivative of formula (3).

[0060] The compounds of the present invention are useful in the inhibition of HIV reverse transcriptase, and in particular HIV-1 reverse transcriptase and the prevention or treatment of infection by the human immuno deficiency virus (HIV) and of HIV-related diseases, such as AIDS.

[0061] For these purposes, the compounds of the present invention may be administered orally, parenterally (including sub-cutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tectoniques), by inhalation spray, or rectally, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.

[0062] Thus, another object of the present invention is a method, and a pharmaceutical composition for treating HIV related diseases, HIV infection, and in particular AIDS.

[0063] The invention relates also to these compounds for use as medecine and to their use for the manufacture of a medecine for the treatment of HIV related diseases, HIV infection, and in particular AIDS.

[0064] These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets, nasal sprays, sterile injectable preparations, or suppositories.

[0065] The present invention is illustrated without being limited by the following examples.

EXAMPLES

Example 1

Preparation of 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one

[0066] 1) 5-Ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine

[0067] This compound has been prepared as indicated by DOLLE et al. (1997, Tetrahedron, vol.53, n°37, 12.505-12.524). The content of this article is hereby incorporated by reference.

[0068] 3.68 g of 3-Amino-5-ethyl-2-methoxy-6-methylpyridine (22.14 mmol), obtained as indicated by HOFFMAN et al. (1993, J. Med. Chem., 36, 953-966), was dissolved in a mixture of dichloromethane (260 ml) and triethylamine (3.39 ml). The mixture was cooled at 0° C. and 3.00 ml of trimethylacetyl chloride was added dropwise. The solution was stirred at 0° C. for 15 min. and then washed with 100 ml water. The aqueous layer was extracted with 3×200 ml dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane as eluant to provide the 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5.31g; 96%). Elemental analysis calculated for C14H22N2O2; C, 67.17. H, 8.86; N, 11.19; 0, 12.78; found : C, 67.11; H. 8.56; N, 10.91; O, 12.67.

[0069] 2)4-(3,5-Dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine

[0070] i) By Lithiation of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine:

[0071] 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine and 3,5-dimethylbenzyl bromide were dried in the presence of phosphorus pentoxide under vacuum at room temperature during 24 hours. Copper iodide (CuII) was dried in the presence of phosphorus pentoxide under vacuum at 50° C. for 24 hours. 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (1.06 g) and freshly distilled tetramethylethylenediamine (TMEDA) (2.24 mL) were dissolved in dry tetrahydrofuran (THF) (26 mL) and the mixture was cooled at −78° C. under a nitrogen atmosphere. n-Butyllithium (1.6 M in hexane, 9.26 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C.

[0072] CuII: dimethyl sulfide complex, prepared by adding dimethylsulfide (14 mL) to a suspension of copper iodide (2.82 g) in dry THF (52 ml) at −78° C. under N2 atmosphere, was then added dropwise to the mixture at −78° C. The mixture was stirred at 0° C. for 30 min and cooled again at −78° C. to allow the addition of 3,5-dimethylbenzyl bromide (3.81 g) dissolved in THF (4 mL). The resulting mixture was stirred at 0° C. for 3 hours and at room temperature for 12 hours. 16 mL of water and 20 mL of 28% aqueous ammonium hydroxide were added. The aqueous layer was extracted with 3×80 mL of ether. The combined organic layers were washed with 40 mL of brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using cyclohexane-ethyl acetate (1:0 to 8:2) as eluant giving 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (577 mg, 37%) mp 138-139° C.

[0073] ii) By hydrogenolysis of ±(5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridin-4-yl)-(3,5-dimethylphenyl)-methyl Acetate

[0074] (+, −) (5-Ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridin-4-yl)-(3,5-dimethylphenyl)-methylacetate

[0075] 8.34 g of (+, −)-(3,5-dimethylphenyl)-(5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridin-4-yl)-methanol, prepared as described below, was dissolved in pyridine (200 mL) and added to acetic anhydride (10.24 mL), and the solution was stirred for 1.5 h at room temperature and for 60 h at 60° C. An additional 10.24 mL of acetic anhydride (108.51 mmol) was added and heating was continued at 60° C. for 24 h. The pyridine was evaporated under reduced pressure and the residue was taken up in 500 mL of ethyl acetate. The organic layer was washed with 170 mL of an aqueous saturated sodium bicarbonate solution, 170 mL of water and 170 mL of brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by column chromatography using dichloromethane-ethanol (1:0 to 95:5) to give the titled compound (8.78 g, 95%) mp 70-71° C.

[0076] A mixture of this compound (850 mg) and Pd-C (30%, 850 mg) in acetic acid-water-dioxane (42.5 mL, 2:1:2, v/v/v) was stirred at room temperature for 24 hours under 10 atm of hydrogen. The catalyst was removed by filtration and washed with ethanol. The solvent of the combined filtrates was evaporated under reduced pressure giving 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (726 mg, 99%) which was identical to the compound as prepared in example 1.2.i).

[0077] 3) 3-Amino4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one

[0078] 3M aqueous hydrochloric acid (150 mL) was added to a suspension of 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (2.36 g) in water (300 mL). The mixture was refluxed for 3.5 h and then stirred at room temperature for 12 h. The solution was basified by adding concentrated ammonium hydroxyde and was extracted with 3×800 mL ethyl acetate. The combined organic layers were washed with 110 mL brine, dried over magnesium sulfate and concentrated under reduced pressure giving 3-amino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one. (1.79 g, 100%). mp 204-205° C.

[0079] 4) 3-Dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2-(1H)-one

[0080] To a stirred solution of 3-amino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one (200 mg) and 37% of aqueous formaldehyde (0.60 mL) in 5 mL of acetonitrile was added 139 mg of sodium cyanoborohydride. Glacial acetic acid (0.07 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. An additional 0.07 mL of glacial acetic acid was added, and stirring was continued for 30 minutes. The solvent was evaporated and 15 mL ether were added to the resulting residue. The organic layer was washed with 3×30 mL 1N aqueous potassium hydroxide and 3 mL brine, dried over magnesium sulfate and concentrated under reduced pressure to give 3-dimethylamino4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one (200 mg, 91%) mp 229-230° C.

Example 2

[0081] 1) Biological Activity of the Compound According to Example 1

[0082] 1. Material and Methods

[0083] The antiviral activity, the expression and purification of the recombinant HIV-RT enzyme, the reverse transcriptase activities and the inhibition of RT were evaluated as described in WO 97/05 113.

[0084] The retrovirucidal effect and the reverse transcription were measured as described hereinafter.

[0085] 1.1. Retrovirucidal Effect

[0086] HIV-1 viral suspensions were obtained by coculture of MT4 cells and H9 cells chronically infected by HIV-ILai isolate. 200 μl of a cell supernatant containing viral particles (HIV-ILai: 100 TCID50) were incubated at room temperature with various concentrations of different inhibitors. After 3 hours, virions were washed through 0.02 μm anopore membrane in 1.5 mL Vectaspin tube (Whatman) for 10 minutes at 5 000 g. Each of the three subsequent washes was performed in the same conditions after the viral concentrate was refilled with 500 μL of RPMI medium. Then, the viral concentrate was readjusted to the initial volume with RPMI plus 10% foetal calf serum (FCS). The residual infectivity was assayed on P4 cells as described by CHARNEAU et al.. (1994, J. Mol. Biol., 241, 651-662). Briefly, P4 cells were plated using 100 μL of DMEM medium plus 10% FCS in 96 plate multi-wells at 20×105 cells per mL. After overnight incubation at 37° C., the supernatant was discarded and the viral preparation (200 μL) was added. One day later the wells were washed three times in PBS. Each well was refilled with 200 μL of a reaction buffer containing 50 mM Tris-HCl pH 8.5, 100 mM 2-mercaptoethanol, 0.05% Triton X-100 and 5 mM 4-methylumbelliferyl β-D-galactopyranoside (MUG). After 3 hours at 37° C., the level of the reaction was measured in a fluorescence microplate reader.

[0087] 1.2) Reverse Transcription

[0088] The plasmid pAV4 containing the 50-997 HIV-1 nucleotide fragment (MAL strain) in pSP64, under the control of the bacteriophage T7 promoter was a kind gift from Dr. J. L. DARLIX (INSERM-Lyon, France). E. coli HB 101 recA− was used for plasmid amplification. After digestion of this clone with PstI and in vitro transcription using T7 RNA polymerase, a HIV-1 genomic RNA fragment starting at position +50 of the MAL sequence was obtained. In vitro transcription using T7 RNA polymerase as performed as follows. Three μg of linearized plasmid DNA were transcribed in 100 μL of 40 mM Tris -HCl pH 8.0, 8 mM MgCl2, 10 mM spermidine, 25 mM NaCl, 10 mM dithiothreitol, 0.5 mM of each ribonucleoside triphosphate, with 100 units of T7 RNA polymerase and in the presence of 20 units of human placenta ribonuclease inhibitor, for 2 hours at 37° C. After treatment with 12 units of Rnase-free Dnase I (for 10 minutes at 37° C.), the RNA transcripts were extracted with 1 volume of phenol/chloroform/isoamyl alcohol (24:24:1) and with chloroform and precipitated in 2.5 volumes of ethanol and 0.3 M ammonium acetate (pH 5.5).

[0089] Reverse transcription was performed in a total volume of 50 μL containing 50 mM Tris-HCl pH 8.0, 6 mM MgCl2, 2 mM dithiothreitol, 12 mM NaCl, 150 nM HIV-1 RNA, and either 200 nM of a synthetic oligodeoxynucleotide primer (18-mer ODN) complementary to the PBS of HIV-1 RNA, or 200 nM tRNALys3. When the 18-mer ODN was used as primer, incubation was carried out at 37° C. with the template and 300 nM RT. After 30 minutes, 10 μCi [α-32P]dGTP (3000 Ci/mmol) and 0.1 mM of each dNTP were added and the incubation proceeded for 30 minutes at 37° C. With tRNALYS3 as primer, the same conditions were used except that tRNA and RNA were prehybridized by heating for 2 minutes at 90° C. and then slowly cooled. Samples were extracted with phenol-chloroform and collected by ethanol precipitation. Reaction products were analyzed on 8% polyacrylamide-TBE (90 mM Tris pH 8.3, 90 mM borate, 2 mM EDTA)-7 M urea gels.

RESULTS

[0090] The antiviral activity of the compounds according to example 1 has been tested on various strains.

[0091] On HIV-LAI wild type this compound shows the following activities: IC50=0.2 nM; CC50>105 nM (S.I.>33.333).

[0092] On an HIV-1 novirapine resistant strain the activities of the compound of example 1 are as follows:

[0093] IC50>104 nM

[0094] CC50>104 nM

[0095] The compound of example 1 has been also tested on various HIV strains and primary cell cultures. The table 1 illustrates the activity of this compound on these strains.

[0096] The retrovirucidal effect of the compound according to example 1 has been tested. Table 2 illustrates this effect at various doses of this compound.

[0097] The IC50 of the compound of example 1 for the inhibition of the reverse transcriptase is 20 nM.

TABLE 1
Anti HIV-1 activity of the compound of
example 1 on various HIV strains and primary cell cultures
IC50(nM)/CC50(nM)
					HIV-1 Bal/
	HIV-1	HIV-1	HIV-1	HIV-2 D	Mono/
	IIIIB/	AZTres./	IIIB/	194/	macro-
Compound	MT4	MT4	PBMC	PBMC	phages
Example 1	2.4/	0.2/>1000	0.58/	>1000/>1000	0.004/>1000
	>1000		>1000

[0098]

TABLE 2
Inhibition of infectivity of the compound of example 1
	Dosage of compound of example 1	% inhibition of infectivity
	10	nM	26%
	100	nM	46%
	1	μm	83%
	10	μm	99%

Example 3

Other 3-(amino- or aminoalkyl) Pyridinone Derivatives and Their Retrovirucidal Activity Against Two Different HIV-1 Strains

[0099] 3.1 Compounds

[0100] Further compounds according to the general formula (I) (compounds n°1-25, 27-108, 110-125, 127-145 and 147-203) as well as four intermediate compounds used for synthesis (compounds n°26, 109, 126 and 146) have been synthesized and are listed in table 3 below.

[0101] The meaning of each of the groups Y, Q and R3 - R6 is defined for every exemplified pyridinone derivative.

[0102] 3.2 Retrovirucidal Effect

[0103] The retrovirucidal effect of each pyridinone derivative listed in table 3 has been assayed according to the teachings of example 2, excepted that the anti-viral effect has been tested on the two following HIV-1 strains:

[0104] a) HIV-1 strain IIIB (see example 2);

[0105] b) HIV-1 strain 103 N which is a mutant strain bearing a point mutation in the reverse transcriptase gene leading to an enzyme wherein the initial Lys-103 residue is replaced for a Asn residue.

[0106] HIV-1 103N strain exhibits resistance to the reverse transcriptase inhibitor TIBO R82913 (BALZARINI J. et al. 1993, Virology, 192: 246-253). The HIV-1 103 N strain has also been described by SAHLBERG et al.,(1998, Antiviral Res., 37 (3): ASS) and BALZARiNI et al. (1996, Antimicrobial Agents and Chemotherapy, 40 (6): 1454-1466).

[0107] The results are expressed as pIC50 (pIC50=−log IC50), of every of compound as regards to each of the HIV-1 strains IIIB and 103N. Thus, the pIC50 value of compound n°1 as regards to HIV-1 IIIB being 7,6999, the IC50 can be directly deduced as being equal to 10−7.6999M.

[0108] Such high retrovirucidal activities had never been observed previously when using prior art reverse transcriptase inhibitors.

[0109] Consequently, the novel pyridinone derivatives according to the present invention are of a high therapeutical value against HIV related diseases, particularly against HIV-1 related diseases.

	TABLE 3
	HIV1 pIC50
							strain	strain
	Y	Q	R3	R4	R5	R6	IIIB	103N
1	O	NH2	6Chemistry 4	Et	Me	H	7.699	6.671
2	O	NH2	73,5-Dimethylbenzyl	Et	Me	H	6.612	6.64
3	O	NMe2	83,5-Dimethylbenzyl	Et	Me	H	8.004	7.438
4	O	9Chemistry 33	103,5-Dimethylbenzyl	Et	Me	H	5.094	<4
5	O	NH2	113,5-Dimethylbenzyl	Et	Me	H	6.621	5.636
6	O	NH2	12Chemistry 52	Et	Me	H	5.795	5.026
7	O	NH2	13Chemistry 58	Et	Me	H	<4	<4
8	O	NH2	144-Methylbenzyl	Et	Me	H	4.373	4.39
9	O	NH2	153-Methylbenzyl	Et	Me	H	5.373	5.103
10	O	NMe2	16Chemistry 82	Et	Me	H	6.241	4.389
11	O	NMe2	173,5-Dimethylbenzyl	Et	Me	Me	7.215	6.094
12	O	NEt2	183,5-Dimethylbenzyl	Et	Me	H	8.022	6.363
13	O	NMe2	193-Methylbenzyl	Et	Me	H	8.824	7.622
14	O	NMe2	202-Methylbenzyl	Et	Me	H	7.676	5.849
15	O	NH2	213,5-Dimethylbenzyl	H	H	H	<4.17	4.138
16	O	NMe2	223,5-Dimethylbenzyl	H	H	H	5.061	4.401
17	O	N(n-Pr)2	233,5-Dimethylbenzyl	Et	Me	H	6.285	4.379
18	O	NMe2	244-Methylbenyl	Et	Me	H	6.454	4.895
19	O	NMe2	253,4-Dimethylbenzyl	Et	Me	H	7.447	5.947
20	O	NMe2	262,3-Dimethylbenzyl	Et	Me	H	6.926	5.585
21	O	NMe2	27Benzyl	Et	Me	H	8.409	6.65
22	O	NMe2	283,5-Dimethylbenzyl	Et	Me	Benzyl	4.603	<4
23	O	NMe2	293,5-Dimethlylbenzyl	Et	Me	30Chemistry 163	5.254	<4
24	O	31Chemistry 165	323,5-Dimethylbenzyl	Et	Me	H	4.262	<4
25	O	33Chemistry 171	343,5-Dimethylbenzyl	Et	Me	H	<4	4.259
26	O	35Chemistry 177	363,5-Dimethylbenzoyl	Et	Me	H
27	O	NH2	373,5-Dimethylbenzyl	Me	Et	H	5.949	5.098
28	O	NMe2	383,5-Dimethylbenzyl	Me	Et	H	8.032	6.943
29	O	NHCH2Ph	393,5-Dimethylbenzyl	Et	Me	H	6.555	5.496
30	O	40Piperidin-1-yl	413,5-Dimethylbenzyl	Et	Me	H	6.214	4.224
31	O	NH2	422,4-Dimethylbenzyl	Et	Me	H	<4	<4
32	O	NH2	433,5-Dimethylbenzyl	Me	Me	H	6.104	<5
33	O	NMe2	443,5-Dimethylbenzyl	Me	Me	H	8.42	6.285
34	O	NMe2	452,4-Dimethylbenzoyl	Et	Me	H	5.019	<4
35	O	NMe2	463,5-Dimethylbenzyl	Et	Me	H	8.585	7.987
36	O	47N-Morpholino	483,5-Dimethylbenzyl	Et	Me	H	6.763	<4
37	O	NMe2	492,5-Dimethylbenzyl	Et	Me	H	6.796	5.729
38	O	NMe2	503,5-Difluorobenzyl	Et	Me	H	8.155	7.402
39	O	NH2	513-Chlorobenzyl	Et	Me	H	5	4.751
40	O	NMe2	523-Chlorobenzyl	Et	Me	H	8.585	7.412
41	O	NH2	533-Fluorobenzyl	Et	Me	H	5.131	4.473
42	O	NMe2	543-Fluorobenzyl	Et	Me	H	8.569	7.18
43	O	NMe2	55Chemistry 280	Et	Me	H	7.377	6.422
44	O	NMe2	56Chemistry 286	Et	Me	H	7.889	6.355
45	O	NMe2	573,5-Dimethylbenzyl	Et	Me	Et	5.519	4.095
46	O	NHMe	583,5-Dimethylbenzyl	Et	Me	H	8.119	7.034
47	O	59Chemistry 303	603,5-Dimethylbenzyl	Et	Me	H	7.767	6.968
48	O	NMe2	61Chemistry 310	Et	Me	H	8	6.711
49	O	NH2	62Chemistry 316	Et	Me	H	<4	<5
50	O	NH2	633-Trifluoromethylbenzyl	Et	Me	H	<5	<5
51	O	NH2	64Chemistry 334	Et	Me	H	5.384	<5
52	O	NH2	654-Trifluoromethylbenzyl	Et	Me	H	<4	<5
53	O	NMe2	664-Trifluoromethylbenzyl	Et	Me	H	5.828	<5
54	O	NH2	674-Chlorobenzyl	Et	Me	H	<4	<5
55	O	NMe2	684-Chlorobenzyl	Et	Me	H	6.651
56	O	69Chemistey 363	703,5-Dimethylbenzyl	Et	Me	H	8.194	7.11
57	O	NMe2	713-Trifluoromethylbenzyl	Et	Me	H	8.066	6.414
58	O	NH2	722,4,6-Trimethylbenzyl	Et	Me	H	<4	<5
59	O	NMe2	732,4,6-Trimethylbenzyl	Et	Me	H	5.029	<5
60	O	NMe2	743-Bromobenzyl	Et	Me	H	8.444	7.001
61	O	75Chemistry 393	763,5-Dimethylbenzyl	Et	Me	H	7.693	5.922
62	O	77Chemistry 399	783,5-Dimethylbenzyl	Et	Me	H	6.604	5.305
63	O	NMe2	793,5-Dimethylbenzyl	Me	n-Pr	H	7.029	6.334
64	O	NHC(═O)i-Pr	803,5-Dimethylbenzyl	Et	Me	H
65	O	NMe2	812-Chlorobenzyl	Et	Me	H	8.284	6.405
66	O	NMe2	82Chemistry 430	Et	Me	H	7.588	5.72
67	O	83Chemistry 435	843,5-Dimethylbenzyl	Et	Me	H	6.804	4.955
68	O	85Chemistry 441	863,5-Dimethylbenzyl	Et	Me	H
69	O	NH(n-Bu)	873,5-Dimethylbenzyl	Et	Me	H	6.891	5.655
70	O	NMe2	883,5-Dimethylbenzyl	89Chemistry 45	Me	H	7.752	7.159
71	O	NMe2	903,5-Dimethylbenzyl	n-Pr	Me	H	7.777	7.049
72	O	91Chemistry 485	923,5-Dimethylbenzyl	Et	Me	H	7.079	<4
73	O	NH2	93Chemistry 472	Et	Me	H	8.027	6.92
74	O	NH2	94Chemistry 476	Et	Me	H	<4	<4
75	O	NMe2	95Chemistry 490	Et	Me	H	5.252	4.132
76	O	NH2	963,5-Dimethylbenzyl	H	i-Am	H	<5.494	<4
77	O	NMe2	973,5-Dimethylbenzyl	H	i-Am	H	5.827	<4
78	O	98Chemistry 507	993,5-Dimethylbenzyl	Et	Me	H	8.678	7.128
79	O	100Chemistry 513	1013,5-Dimethylbenzyl	Et	Me	H	6.987	5.47
80	O	NH2	102Chemistry 520	Et	Me	H	<4	<4
81	O	NHEt	1033,5-Dimethylbenzyl	Et	Me	H	7.866	6.444
82	O	104Chemistry 531	1053,5-Dimethylbenzyl	Et	Me	H	7.735	5.813
83	O	NH2	106Chemistry 538	Et	Me	H	<4.033	<4
84	O	NH2	107Chemistry 544	Et	Me	H	<4	<4
85	O	NH2	1083-Methylbenzyl	Me	Me	H	4.954	<4
86	O	NH2	1093-Methylbenzyl	Et	Me	H	7.863	5.936
87	O	NH2	1103-Methylbenzoyl	Et	Me	H	6.46	5.653
88	O	NMe2	111Chemistry 568	Et	Me	H	<4
89	O	NMe2	1123,5-Dimethylbenzyl	H	n-Bu	H	6.237
90	O	NMe2	1133,5-Dimethylbenzyl	H	n-Bu	H	6.359
91	O	NH2	1143-Methylbenzyl	(CH2)4	(CH2)4	H	5.73
92	O	NMe2	1153-Methylbenzyl	(CH2)4	(CH2)4	H	7.807
93	O	NMe2	1163-Methylbenzoyl	Et	Me	H	8.721
94	O	NH2	1173-Methylbenzoyl	Me	Me	H	5.153
95	O	NEt2	1183-Methylbenzoyl	Et	Me	H	8.268
96	O	NMe2	1193-Methylbenzoyl	Me	Me	H	7.824	6.37
97	O	NH2	120Chemistry 622	Et	Me	H	<4	<4
98	O	NH2	1213-Ethylbenzyl	Et	Me	H	5.358	4.578
99	O	NMe2	1223-Ethylbenzyl	Et	Me	H	8.569	6.718
100	O	NH2	1233,5-Dimethylbenzyl	H	Me	H	4.871	<4
101	O	NMe2	1243,5-Dimethylbenzyl	H	Me	H	6.341	4.25
102	O	NMe2	125Chemistry 652	Et	Me	H	4.369	<4
103	O	NH2	126Chemistry 658	Et	Me	H	5.747
104	O	NMe2	127Chemistry 664	Et	Me	H	8	7.058
105	O	NH2	1283,5-Dimethylbenzyl	Cl	H	H	4.943
106	O	NMe2	1293,5-Dimethylbenzyl	Cl	H	H	7.063
107	O	NMe2	1303-Methylbenzoyl	(CH2)4	(CH2)4	H	7.231
108	O	NMe2	1313-Methylbenzoyl	Me	Et	H	7.005
109	O	132Chemistry 699	1333,5-Dimethylbenzyl	H	OMe	H
110	O	NMe2	134Chemistry 706	Et	Me	H	7.783
111	O	NH2	135Chemistry 712	Et	Me	H	<4
112	O	NMe2	136Chemistry 718	Et	Me	H	6.394
113	O	NH2	137Chemistry 724	Et	Me	H	5.273
114	O	138Chemistry 729	139Chemistry 730	Et	Me	H
115	O	NMe2	1403-Methylbenzoyl	Et	Me	141Chemis- try 745	<4.307
116	O	NMe2	142Chemistry 748	Et	Me	H	6.627
117	O	CH2NMe2	1433-Methylbenzyl	(CH2)4	(CH2)4	H	<4.139
118	O	NH2	1443-Dimethylbenzyl	Me	i-Pr	H	4.042
119	O	NMe2	1453-Dimethylbenzyl	Me	i-Pr	H	6.114
120	O	NH2	1463-Methoxybenzyl	Et	Me	H	5.033
121	O	NMe2	1473-Methoxybenzyl	Et	Me	H	8.469	6.948
122	O	NMe2	1483-OHbenzyl	Et	Me	H	7.196
123	O	149Chemistry 789	1503,5-Dimethylbenzyl	Et	Me	H	8.444	6.918
124	O	NH2	151Chemistry 796	Et	Me	H	4.389
125	O	NHCHO	1523-Methylbenzyl	Et	Me	H
126	O	NHCHO	1533-Methylbenzoyl	Et	Me	H
127	O	NMe2	154Chemistry 814	Et	Me	H	4.174
128	O	NMe2	155Chemistry 820	Et	Me	H	7.848
129	O	156Chemistry 825	1573,5-Dimethylbenzyl	Et	Me	H	8.398	7.057
130	O	NH2	158Chemistry 832	Et	Me	H	<4
131	O	NH2	1593-Methylbenzyl	(CH2)3	(CH2)3	H	5.799
132	O	NMe2	1603-Methylbenzyl	(CH2)3	(CH2)3	H	7.863
133	O	NMe2	161Chemistry 850	Et	Me	H	4.94
134	O	NH2	162Chemistry 856	Et	Me	H	4.056
135	O	NMe2	163Chemistry 862	Et	Me	H	6.688
136	O	164	1653-Methylbenzyl	Et	Me	H	9	6.996
137	S	NMe2	1663,5-Dimethylbenzyl	Et	Me	H	7.658
138	S	NMe2	1673,5-Dimethylbenzoyl	Et	Me	H	8.215	7.401
139	O	NHMe	1683-Trifluoromethylbenzyl	Et	Me	H	6.908
140	O	NH2	1693-Trifluoromethylbenzoyl	Et	Me	H	5.766
141	O	NH2	170Chemistry 898	Et	Me	H	4.642
142	O	NH2	1713-Methylbenzoyl	(CH2)3	(CH2)3	H	4.869
143	O	NMe2	172Chemistry 910	Et	Me	H	7.421
144	O	173Chemistry 915	1743-Methylbenzyl	Et	Me	H	6.446
145	O	175Chemistry 921	1763-Methylbenzyl	Et	Me	H	8.42	6.028
146	O	177Chemistry 927	178Chemistry 928	Et	Me	H
147	O	NMe2	179Chemistry 934	Et	Me	H	7.721
148	O	NMe2	1803-Methylbenzoyl	(CH2)3	(CH2)3	H	7.863
149	O	NMe2	181Chemistry 946	Et	Me	H	8.959	7.883
150	O	NH2	182Chemistry 952	Et	Me	H	4.881
151	O	NMe2	183Chemistry 958	Et	Me	H	7.845
152	O	NMe2	1843,5-Dimethylbenzyl	Et	Me	Ph	4.21
153	O	NMe2	1853,5-Dimethylbenzyl	Et	Me	NH2	6.749
154	O	186Chemistry 981	1873-Methylbenzyl	Et	Me	H	8.009	6.262
155	O	188Chemistry 987	1893-Methylbenzyl	Et	Me	H	7.514
156	O	NH2	190Chemistry 994	Et	Me	H	4.934
157	O	NMe2	191Chemistry 1000	Et	Me	H	6.413
158	O	NMe2	192Chemistry 1006	Et	Me	H	8.041	6.625
159	O	NH2	193Chemistry 1012	Et	Me	H	7.011
160	O	NMe2	194Chemistry 1018	Et	Me	H	8.678	7.177
161	O	195Chemistry 1023	1963-Trifluoromethylbenzyl	Et	Me	H	7.821	5.814
162	O	NMe2	197Chemistry 1030	Et	Me	H	6.418	5.026
163	O	NMe2	198Chemistry 1036	Et	Me	H	5.596	4.236
164	O	199Chemistry 1041	2003-Methylbenzyl	Et	Me	H	7.818	6.505
165	O	NMe2	201Chemistry 1048	Et	Me	H	4.354	<4
166	O	NMe2	202Chemistry 1054	Et	Me	H	5.693	4.518
167	O	NMe2	203Chemistry 1060	Et	Me	H	6.338	5.828
168	O	NH2	204Chemistry 1066	Et	Me	H	4.525	4.806
169	O	NMe2	205Chemistry 1072	Et	Me	H	7.101	5.771
170	O	NMe2	206Chemistry 1078	Et	Me	H	8.553	7.224
171	O	NMe2	207Chemistry 1084	Et	Me	H	5.895	4.74
172	O	NH2	2083,5-Dimethylbenzyl	(CH2)4	(CH2)4	H	6.419	4.903
173	O	NMe2	2093,5-Dimethylbenzyl	(CH2)4	(CH2)4	H	8.086	6.489
174	O	NMe2	2103-Bromobenzoyl	Et	Me	H	8.921	7.68
175	O	211Chemistry 1107	2123-Methylbenzoyl	Et	Me	H	8.921	7.717
176	O	NMe2	213Chemistry 1114	Et	Me	H	8.432	6.436
177	O	NH2	214Chemistry 1120	Et	Me	H	5.106	<4
178	O	NMe2	215Chemistry 1126	Et	Me	H	7.873	6.461
179	O	NHMe	2163-Bromobenzoyl	Et	Me	H	8.42	7.182
180	O	217Chemistry 1137	2183-Methylbenzyl	Et	Me	H	5.988
181	O	NMe2	219Chemistry 1150	Et	Me	H	7.928
182	O	NH2	220Chemistry 1156	Et	Me	H	5.933
183	O	NMe2	221Chemistry 1162	Et	Me	H	8.481
184	O	222Chemistry 1167	2233-Bromobenzyl	Et	Me	H	8.523	6.804
185	O	224Chemistry 1173	2253-Bromobenzoyl	Et	Me	H	8.745	7.433
186	O	NH2	226Chemistry 1180	Et	Me	H	5.781
187	O	NMe2	227Chemistry 1186	Et	Me	H	8.481	7.006
188	O	NH2	228Chemistry 1192	Et	Me	H	7.063
189	O	NH2	2293,5-Dichlorobenzyl	Et	Me	H	6.401
190	O	NH2	2303,5-Dichlorobenzyl	Et	Me	H	7.757
191	O	NMe2	2313,5-Dichlorobenzyl	Et	Me	H	8.097	7.553
192	O	NMe2	2323,5-Dichlorobenzyl	Et	Me	H	8.699	8.319
193	O	NMe2	233Chemistry 1222	Et	Me	H	8.481	7.245
194	O	NH2	234Chemistry 1228	Et	Me	H	4.665
195	O	235Chemistry 1233	2363-Methylbenzyl	Et	Me	H	8.569	6.52
196	O	NMe2	237Chemistry 1240	Et	Me	H	6.411
197	O	NH2	238Chemistry 1246	Et	Me	H	7.307
198	O	NH2	239Chemistry 1252	Me	H	H	4.457
199	O	240Chemistry 1257	2413-Methylbenzyl	Et	Me	H	7.924
200	O	242Chemistry 1263	243Benzyl	Et	Me	H	8.42	5.95
201	O	NMe2	244Chemistry 1276	Et	Me	H	8.585	7.231
202	O	NH2	2452-Bromobenzyl	Et	Me	H	5.715
203	O	NMe2	2462-Bromobenzyl	Et	Me	H	8.161

Claims

1. A compound having the formula (1)

2. A compound according to claim 1 wherein R1 and R2 represent each a methyl group.

3. A compound according to claim 1 wherein X represents —CH2— and R3 represents a phenyl group substituted with two methyl groups.

4. A compound according to claim 1 which is the 3-dimethylamino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one.

5. A process for the obtention of compounds according to claim 1 wherein X represents —CH2—, Y represents O, R3 is an optionally phenyl group substituted and R6 is hydrogen comprising the following steps: a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C1-C6 alkyllithium, resulting in a lithiated derivate of the said pyridine. b) transforming said lithiated derivate into an organocopper reagent by reacting it with a complex formed by Cu I and dimethyl sulphide. c) obtaining a protected pyridinone by reacting the organocopper reagent with optionally substituted benzyl halide. d) hydrolysing said protected pyridinone and obtaining a deprotected pyridinone. e) substituting the amine-3 group of said deprotected pyridinone and obtaining the desired pyridinone compound.

6. A process for the obtention of compounds according to claim 1 wherein X represents —C(═O), Y represents O, R3 is an optionally substituted phenyl group, and R6 is hydrogen wherein: a) reacting a pyridine, substituted in position 2 with an alkoxy group and in position 3 with an amidoalkyl group, with a C1-C6 alkyllithium, resulting in a lithiated derivate of said pyridine. b) reacting the lithiated derivative with an optionally substituted benzaldehyde, resulting in a substituted pyridinone, c) oxidizing said substituted pyridinone, resulting in a protected pyridinone, d) deprotecting said protected pyridinone by hydrolysis, resulting in the desired pyridinone compound.

7. Lithiated derivative having the following formula:

8. Pharmaceutical compositions comprising a therapeutically effective amount of at least a compound according to claim 1 and pharmaceutical carriers.

9. Method of treatment of HIV-related diseases comprising the administration of an effective amount of a compound according to claim 1.

10. Method of treatment of HIV-infection comprising the administration of an effective amount of a compound according to claim 1.