Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-15
2000-01-18
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514309, 546297, 546298, 546142, A61K 3144, C07D21370, C07D21373, C07D21375, C07D21538
Patent
active
060158204
DESCRIPTION:
BRIEF SUMMARY
The purpose of this invention is 4-aryl-thio-pyridin-2(1H)-ones and their applications as medicines.
It relates particularly to their uses in the treatment of illnesses linked to the human immunodeficiency virus (HIV).
The derivatives of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and of pyridinones are known for their inhibiting properties for the inverse transcriptase of HIV-1.
HEPT and another derivative of the same family, named E-EPU (5-ethyl-l-ethoxymethyl-6-(phenylthio)-uracil) are represented respectively in FIG. 1 by the formulae (1a) and (1b). Pyridinones having inhibiting properties with respect to the inverse transcriptase are represented in FIG. 2 by the formulae (2a) and (2b).
Other compounds which are inhibitors of the HIV virus inverse transcriptase, including pyridinones, are also described in the patent application EP-0.462.800 (Merck). This application describes, in a general manner, a group of pyridinones that have a particular structure, in which the group R.sub.4 in position 4 of the ring is an alkylthio or alkylamino group, and the group in position 3 has to be substituted with an aryl or heterocyclic group, which may be substituted, bonded to the pyridinone nucleus by an X-CHnR.sub.3 chain which cannot be NHCO. Nevertheless, only compounds in which R.sub.4 is an atom of hydrogen have been synthesised. In any case, this document does not mention that the compounds penetrate the viral particle.
These compounds have the disadvantage of causing the rapid appearance of resistant strains of HIV-1 and their use in a long term course of monotherapy in man in the treatment of illnesses linked to the HIV virus is therefore made difficult.
Another problem posed in the treatment of illnesses linked to the HIV virus is in the blocking of the conversion of genomic RNA into proviral DNA, a step essential to the integration into the eucaryote genome. Recent work clearly shows that this retro-transcription can take place even within the virion, when it is still in its extra-cellular phase. Hence, up to 2% of the viral cells, in the case of seminal liquid, can have their retro-transcription terminated before merging with the target cell. Therefore it is essential that the inhibitors of the inverse transcriptase (IT) can penetrate the virion before it has reached the cell.
Studies by Perelson et al. (1996, Science 271.1582-1586) on viral dynamics show that the average life of a viral particle in blood plasma is of the order of 8 hours or about a quarter of the estimated life of HIV-1 in vivo. The virion, in its extra-cellular phase is therefore a potential target for these inhibitors.
It should be noted that other thiopyridinones not having any anti-HIV-1 activity have been described.
The article by CROISY-DELCEY at al. (1983 J. Med. Chem. vol.26, No. 9, 1329-1333) describes the synthesis of analogues of lucanthone which shows anti-tumour and bactericide activity. The intermediate compounds 7b, 17a and 17b are pyridinones.
The article by RIVALLE et al. ((1980) J. Heterocycl. Chem., Vol.17, No. 2, 245-248) describes the synthesis of pyridoquinolines, from intermediate compounds, some of which are pyridinones. No activity is mentioned, either for the final compounds or the intermediates.
The article by UPTON ((1986) J. Chem. Soc. Perkin Trans. 1, No. 7, 1225-1229), describes the synthesis of anthracenes by the use of, in particular, hydroxypyridines and not pyridinones.
The applicant has become interested in finding new molecules showing strong inhibiting activity, that is to say, being active at low doses, low cytotoxicity and which penetrate the viral particle.
He has shown that the substituted 4-aryl-thio-pyridin-2(1H)-ones exhibit strong inhibiting action and low cytotoxicity while penetrating the viral particle.
Hence the object of this invention is compounds of formula (3), represented in FIG. 3, in which: aliphatic group or an alkyloxyalkyl group in which the alkyl chains are from C.sub.1 to C.sub.4 or together form an aromatic ring; COR.sub.6 group in which R.sub.6 is an aliphatic o
REFERENCES:
V. Dolle et al., Journal of Medicinal Chemistry, vol. 38, pp. 4679-4686 (1995).
Andreola Marie-Line
Aubertin Anne-Marie
Bisagni Emile
Dolle Valerie
Kirn Andre
Centre National de la Recherche Scientifique "CNRS"
Rotman Alan L.
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