N4-substituted cytosinyl 1,3-oxathiolane nucleoside analogues, a

Details N4-substituted cytosinyl 1,3-oxathiolane nucleoside analogues, a N4-substituted cytosinyl 1,3-oxathiolane nucleoside analogues, a

1996-03-25

1998-01-13

Kight, John

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544311, 544312, 536 285, 536 2851, 536 2852, 514 49, A61K 31505, C07D23902

Patent

active

057080003

DESCRIPTION:

BRIEF SUMMARY
This invention relates to the field of organic chemistry and more precisely to that of medicinal chemistry.
More particularly it has as a subject matter 2',3'-didesoxynucleosides substituted in position 2 with an oxathiolane ring.
Specifically this invention has as a subject matter the 5-(citosinyl)1,3-oxathiolanes of cis configuration (2R-5S) or (2S-5R) having the general formula: ##STR1## which may be represented with one out the two spatial representations: ##STR2## wherein R is an acyl radical or an aralkyl radical, derived from a monocyclic or bicyclic nitrogenous heteroring and the hydroxymethyl group in position 2 is in cis position relating to the plane determined by the two positions 2 and 5.
Among the various definitions taken by the substituent R, it may be differentiated
a) the nicotinic derivatives where the heteroring is a pyridinic structure and the acyl moiety is in position 2, 3 or 4, having the formula Ia ##STR3## wherein X is a hydrogen, a halogen atom, a nitro group, a lower alkoxy or a trifluoromethyl radical and n is a integer from 1 to 3
b) the dihydropyridic derivatives wherein the heteroring is a 1,4-dihydropyridinic structure and the acyl radical is in position 2, 3 or 4, having the formula Ib ##STR4## wherein R.sub.1 is an alkyl radical having from 1 to 10 carbon atoms and X and n are defined as previously
c) the quaternized nicotinic derivatives wherein the nitrogen atom bears an alkyl substituent and the acyl radical is in position 2, 3, or 4, having the general formula Ic ##STR5## wherein A is an inorganic or organic anion and R.sub.1, X and n are defined as previously
d) the quinoleinic derivatives wherein the heteroring is a bicyclic structure, having the general formula Id ##STR6## wherein the carbonyl radical may be in position 2, 3, or 4, X represents a hydrogen, a halogen, a trifluoromethyl radical, a lower alkoxy or a nitro group and n' represents an integer from 1 to 6.
e) the dihydroquinoleines of general formula Ie ##STR7## wherein R.sub.1 and X are defined as previously and n' is an integer from 1 to 6.
f) the quaternized quinoleins of general formula If ##STR8## wherein R.sub.1, X and n' are defined as previously the acyl radical is present in position 2, 3, or 4, and A is an inorganic or organic anion
g) the (dihydropyridyl) alkyl derivatives of general formula Ig ##STR9## wherein R.sub.1, X and n are defined as previously and m is an integer from 1 to 6 as well as the acid addition salts thereof with a mineral or organic acid.
The compounds of formula I may be resolved in their optically-active isomers. It may thus be obtained the isomer (+) and the isomer (-).
The retroviral infections are the cause of severe infections, particularly that of acquired immunodeficiency syndrom (AIDS) which is a vital infection often lethal and to a lesser degree hepatitis. Several compounds of nucleosidic or hetero-nucleosidic types are presently clinically utilized for the treatment of these retroviral infections. The former ones are the derivatives of AZT (3'-azido-2',3'-didesoxythymidine) (Proc. Natl. Acad. Sci. 82, 7096-7100, 1985), ddC (2',3'-didesoxycytidine)(Proc. Natl. Acad. Sci. 86, 1911-15, 1986), d4T (2',3'-didehydro-3'-desoxythymidine) (Biochem, Biophys, Res. Comm. 142, 128-34, 1987), ddl (2',3'-didesoxyinosine) (Antiviral, Chem Chemother 2, 221, 1991), BCH-189 or 3TC (2',3'-dideoxy 3'-thiacytidine) disclosed in the european patent application 90301335.7 and the followings. The limited number of the anti-retroviral compounds available to the practioner ant the limited efficacy suggested the search of new compounds, the therapeutic virtues of which would be increased and the side-effects will be decreased namely the esters of the hydroxymethyl function (european patent application 0,382,526) or the halogenated derivatives in position 5' of the pyrimidine ring are already known (R. F. SCHINAZI et al. Antimicrob Agents and Chemotherapy 36(1992)2423-2431).
The compounds of this invention possess the ability to inhibit the replication of human retroviruses, particularly VIH

REFERENCES:
Camplo et al., "Synthesis and Antiviral of N-4'-dihydropyridinyl and e Derivatives Against Human Immunodeficiency Virus and Duck Hepatitis B Virus," European J. Medicinal Chem., 31, 539-546 (1996).
Storer et al., "The Resolution and Absolute Stereochemistry of the Nucleosides and Nucleotides, 12(2), 225-236 (1993); Chem. Abstr., 119(5), p. 999, Abstr. No. 49821h (Aug. 2, 1993); only Abstract supplied.
Camplo et al., "Synthesis and Antiviral Activity of a Potential Prodrug: N.sup.4 -Retinoyl-3'-thia-2',3'-dideoxycytidine," Medicinal Chem. Res., 3(2), 87-95 (1993); Chem. Abstr., 119(23), p. 16, Abstr. No. 240935c (Dec. 6, 1993); only Abstract supplied.
Camplo et al., "Synthesis and Comparative Anti-HIV Activities of New Acetylated 2',3'-Dideoxy-3'-thiacytidine Analogs," European J. Medicinal Chem., 29(5), 357-362 (1994); Chem. Abstr., 121(21), p.53, Abstr. No. 245179k (Nov. 21, 1994); only Abstract supplied.
Charvet-Faury et al., "Inhibition of Human Immunodeficiency Virus Type 1 Replication by Phosphonoformate-and Phosphonoacetate-2',3'-Dideoxy-3'-thiacytidine Conjugates," J. Medicinal Chem, 37(14), 2216-2223 (1994); Chem. Abstr., 121(19), p. 1143, Abstr. No. 231238s (Nov. 7, 1994); only Abstract supplied.
Kim et al., "Potent Anti-HIV and Anti-HBV Activities of (-)-L-.beta.-Dioxolane-C and (+)-L-.beta.-Dioxolane-T and Their Asymmetric Syntheses," Tetrahedron Letters, 33(46), 6899-6902 (1992).

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