Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-30
2002-02-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S314000, C544S317000
Reexamination Certificate
active
06350753
ABSTRACT:
The present invention relates to novel substituted 1,3-oxathiolane and substituted-1,3-dioxolane cyclic compounds having pharmacological activity, to processes for and intermediates of use in their preparation, to pharmaceutical compositions containing them, and to the use of these compounds in the antiviral treatment of mammals.
Retroviral infections are a serious cause of disease, most notably, the acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus (HIV) has been recognized as the etiologic agent of AIDS, and compounds having an inhibitory effect against HIV multiplication have been actively sought.
Mitsuya et al., “3′-Azido-3′-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lympho-tropic virus type III/lymphadenopathy-associated virus in vitro”,
Proc. Natl. Acad. Sci. U.S.A
., 82, pp. 7096-7100 (1985), refers to a compound of formula (A) (3′-azido-2′,3′-dideoxythymidine), commonly referred to as AZT. This compound is said to be useful in providing some protection for AIDS carriers against the cytopathogenic effect of immunodeficiency virus (HIV).
Mitsuya et al., “Inhibition of the in vitro infectivity and cytopathic effect of human T-lympho-trophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′3′-dideoxynucleosides”,
Proc. Natl. Acad. Sci. U.S.A
., 86, pp. 1911-15 (1986), have also referred to a group of 2′,3′-dideoxynucleosides shown in formula (B) which are said to possess protective activity against HIV-induced cytopathogenicity.
Balzarini et al., “Potent and selective anti-HTLV-III/LAV activity of 2′,3′-dideoxycytidinene, the 2′,3′-unsaturated derivative of 2′,3′-dideoxycytidine”,
Biochem. Biophys. Res. Comm
., 140, pp. 735-42 (1986), refer to an unsaturated analogue of these nucleosides—2′,3′-dideoxycytidine, shown in formula (C)—as being characterized by antiretroviral activity.
Baba et al., “Both 2′,3′-dideoxythymidine and its 2′,3′-unsaturated derivative (2′,3′-dideoxythymidine) are potent and selective inhibitors of human immunodeficiency virus replication in vitro”,
Biochem. Biophys. Res. Comm
., 142, pp. 128-34 (1987), refer to the 2′,3′-unsaturated analogue shown in formula (D) of 2′,3′-dideoxythymidine. This analogue is purported to be a potent selective inhibitor of HIV replication.
Analogues of AZT known as 3′-azido-2′,3′-dideoxyuridine shown in formula (E), where Y is bromine or iodine, have been said to have an inhibitory activity against Moloney murine leukemia in T. S. Lin et al., “Synthesis and antiviral activity of various 3′-azido,3′ amino,2′,3′-unsaturated and 2′,3′-dideoxy analogues of pyrimidine, deoxyribonucleosides against retroviruses”,
J. Med. Chem
., 30, pp. 440-41 (1987).
Finally, the 3′-fluoro analogues of 2′,3′-dideoxythymidine shown in formula (F) and of 2′,3′-dideoxythymidine shown in formula (G) are referred to in Herdewijn et al., “3′-Substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV(HTLV-III/LAV) agents”,
J. Med. Chem
., 30, pp. 1270-78 (1987), as having potent antiretroviral activity.
The most potent anti-HIV compounds thus far reported are 2′,3′-dideoxynucleosides, more particularly, 2′,3′-dideoxy cytidine (ddCyd) and 3′-azido-2′,3′-dideoxythymidine (AzddThd or AZT). These compounds are also active against other kinds of retroviruses such as the Moloney murine leukemia virus. Because of the increasing incidence and the life-threatening characteristics of AIDS, efforts are being expended to discover and develop new non-toxic and potent inhibitors of HIV and blockers of its infectivity. It is therefore an object of the present invention to provide effective anti-HIV compounds of low toxicity and a synthesis of such new compounds that is readily feasible.
A structurally distinct class of compounds known as 2-substituted-5-substituted-1,3-oxathiolanes and 2-substituted-4-substituted-1,3-dioxolanes has now been discovered and found to have antiretroviral activity. In particular, these compounds have been found to act as non-toxic inhibitors of the replication of HIV-1 in T-lymphocytes over prolonged periods of time.
There are accordingly provided in a first aspect of this invention compounds of formula (I)
wherein R
1
is hydrogen or an acyl radical from 1 to 16 carbon atoms, preferably a benzoyl or a benzoyl substituted in any position by at least one halogen (bromine, chlorine, fluorine or iodine), C
1-6
alkyl, C
1-6
alkoxy, nitro or trifluoromethyl groups;
R
2
is a purine or pyrimidine base or an analogue or derivative thereof;
Z is O, S, S═O or SO
2
; and
R
1
can be, for example, acetyl, hexanoyl, or aroyl.
The art that the compounds of formula (I) contain at least two chiral centers (shown as * in formula (I)) and thus exist in the form of two pairs of optical isomers (i.e., enantiomers) and mixtures thereof including racemic mixtures. Thus the compounds of formula (I) may be either cis isomers, as represented by formula (II), or trans isomers, as represented by formula (III), or mixtures thereof. Each of the cis and trans isomers can exist as one of two enantiomers or as mixtures thereof including racemic mixtures. All such isomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
The compounds of formula (I) are preferably in the form of their cis isomers.
It will also be appreciated that when Z is S═O the compounds exist in two additional isomeric forms as shown in formulas (IIa) and (IIb) which differ in the configuration of the oxide oxygen atom relative to the 2,5-substituents. The compounds of the invention additionally embrace such isomers and mixtures thereof.
The purine or pyrimidine base or analogue or derivative thereof R
2
will be linked at the 9- or 1-position, respectively.
By “purine or pyrimidine base” or an analogue or derivative thereof is meant a purine or pyrimidine base found in native nucleosides or an analogue thereof which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the native bases but may either possess additional or lack certain of the functional properties of the native bases. Such analogues include those derived by replacement of a CH
2
moiety by a nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine) or vice verse (for example 7-deazapurines, for example 7-deazadenosine or 7-deazaguanosine) or both (e.g., 7-deaza-8-azapurines). By derivatives of such bases or analogues are meant those compounds wherein ring substituents are either incorporated, removed or modified by conventional substituents known in the art, e.g., halogen, hydroxyl, amino, C
1-6
alkyl. Such purine or pyrimidine bases, analogues and derivatives will be well known to those skilled in the art.
Conveniently the group R
2
is selected from:
wherein R
3
is selected from the group of hydrogen, acetyl, hydroxyl or C
1-6
alkyl or alkenyl groups;
R
4
and R
5
are independently selected from the group of hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted C
1-6
alkyl or alkenyl groups, bromine, chlorine, fluorine, or iodine; R6 is selected from the group of hydrogen, cyano, carboxy, ethoxycarbonyl, carbamoyl, or thiocarbamoyl; and
X and Y are independently selected from the group of hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy groups.
Preferably R
2
is
wherein R
3
and R
4
are as defined hereinabove.
Z is preferably —S—.
When the compound of formula (I) is a 1,3-oxathiolane of formula (Ia), where Z is S, S═O or SO
2
,
preferably:
R
1
is selected from a group consisting of hydrogen and an acyl group having 1 to 16 carbon atoms;
R
2
is a heterocyclic radical selected from the group consisting of:
R
3
and R
4
are ind
Belleau Bernard
Belleau Pierette
Dixit Dilip M.
Nguyen-Ba Paul
Belleau Pierette
Biochem Pharma Inc.
McKenzie Thomas
Millen White Zelano & Branigan P.C.
Raymond Richard L.
LandOfFree
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