Substituted 1,3-oxathiolanes with antiviral properties

Details Substituted 1,3-oxathiolanes with antiviral properties Substituted 1,3-oxathiolanes with antiviral properties

1996-11-26

2001-05-08

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S274000, C544S317000

Reexamination Certificate

active

06228860

ABSTRACT:

The present invention relates to novel substituted 1,3-oxathiolane compounds having pharmacological activity, 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.
Compounds having an inhibitory effect on HIV multiplication or otherwise effective in the therapy of retroviral infections are being actively sought.
H. Mitsuya et al., “3′-Azido-3′-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro”,
Proc. Natl. Acad. Sci. USA,
82, pp. 7096-7100 (1985), refers to 3′-azido-3′-deoxythymidine of formula (A), 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).
H. Mitsuya and S. Broder, “Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides”,
Proc. Natl. Acad. Sci. USA,
83, 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.
P. Herdewijn et al., “3′-Substituted 2′,3′-dideoxynucleoside analogues as potential anti-HIV(HTLV-III/LAV) agents”,
J. Med. Chem.,
30, pp. 1270-1278 (1987), describe the anti-HIV activity of a series of 3′-substituted nucleoside analogues. While 3′-fluoro analogues of 3′-deoxythymidine and 2′,3′-dideoxy-cytidine shown in formulas (C) and (D) are found to possess potent antiretroviral activity, substituents linked to the 3′-carbon via a thio or oxygen bridge did not yield active products.
Analysis of molecular conformation studies in P. Van Roey et al., “Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus”,
Proc. Natl. Acad. Sci. USA,
86(10), pp. 3929-3933 (1989), indicate that active anti-HIV nucleoside analogues have 3′ carbon conformations on the side opposite to the base.
D. Huryn et al., “Synthesis of iso-ddA, member of a novel class of anti-HIV agents”,
Tetrahedron Lett.,
30(46), pp. 6259-6262 (1989), refer to the iso-nucleoside analogue of formula (E) as a stable inhibitor of HIV replication.
R. Vince and M. Hua, “Synthesis and anti-HIV activity of carbocyclic 2′,3′-didehydro-2′,3′-dideoxy 2,6-disubstituted purine nucleosides”,
J. Med. Chem.,
33(1), pp. 17-21 (1990), describe the analogues shown in formulas (F) and (G) as having anti-HIV activity. The unsaturated analogue (F) shows greater selectivity and potency as an inhibitor of HIV replication than the saturated analog (G).
C. Chu et al., “Synthesis and structure-activity relationships of 6-substituted 2′,3′-dideoxypurine nucleosides as potential anti-human immunodeficiency virus agents”,
J. Med. Chem.,
33(6), pp. 1553-1561 (1990), describe the N
6
-methyl derivative shown in formula (H) as having greater potency against HIV than unmethylated 2′,3′-dideoxyadenosine.
Finally, B. Belleau et al., “Design and activity of a novel class of nucleoside analogues effective against HIV-1”, Abstracts of papers, Fifth International Conference on AIDS, Montreal, T.C.O. 1, p. 515 (1989), refer to dioxolanes and oxathiolanes of formulas (J) and (K) as having potent anti-HIV activity.
The cis isomer of formula (K) has been found to be active against HIV and HBV, and its unnatural enantiomer ((2R,5S cis) referred to as “the (-) enantiomer” has been found to have surprisingly low toxicity. Now named lamivudine or “3TC™”, this new anti-viral drug is becoming the treatment of choice for combination therapy of AIDS patients and for sole therapy for HBV patients.
Although lamivudine (3TC™) has been found to be an extremely interesting compound in the clinic, there is always the possibility that the patient develops virus strains that are resistant to it after prolonged periods of treatment. There is therefore, still a need to develop anti-viral agents that are active against nucleoside-resistant viral strains, in particular, against 3TC™-resistant viral strains.
SUMMARY OF THE INVENTION
Classes of compounds known as 2-substituted 4-substituted 1,3-oxathiolanes have been found to have potent antiviral activity. In particular, these compounds have been found to act as potent inhibitors of HIV-1 replication in T-lymphocytes over a prolonged period of time with less cytotoxic side effects than compounds known in the art. These compounds have also been found active against 3TC-resistant HIV strains. These compounds are also useful in prophylaxis and treatment of hepatitis B virus infections.
There are accordingly provided in a first aspect of this invention a single enantiomer of compounds of formula (I) in the cis configuration:
wherein R
1
is hydrogen,
R
2
is cytosine or 5-fluorocytosine, and pharmaceutically acceptable salts and esters thereof.
As used herein, “a pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an antivirally active metabolite or residue thereof.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, p-toluene sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C
1-4
alkyl)
4
+
salts.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable salts and esters thereof, at functional groups in both the cytosine moiety, and at the hydroxymethyl group of the oxathiolane ring, respectively. Modification at all such functional groups is included within the scope of the invention. However, of particular interest are pharmaceutically acceptable salts and esters (e.g., esters or esters of amino acids) obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
Preferred esters of the compounds of formula (I) include the compounds in which R
1
is replaced by a carboxyl function R-(CO) in which the non-carbonyl moiety R of the ester grouping is selected from hydrogen, straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl optionally substituted by halogen, C
1-4
alkyl or C
1-4
alkoxy); substituted dihydro pyridinyl (e.g., N-methyldihydro pyridinyl); sulphonate esters such as alkyl- or aralkylsulphonyl (e.g., methanesulphonyl); sulfate esters; amino acid esters (e.g., L-valyl or L-isoleucyl) and mono, di- or triphosphate esters.
Also included within the scope of such esters are esters derived from polyfunctional acids such as carboxylic acids containing more than one carboxyl group, for example, dicarboxylic acids HO
2
C(CH
2
)
n
CO
2
H where n is an integer of 1 t

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