Processes for preparing substituted 1, 3-oxathiolanes with...

Details Processes for preparing substituted 1, 3-oxathiolanes with... Processes for preparing substituted 1, 3-oxathiolanes with...

2001-01-16

2004-12-14

McKenzie, Thomas (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S212000, C544S218000, C544S223000, C546S280400, C546S281400, C548S263200, C548S263800, C548S311100, C548S527000

Reexamination Certificate

active

06831174

ABSTRACT:

The present invention relates to processes for preparing substituted 1,3-oxathiolanes with antiviral activity and intermediates of use in their preparation.
BACKGROUND OF THE INVENTION
Nucleosides, and in particular, 1,3-oxathiolanes and their analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleosides have shown antiviral activity against retroviruses such as human immunodeficiency viruses (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV).
The most potent anti-HIV compounds thus far reported are 2′,3′-dideoxynucleosides, more particularly, 2′,3′-dideoxycytidine (ddC) and 3′-azido-2′,3′-dideoxythymidine (AZT). These compounds are also active against other kinds of retroviruses such as the Moloney murine leukemia virus. However, clinically, both compounds are toxic.
A structurally distinct class of compounds known as 2-substituted-5-substituted-1,3-oxathiolanes has been found to have superior antiviral and antiretroviral activity without cell toxicity. See, e.g., EP 0382526A and WO 91/17159 the disclosures of which are incorporated herein by reference.
Because of the increasing incidence and the life-threatening characteristics of AIDS, there is a great need to develop a general synthetic scheme for substituted 1,3-oxathiolanes which is efficient, amenable to large scale, inexpensive and based on readily available starting material. It is therefore an advantage of the present invention to provide synthesis of substituted 1,3-oxathiolanes that is readily feasible.
DESCRIPTION OF THE INVENTION
The processes of this invention may be used to prepare the compounds of formula (I) and pharmaceutically acceptable salts or esters thereof:
wherein R
2
is a purine or pyrimidine base or an analogue or derivative thereof; and Z is S, S═O or SO
2
.
It will be appreciated by those skilled in 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. The preparation of all such isomers and mixtures thereof including racemic mixtures is included within the scope of the invention.
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 processes of this invention additionally embrace the preparation of such isomers and mixtures thereof.
The purine or pyrimidine base or analogue or derivative thereof R
2
will be linked at any position of the base, preferably at the N9- or N1-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.
Preferably the group R
2
is selected from:
wherein:
X is oxygen or sulfur; Y is oxygen or sulfur;
R
3
and R
4
are independently selected from the group consisting of hydrogen, hydroxyl, amino, substituted or unsubstituted C
1-6
alkyl, or C
1-6
alkenyl or C
1-6
alkynyl, and substituted or unsubstituted C
1-10
acyl or aracyl;
R
5
and R
6
are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, thioaryl, substituted or unsubstituted C
1-6
alkyl or C
1-6
alkenyl or C
1-6
alkynyl, and substituted or unsubstituted C
1-10
acyloxy;
and
wherein:
R
7
and R
8
are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, substituted amino, halogen, cyano, carboxy, alkoxycarbonyl, carbamoyl, substituted or unsubstituted C
1-6
alkyl, or alkenyl, or alkynyl, and substituted or unsubstituted C
1-10
acyloxy; and
R
9
and R
10
are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, substituted amino, halogen, azido, substituted or unsubstituted C
1-6
alkyl or alkenyl or alkynyl, and substituted or unsubstituted C
1-10
acyloxy.
More preferably, the R
2
group is selected from:
wherein each R
11
is independently selected from hydrogen, acetyl, and C
1-6
alkyl groups;
R
12
and R
13
are independently selected from hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted C
1-6
alkyl or alkenyl, bromine, chlorine, fluorine, and iodine;
R
14
is selected from hydrogen, cyano, carboxy, ethoxycarbonyl, carbamoyl, and thiocarbamoyl; and each W is independently selected from hydrogen, bromine, chlorine, fluorine, iodine, amino, and hydroxyl groups.
Most preferably R
2
is
wherein R
3
and R
6
are hydrogen, and R
4
and R
5
are as defined above.
Z is preferably —S—.
By “a pharmaceutically acceptable salt or ester” is meant any 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.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof, at functional groups in both the base moiety, R
2
, and at the hydroxymethyl group of the oxathiolane ring. Modification at all such functional groups is included within the scope of the processes of this invention. However, of particular interest are pharmaceutically acceptable derivatives (e.g., esters) obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
Preferred esters of the compounds of formula (I) produced by the process of this invention include the compounds in which OH is replaced by a carboxyl function R(CO)O— in which the non-carbonyl moiety R 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 dihydropyridinyl (e.g. N-methyldihydropyridinyl). The OH function may also be replaced by sulphonate esters such as alkyl or aralkylsulphonyl (e.g. methanesulphonyl); sulfate esters, amino acid esters (e.g. L-valyl or L-isoleucyl), or mono-, di- or tri-phosphate 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 HOOC(CH
2
)
q
COOH where q is an integer of 0 to 10 (for example, succinic acid) or phosphoric acids.
Methods for preparing such esters are well known. See, for example, Hahn et al., “Nucleotide Dimers as anti-Human Immunodeficiency Virus Agents”,
Nucleotide Analogues
, pp. 156-159 (1989)

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