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US 2001/0020026 A1Published application
Substituted-1,3-oxathiolanes and substituted-1,3-dioxolanes with antiviral properties
OwnerBernard Belleau, Pierette Belleau +1inventors
InventorsBERNARD BELLEAU, PIERETTE BELLEAU, NGHE NGUYEN-BA
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Abstract
Disclosed are compounds of the formula wherein R1 is hydrogen or an acyl group having 1 to 16 carbon atoms; R2 is a purine or pyrimidine base or an analogue or derivative thereof; Z is O, S, S═O or SO2; and pharmaceutically acceptable derivatives thereof. Also described are processes for and intermediates of use in their preparation, pharmaceutical compositions containing these compounds, and the use of these compounds in the antiviral treatment of mammals.
Claims37
A compound of formula (I), the geometric and optical isomers thereof, and mixtures of those isomers:
- 73
- wherein:
- R1 is selected from the group consisting of hydrogen and an acyl group having from 1 to 16 carbon atoms;
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- and
- Z is selected from the group consisting of O, S, S═O, and SO2;
- and
- pharmaceutically acceptable derivatives of such compounds.
5 more elements
A compound selected from the group consisting of:
- Cis-2-hydroxymethyl-5-(N4′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(N4′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-hydroxymethyl-5-(N-dimethylamino-methylene cytosin-1′-yl)-1,3-oxathiolane;
- Bis-Cis-2-succinyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane;
- Cis-2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-yl)-1,3-oxathiolane;
- trans-2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(6′-hydroxypurin-N-9′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-benzoyloxymethyl-5-(N4′-acetyl-5′-fluorocytosin-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N4′-acetyl-5′-fluorocytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-hydroxymethyl-5-(5′-fluorocytosin-1′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(5′-fluorocytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-hydroxymethyl-5-(N-dimethylamino methylene cytosin-1′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(N-dimethylamino methylene cytosin-1′-yl)-1,3-dioxolane, and mixtures thereof;
- and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.
9 more elements
A compound selected from the group consisting of:
- Cis-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-benzoyloxymethyl-5-(N41-acetyl-cytosin-1′-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N4′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, and mixtures thereof;
- and
- Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-oxathiolane;
- Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane;
- trans-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane;
- and mixtures thereof;
- Cis-2-hydroxymethyl-5-(uracil-N-1′-yl)-1,3-oxathiolane;
- Cis-2-hydroxymethyl-5-(adenin-9′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(adenin-9′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-hydroxymethyl-5-(inosin-9′-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(inosin-9′-yl)-1,3-oxathiolane, and mixtures thereof;
- Cis-2-hydroxymethyl-5-(thymin-N-1′-yl)-1,3-oxathiolane;
- and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.
9 more elements
A compound selected from the group consisting of:
- Cis-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, trans-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane, trans-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(cytosin-1-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, trans-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(adenin-9′-yl) -1,3-dioxolane, trans-2-hydroxymethyl-4-(adenin-9-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-benzoyloxylmethyl-4-(2′-amino-6′-chloro-(purin-9-yl) -1,3-dioxolane, trans-2-benzoyloxylmethyl-4-(2-amino-6′-chloro-(purin-9′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(2′-amino-6′-chloro-(purin-9′-yl)(-1,3-dioxolane, trans-2-hydroxymethyl-4-(2′-amino-6′-chloro-(purin-9′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(2′-amino-purin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2′-amino-purin-9′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)-1,3-dioxolane, and mixtures thereof;
- Cis-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane, and mixtures thereof;
- and pharmaceutically acceptable derivatives thereof in the form of a racemic mixture or single enantiomer.
9 more elements
Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, and pharmaceutically acceptable derivatives thereof.
Cis-2-hydroxymethyl-5-(51-fluorocytosin-1′-yl)-1,3-oxathiolane, and pharmaceutically acceptable derivatives thereof.
The ester of formula (IV), the geometric and optical isomers thereof, and mixtures of those isomers:
- 78
- wherein:
- W is PO4−, SPO3−, or —O—C—(CH2)n—C—O— where n is an integer of 1 to 10;
- J is any nucleoside or nucleoside analog or derivative thereof;
- Z is O, S, S═O, or SO2;
- and
- R2 is a purine or pyrimidine base or analogue or derivative thereof.
4 more elements
A process for preparing an oxathiolane of formula (Ia), the geometric and optical isomers thereof, and mixtures of those isomers:
- 80
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- Z is selected from a group consisting of S, S═O, and SO2;
- the process comprising the steps of:
- a) reacting a compound having the formula HSCH2CH(ORx)2, wherein is substituted or unsubstituted C1-6 alkyl, with a compound having formula RyCO—OCH2CHO, wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl, in an inert solvent containing an acid catalyst to produce an intermediate having a formula:
- 81
- b) reacting the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the formula:
- 82
- c) optionally treating the resulting compound with an oxidizing agent in a suitable solvent to produce the corresponding sulfoxides of formula (Ia), wherein Z is S═O or SO2.
8 more elements
A process for preparing an oxathiolane of formula (Ia), the geometric and optical isomers thereof, and mixtures of those isomers:
- 85
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- and
- Z is selected from a group consisting of S, S═O or SO2;
- the process comprising the steps of:
- a) reacting a mercaptoacetaldehyde with a compound having formula RyCO—OCH2CHO, wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl, to produce an intermediate having a formula:
- 86
- b) converting the hydroxyl group of the intermediate to a suitable leaving group;
- and
- c) treating the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the formula:
- 87
10 more elements
A process for preparing an oxathiolane of formula (Ia), the geometric and optical isomers thereof, and mixtures of those isomers:
- 88
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- and
- Z is selected from a group consisting of S, S═O, and SO2;
- the process comprising the steps of:
- a) treating a mercaptoacetaldehyde with a compound having formula RyOOCCHO, wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl, to produce an intermediate having a formula:
- 89
- b) converting the hydroxyl group of the intermediate to a suitable leaving group;
- and
- c) treating the intermediate with a silylated pyrimidine or purine or an analogue thereof, in the presence of a Lewis acid to produce a compound of the following formula:
- 90
- d) reducing the Ry containing ester and protecting the resulting hydroxyl group with a suitable protecting group;
- e) optionally interconverting the purine or pyrimidine base substituent to another pyrimidine or purine base;
- f) removing the protecting group to give a compound of formula (Ia).
13 more elements
A process for preparing an oxathiolane of formula (Ia), the geometric and optical isomers thereof, and mixtures of those isomers:
- (Ia)
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- and
- Z is selected from a group consisting of S, S═O, and SO2;
- the process comprising the steps of:
- a) converting the hydroxyl group of an intermediate of the following formula to a suitable leaving group:
- 91
- wherein Ry is C1-6 substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
- b) reducing the ester group and protecting the resulting hydroxyl group with a suitable protecting group;
- c) reacting the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid;
- d) removing the protecting group to give a compound of formula (Ia).
10 more elements
A process for preparing a dioxolane of formula (Ib), the geometric and optical isomers thereof, and mixtures of those isomers, 92
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- and
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- the process comprising the steps of:
- a) condensing a compound having a formula RzCH2CH(ORx), wherein Rz is a halo selected from bromo, chloro, fluoro or iodo and Rx is substituted or unsubstituted C1-6 alkyl, with glycerol in an inert solvent containing an acid catalyst to produce an intermediate having a formula 93
- b) oxidizing the hydroxymethyl group of the intermediate with an oxidizintg agent to the acid and further oxidizing with an organic peracid to produce a compound of the following formula 94
- wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl;
- c) treating the intermediate with a silylated pyrimidine or purine base or an analogue therof, in the presence of a Lewis acid to produce a compound of the following formula 95
- d) displacing the Rz group with a.salt of an acid.
7 more elements
A process for preparing a dioxolane of formula (Ib), the geometric and optical isomers thereof, and mixtures of those isomers, 96
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms and a hydroxyl protecting group;
- and
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- the process comprising the steps of:
- a) condensing a compound having a formula RzCH2CH(ORx), wherein Rz is a halo selected from bromo, chloro, fluoro or iodo and Rx is substituted or unsubstituted C1-6 alkyl, with glycerol in an inert solvent containing an acid catalyst to produce an intermediate having a formula
- b) displacing the Rz group with a salt of an acid to produce a compound of the following formula 97
- wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl;
- c) oxidizing the hydroxymethyl group of the intermediate with an oxidizing agent to the acid and further oxidizing with an organic peracid to produce a compound of the following formula 98
- d) treating the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the following formula 99
7 more elements
A process for preparing a dioxolane of formula (Ib), the geometric and optical isomers thereof, and mixtures of those isomers:
- 100
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- and
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- the process comprising the steps of:
- a) condensing a compound having a formula RyCO—OCH2CHO, wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl, with the hydroxyacetal of formula HOCH2CH(ORx)2, wherein Rx is a substituted or unsubstituted C1-6 alkyl, in an inert solvent containing an acid catalyst to produce an intermediate having a formula:
- 101
- b) treating the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the following formula:
- 102
7 more elements
A process for preparing a dioxolane of formula (Ib), the geometric and optical isomers thereof, and mixtures of those isomers:
- 103
- wherein:
- R1 is selected from a group consisting of hydrogen, an acyl group having from 1 to 16 carbon atoms, and a hydroxyl protecting group;
- and
- R2 is a purine or pyrimidine base or an analogue or derivative thereof;
- the process comprising the steps of:
- a) condensing a compound having a formula RyCO—OCH2CHO, wherein Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl, with an epoxide in an inert solvent containing an acid catalyst to produce an intermediate having a formula:
- 104
- b) oxidizing the ketone of the intermediate with an organic peracid and treating the intermediate with a silylated pyrimidine or purine base or an analogue thereof, in the presence of a Lewis acid to produce a compound of the following formula:
- 105
7 more elements
Intermediates useful for the production of oxathiolane compounds selected from the group consisting of:
- 2-thiobenzoylacetaldehyde diethylacetal;
- and
- cis- and trans-2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane.
Intermediates useful for the production of oxathiolane and dioxolane compounds selected from the group consisting of:
- cis- and trans-2-chloromethyl-4-(m-chloro-benzoyloxy)-1,3-dioxolane;
- cis- and trans-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid;
- and
- cis- and trans-2-benzoyloxymethyl-4-(m-chlorobenzoyloxy)-1,3-dioxolane.
1 more element
Intermediates useful for the production of oxathiolane and dioxolane compounds selected from the group consisting of:
- cis- and trans-2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane;
- cis- and trans-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane;
- cis- and trans-2-ethoxycarbonyl-5-hydroxy-1,3-oxathiolane;
- cis- and trans-2-ethoxycarbonyl-5-acetoxy-1,3-oxathiolane;
- cis- and trans-2-ethoxycarbonyl-5-(uracil-1′-yl)-1,3-oxathiolane;
- cis- and trans-2-t-butyldimethylsilyloxy-methyl-5-(uracil-1′-yl)-1,3-oxathiolane;
- cis- and trans-2-t-butyldimethylsilyloxy-methyl-5-(cytosin-1′-yl)-1,3-oxathiolane;
- cis- and trans-2-ethoxycarbonyl-5-(methoxycarbonyloxy)-1,3-oxathiolane;
- cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(methoxycarbonyloxy)-1,3-oxathiolane;
- cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(cytosin-1′-yl)-1,3-oxathiolane;
- cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(N-acetylcytosin-1′-yl)-1,3-oxathiolane;
- 2-benzoyloxyacetaldehyde bis (2-methoxyethyl) acetal;
- 2-hydroxyacetaldehyde bis(2-methoxyethyl) acetal;
- cis- and trans-2-benzoyloxymethyl-4-(2-methoxyethoxy)-1,3-dioxolane;
- cis- and trans-2-benzoyloxymethyl-4-acetyl-1,3-dioxolane;
- cis- and trans-2-benzoyloxymethyl-4-acetoxy-1,3-dioxolane;
- 2-thiobenzoylacetaldehyde bis(2-methoxy-ethyl) acetal;
- 2-thioacetaldehyde bis(2-methoxyethyl acetal;
- cis- and trans-2-benzoyloxymethyl-5-(2-methoxyethoxy)-1,3-oxathiolane;
- cis- and trans-2-hydroxymethyl-5-hydroxy-1,3-oxathiolane;
- and
- cis- and trans-2-acetoxymethyl-5-1,3-oxathiolane.
19 more elements
Dependencies are inferred from the claim text.