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US 6,747,149 B2Granted
Glucamine salts for treating hepatitis virus infections
AssigneeG. D. Searle & Co.
InventorsRichard A. Mueller, Martin L. Bryant, Richard A. Partis
Life of this patent
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Abstract
N-Substituted glucamine compounds of formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections the compounds of formular I may be used alone, or in combinatioin with another antiviral agent selected from among nucleosides, nucleotides, immunomodulators, immunostimulants or various combination of such other agents.
Claims13
A salt of an N-substituted glucamine compound and an antibacterial compound selected from the group consisting of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC), 1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine triphosphate (FIACTP), acyclovir triphosphate (ACVTP), E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate, and 9-beta-D-arabinofuranosyl-9H-purine-6-amine-5′-monophosphate monohydrate (Ara-AMP), said glucamine compound corresponding to Formula I:
- wherein:
- R and R5 are independently selected from the group consisting of substituted alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl, arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl, cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl, tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl, bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl, tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl, cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl, aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl, aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl, heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl, aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl, dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl, haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl, or hydroxysulfonealkylcarbonyl, wherein R and R5 are independently substituted by one or more substituents selected from the group consisting of amino, substituted amino, disubstituted amino, heterocyclo containing at least one nitrogen, or heteroaryl containing at least one basic nitrogen,
- R and R5 are independently selected from the group consisting of substituted alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonyl, aminoalkylcarbonyl, arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, cycloalkenylalkylcarbonyl, cycloalkenylalkenylcarbonyl, cycloalkenylalkynylcarbonyl, bicycloalkenylalkylcarbonyl, tricycloalkenylalkylcarbonyl, tetracycloalkenylalkylcarbonyl, bicycloalkenoxyalkylcarbonyl, tricycloalkenoxyalkylcarbonyl, tetracycloalkenyloxyalkylcarbonyl, cycloalkylalkenylcarbonyl, cycloalkylalkynylcarbonyl, aralkylcarbonyl, aralkoxyalkylcarbonyl, aralkoxyalkenylcarbonyl, aralkoxyalkynylcarbonyl, aralkenoxyalkylcarbonyl, aralkenoxyalkenylcarbonyl, heterocycloalkenylcarbonyl, heteroarylalkenylcarbonyl, heteroarylalkynylcarbonyl, aryloxyalkenylcarbonyl, aryloxyalkynylcarbonyl, dihydroxyalkylcarbonyl, hydroxyalkenylcarbonyl, dihydroxyalkenylcarbonyl, hydroxyalkynylcarbonyl, haloalkoxyalkenylcarbonyl, haloalkoxyalkynylcarbonyl, or hydroxysulfonealkylcarbonyl, wherein R and R5 are independently substituted by one or more substituents selected from the group consisting of amino, substituted amino, disubstituted amino, heterocyclo containing at least one nitrogen, or heteroaryl containing at least one basic nitrogen,
- A, B, C, D and E are independently hydrido, lower alkyl or acyl;
- A and B taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- B and C taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- C and D taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- C and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- and D and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring.
6 more elements
A salt of an N-substituted glucamine compound and an antibacterial compound selected from the group consisting of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC), 1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine triphosphate (FIACTP), acyclovir triphosphate (ACVTP), E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate, and 9-beta-D-arabinofuranosyl-9H-purine-6-amine-5′-monophosphate monohydrate (Ara-AMP), said glucamine compound corresponding to Formula I:
- wherein:
- R and R5 are independently selected from the group consisting of H, aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, alkyl, arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, alkynyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, haloalkyl, haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, perhaloalkylaralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl, tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aralkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heterocycloalkenyl, heteroarylalkenyl, heteroarylalkynyl, aryloxyalkenyl, aryloxyalkynyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkoxyalkenyl, haloalkoxyalkynyl, hydroxysulfonealkyl, R7 or R8, wherein
- R7=R1X1(R2X2)m(R3X3)n(R4X4)pR13;
- R8=R9X9(R10X10)q(R11X11)r(R12X12)sR13
- R1 and R9 are independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
- R2, R3, R4, R10, R11, R12 and R13 are independently selected from the group consisting of alkylene, alkenylene, alkynylene or haloalkylene;
- X1, X2, X3, X4, X9, X10, X11 and X12 are independently oxygen, sulfur, sulfoxide or sulfone;
- m, n, p, q, r and s are independently 0, 1, 2 or 3;
- m+n+p≦3
- q+r+s≦3
- A, B, C, D and E are independently hydrido, lower alkyl or acyl;
- A and B taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- B and C taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- C and D taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- C and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;
- and D and E taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring.
13 more elements
Dependencies are inferred from the claim text.