Glucamine salts for treating hepatitis virus infections

• US 6,747,149 B2
• Filed: 12/17/2002
• Issued: 06/08/2004
• Est. Priority Date: 02/12/1999
• Status: Expired due to Fees

• Current Assignee: GD Searle LLC (Pfizer Inc.)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Bryant, Martin L., Partis, Richard A., Mueller, Richard A.
• Primary Examiner(s): OWENS, AMELIA A
• Application Number:
  US10/322,045
• Publication Number:
  US 20030195229A1
• Time in Patent Office: 539 Days
• Field of Search: 549/13, 544/162, 546/334, 564/305, 564/440, 564/442, 564/443, 564/454, 564/428, 564/501, 564/502, 564/503, 564/504, 564/505, 564/462
• US Class Current: 544/162
• CPC Class Codes: A61K 31/047 having two or more hydroxy groups, e.g. sorbitol
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07C 215/10 with one amino group and at least two hydroxy groups bound to the carbon skeleton

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.

Claims

1. 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.

2. A salt according to claim 1 wherein the antiviral compound is (−

)-2′

-deoxy-3′

-thiocytidine-5′

-triphosphate (3TC).

3. A salt according to claim 2 wherein the antiviral compound is (−

)-2′

-deoxy-3′

-thiocytidine-5′

-triphosphate (3TC).

4. A salt according to claim 3 wherein A, B, C and D are acyl.

5. A salt according to claim 4 wherein A, B, C and D are alkanoyl.

6. A salt according to claim 5 wherein A, B, C and D are butanoyl.

7. 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;

8. A salt according to claim 7 wherein the antiviral compound is (−

)-2′

-deoxy-3′

-thiocytidine-5′

-triphosphate (3TC).

9. A salt according to claim 8 wherein R is hydrogen and R⁵ is alkenyl.

10. A salt according to claim 9 wherein R⁵ is n-nonenyl.

11. A salt according to claim 8 wherein A, B, C and D are acyl.

12. A salt according to claim 11 wherein A, B, C and D are alkanoyl.

13. A salt according to claim 12 wherein A, B, C and D are butanoyl.