Use of substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections

• US 6,545,021 B1
• Filed: 02/14/2000
• Issued: 04/08/2003
• Est. Priority Date: 02/12/1999
• Status: Expired due to Term

• Current Assignee: Unither Virology, LLC. (United Therapeutics Corporation)
• Original Assignee: GD Searle LLC (Pfizer Inc.)
• Inventors: Bryant, Martin L., Mueller, Richard A., Partis, Richard A.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US09/503,945
• Time in Patent Office: 1,149 Days
• Field of Search: 514/235.5, 514/302, 514/315, 514/316, 514/318, 514/319, 514/326, 514/328, 514/885, 546/115, 546/116, 546/193, 546/205, 546/207, 544/129
• US Class Current: 514/318
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/20 for DNA viruses

Abstract

N-Substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of Formula I are effective in treatment of hepatitis infections, including hepatitis B and hepatitis C. In treating hepatitis infections, the compounds of Formula I may be used alone, or in combination with another antiviral agent selected from among nucleosides, nucleotides, immunomodulators, immunostimulats or various combinations of such other agents.

Claims

1. A method for treating a hepatitis virus infection in a mammal, comprising administering to said mammal an anti-hepatitis virus effective amount of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein;

R is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl, tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aralkenyl, aralkynyl, substituted aralkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heteroarylalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, heterocycloalkenyl, heteroarylalkenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkyloxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, amino(alkyl), alkanoylaminoalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl, or R⁵, wherein

R⁵=R¹X¹(R²X²)_m(R³X³)_n(R⁴X⁴)_pR⁶—

wherein;

R¹ is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;

R² is independently alkylene, alkenylene, alkynylene or haloalkylene;

R³ is independently alkylene, alkenylene, alkynylene or haloalkylene;

R⁴ is independently alkylene, alkenylene, alkynylene or haloalkylene;

R⁶ is independently alkylene, alkenylene, alkynylene or haloalkylene;

X¹ is independently oxygen, sulfur, sulfoxide or sulfone;

X² is independently oxygen, sulfur, sulfoxide or sulfone;

X³ is independently oxygen, sulfur, sulfoxide or sulfone;

X⁴ is independently oxygen, sulfur, sulfoxide or sulfone;

m, n and p are independently 0, 1, 2, or 3; and

m+n+p≦

3

A, B, C, and D are independently hydrido, lower alkyl, lower haloalkyl or acyl;

D and R taken together may form a five or six membered ring when R is carbonyl or alkylcarbonyl;

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; and

C and D taken together with the atoms to which they are attached may form a five or six membered heterocyclic ring;

wherein the main chain in R contains between one and twenty atoms; and

the main chain of R⁵ containing between four and twenty atoms.

2. A method as set forth in claim 1 wherein the aryl, heteroaryl, or heterocyclo moiety of a substituent comprising R is substituted with a substituent selected from the group consisting of carboxy, amino, nitro, hydroxy, halo, alkylcarbonyl, alkanoyloxy, sulfo, alkoxy, alkylthio, methylenedioxy, alkyl, alkanoylamino, alkylamino, aryl, heterocycloalkyl, silyl and substituted silyl.

3. The method of claim 1, wherein said pharmaceutically acceptable salt is selected from the group consisting of acetate, adipate, alginate, citrate, phosphate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate.

4. A method as set forth in claim 1 wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl, or R⁵.

5. A method as set forth in claim 4 wherein when all of any X¹, X², X³, and X⁴ linkages are oxygen:

(m+n+p)≧

2; and

Rlis not hydrogen or unsubstituted alkyl, or not all of any R², R³, and R⁴ groups are unsubstituted alkylene.

6. A method as set forth in claim 4 wherein R is R⁵.

7. A method as set forth in claim 1 wherein R is alkenyl, alkynyl, substituted arylalkyl, aryloxyalkyl, haloalkyl, hydroxyalkyl, haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl or R⁵.

8. A method as set forth in claim 7 wherein R is R⁵.

9. A method as set forth in claim 1 wherein each of A, B, C and D is hydrido.

10. A method as set forth in claim 1 wherein each of A, B, C and D is lower alkyl, lower haloalkyl or acyl.

11. A method as set forth in claim 1 wherein R is aryloxyalkoxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, perhaloalkylaralkyl, or R⁵.

12. A method as set forth in claim 11 wherein when all of any X¹, X², X³, and X⁴ are oxygen:

(m+n+p)≧

2; and

R¹ is not hydrogen or unsubstituted alkyl, or not all of any R², R³, and R⁴ groups are unsubstituted alkylene.

13. A method as set forth in claim 1 wherein R is carbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkycarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl or R⁵.

14. A method as set forth in claim 13 when all of any X¹, X², X³, and X⁴ are oxygen:

(m+n+p)≧

2; and

R¹is not hydrogen or unsubstituted alkyl, or not all of any R², R³, and R⁴ groups are unsubstituted alkylene.

15. A method as set forth in claim 1 wherein R is R⁵, A and B are hydrido, and C and D taken together with the atoms to which they are attached may form a five or six membered ring.

16. A method as set forth in claim 1 wherein R is selected from the group consisting of:

aryloxyalkyl, monoalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl and R⁵.

17. A method as set forth in claim 1 wherein R is selected from the group consisting of alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, and alkoxyalkylcarbonyl.

18. A method as set forth in claim 1 wherein the compound of Formula I that is administered to said mammal is produced from an intermediate also corresponding to Formula I, wherein R in said intermediate is alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl, or R⁵ carbonyl.

19. A method as set forth in claim 1 wherein the compound of Formula I that is administered to said mammal is produced from an intermediate also corresponding to Formula I, wherein R in said intermediate is aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, aryloxyalkoxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkylalkyloxyalkylcarbonyl, or R⁵ carbonyl.

20. A method as set forth in claim 1 wherein the compound of Formula I that is administered to said mammal is produced from an intermediate also corresponding to Formula I, wherein R in said intermediate is R⁵ carbonyl.

21. A method as set forth in claim 1 wherein the compound of Formula I that is administered to said mammal is produced from an intermediate also corresponding to Formula I, wherein R in said intermediate is aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, aryloxyalkoxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl, or cycloalkylalkyloxyalkylcarbonyl.

22. A method as set forth in claim 1 wherein R is aryloxyalkoxyalkyl, aminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, alkenyl, arylalkenyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, perhaloalkylaralkyl, or R⁵.

23. A method as set forth in claim 22 wherein:

(m+n+p)≧

2; and

R¹ is not hydrogen or unsubstituted alkyl, or not all of R², R³, and R⁴ are unsubstituted alkylene;

when all of X¹, X², X³, and X⁴ are oxygen.

24. A method as set forth in claim 1 wherein R is aryloxyalkoxyalkyl, aminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, alkenyl, arylalkenyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl or perhaloalkylaralkyl.

25. A method as set forth in claim 24 wherein R is trifluoromethylaralkyl.

26. An N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein R is selected from the group consisting of alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, aryloxyalkyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, alkoxycarbonyl, alkylcarbonyl, aryloxyalkoxyalkylcarbonyl, alkylcarbonyloxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl, arylalkenylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, heteroaryloxyalkylcarbonyl, heteroarylthiaalkylcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyll, cycloalkylalkyloxyalkylcarbonyl or R⁵ carbonyl wherein;

R⁵=R¹X¹(R²X²)_m(R³X³)_n(R⁴X⁴)_pR⁶—

wherein

R¹ is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;

R² is independently alkylene, alkenylene, alkynylene or haloalkylene;

R³ is independently alkylene, alkenylene, alkynylene or haloalkylene;

R⁴ is independently alkylene, alkenylene, alkynylene or haloalkylene;

R⁶ is independently alkylene, alkenylene, alkynylene or aloalkylene;

X¹ is independently oxygen, sulfur, sulfoxide or sulfone;

X² is independently oxygen, sulfur, sulfoxide or sulfone;

X³ is independently oxygen, sulfur, sulfoxide or sulfone;

X⁴ is independently oxygen, sulfur, sulfoxide or sulfone;

m, n and p are independently 0, 1, 2, or 3;

(m+n+p)≦

3;

(m+n+p)≧

1;

when all of any X¹, X², X³, and X⁴ linkages are oxygen;

(m+n+p)≧

2; and

R¹ is not hydrogen or unsubstituted alkyl;

or not all of any R², R³ and R⁴ groups are unsubstituted alkylene;

A, B, C, and D are independently hydrido, lower alkyl, lowerhaloalkyl or acyl;

D and R taken together may form a five or six membered ring when R is carbonyl or alkylcarbonyl;

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;

wherein the main chain in R contains between one and twenty atoms;

the main chain of R⁵ containing between four and twenty atoms;

when all of any X¹, X², X³, and X⁴ linkages are oxygen; and

(m+n+p)≧

2; and

R¹ is not hydrogen or unsubstituted alkyl;

or not all of any R², R³ and R⁴ groups are unsubstituted alkylene.

27. A pharmaceutical composition comprising an antiviral amount of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound as set forth in claim 26 and a pharmaceutically acceptable carrier, diluent or excipient.