US2003220299A1PendingUtilityA1
Use of substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections
Est. expiryFeb 12, 2019(expired)· nominal 20-yr term from priority
A61P 31/20A61P 31/14A61K 31/444A61P 1/16A61K 31/445A61K 31/454A61K 31/436A61K 45/06A61K 31/4535A61K 31/5377A61K 31/4545
53
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Claims
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, immunostimulants or various combinations of such other agents.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
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, heteroarylakenyl, 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, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl, or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 — wherein:
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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, 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; 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 R 5 containing between four and twenty atoms.
2 . A process as set forth in claim 1 wherein said the aryl, heteroaryl, or heterocyclo moiety of a substitutent 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 R 5 .
5 . A method as set forth in claim 4 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
6 . A method as set forth in claim 4 wherein R is R 5 .
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 R 5 .
8 . A method as set forth in claim 7 wherein R is R 5 .
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, alkyl, arylcarbonyloxyalkyl, aminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, aminothiocarbonylaminoalkyl, alkenyl, arylalkenyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aminothiocarbonylalkyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, perhaloalkylaralkyl, and R 5 .
12 . A method as set forth in claim 11 wherein when all of any X 1 , X 2 , X 3 , and X 4 are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups 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 and R 5 .
14 . A method as set forth in claim 13 when all of any X 1 , X 2 , X 3 , and X 4 are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups unsubstituted alkylene.
15 . A method as set forth in claim 1 wherein R is R 5 , 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 R 5 .
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 R 5 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 R 5 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 R 5 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, alkyl, aminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, alkenyl, arylalkenyl, aminocarbonylalkyl, aminosulfonealkyl, arylalkynyl, heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthiaalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, aryloxyalkyl, arylthiaalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, perhaloalkylaralkyl, or R 5 .
23 . A method as set forth in claim 22 wherein: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of R 2 , R 3 , and R 4 are unsubstituted alkylene; when all of X 1 , X 2 , X 3 , and X 4 are oxygen.
24 . A method as set forth in claim 1 wherein R is aryloxyalkoxyalkyl, alkyl, aminoalkyl, arylcarbonylaminoalkyl, alkoxycarbonylaminoalkyl, aminocarbonylaminoalkyl, alkenyl, arylalkenyl, aminocarbonylalkyl, aminosulfonealkykl, 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 . A method for treating a hepatitis virus infection in a mammal, comprising administering to said mammal an anti-hepatitis virus effective amount of an antiviral composition comprising at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof
Formula I
wherein:
R is alkenyl, alkynyl, cycloalkyl, aryl, cycloalkenylalkyl, bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenyloxyalkyl, aralkenyl, aralkynyl, substituted aralkyl, heteroarylalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, heterocycloalkenyl, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, haloalkyl, hydroxyalkyl, haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, alkanoylaminoalkyl, alkanoylalkyl, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein:
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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, 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; and
the main chain of R 5 containing between four and twenty atoms.
27 . A method as set forth in claim 26 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 R 5 .
28 . A method as set forth in claim 27 wherein all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
29 . A method as set forth in claim 28 wherein R is R 5 .
30 . A method as set forth in claim 26 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, perhaloalkylaralkyl or R 5 .
31 . A method as set forth in claim 30 wherein R is R 5 .
32 . A method as set forth in claim 26 consisting essentially of 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.
33 . A method as set forth in claim 32 wherein R is selected from the group consisting of aryloxyalkyl, hydrohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl or R 5 .
34 . A method as set forth in claim 33 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
35 . A method as set forth in claim 26 comprising administering to said mammal an anti-hepatitis virus effective amount of an antiviral composition consisting essentially of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof.
36 . A method as set forth in claim 35 wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl or R 5 .
37 . A method as set forth in claim 36 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
38 . A method as set forth in claim 3 consisting essentially of administering to said mammal an anti-hepatitis virus effective amount of an antiviral composition consisting essentially of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof.
39 . A method as set forth in claim 38 wherein R is selected from the group consisting of aryloxyalkyl, haloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl or R 5 .
40 . A method as set forth in claim 39 when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
41 . A method as set forth in claim 26 comprising administering to said mammal an anti-hepatitis virus effective amount of an antiviral composition containing at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof, said administration begin substantially exclusive of the administration of any antiviral agent comprising a nucleoside, nucleotide, an immunodulator or an immunostimulant.
42 . A method as set forth in claim 41 wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, hydroxyalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, perhaloalkylaralkyl or R 5 .
43 . A method as set forth in claim 41 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
44 . A method as set forth in claim 41 wherein said administration is substantially exclusive of the administration of an antiviral agent other than an agent or agent corresponding to Formula 1.
45 . A method as set forth in claim 41 comprising treating a hepatitis B virus infection comprising administering to said mammal an anti-hepatitis B 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.
46 . A method as set forth in claim 41 comprising treating a hepatitis C virus infection comprising administering to said mammal an anti-hepatitis C 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.
47 . A method as set forth in claim 41 consisting essentially of administering to said mammal an anti-hepatitis virus effective amount of a composition containing an anti-viral agent, said anti-viral agent consisting essentially of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof.
48 . A method as set forth in claim 47 comprising treating a hepatitis B virus infection comprising administering to said mammal an anti-hepatitis B 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.
49 . A method as set forth in claim 47 comprising treating a hepatitis C virus infection comprising administering to said mammal an anti-hepatitis C 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.
50 . A method as set forth in claim 47 wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl or R 5 .
51 . A method as set forth in claim 15 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
52 . A method as set forth in claim 41 comprising treating a hepatitis B virus infection comprising administering to said mammal an anti-hepatitis B 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.
53 . A method as set forth in claim 41 comprising treating a hepatitis C virus infection comprising administering to said mammal an anti-hepatitis C 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.
54 . An N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:
Formula I
wherein:
R is aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,perhaloalkylaralkyl or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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 X 1 , X 2 , X 3 , and X 4 linkages are oxygen;
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 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 R 5 containing between four and twenty atoms;
when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen; and
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 groups are unsubstituted alkylene.
55 . A compound as set forth in claim 543 wherein R is selected from the group consisting of monohaloalkyl, a substituent corresponding to R 5 and haloalkoxyalkyl.
56 . A compound as set forth in claim 55 wherein R is trifluoroalkoxyalkyl.
57 . A compound as set forth in claim 55 wherein R is R 5 .
58 . A pharmaceutical composition comprising an antiviral compound comprising an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound or a pharmaceutically acceptable salt thereof and another antiviral compound selected from the group consisting of a nucleoside, a nucleotide, an immunomodulator, an immunostimulant, and mixtures thereof, said N-substitutted-1,5-dideoxy-1,5-imino-D-glucitol compound corresponding to Formula I:
R is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, cycloalkenylalkyl, cyclyalkenylalkenyl, cycloalkenylalkynyl bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl, bicycloalkenoxyalkyl, tricycloalkenoxyalkyl, tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl, aralkenyl, aralkynyl, substituted aralkyl, aralkoxyalkyl, aralkoxyalkenyl, aralkoxyalkynyl, aralkenoxyalkyl, aralkenoxyalkenyl, heteroarylalkyl, heterocyclooxyalkyl, heterocyclothiaalkyl, heterocycloalkenyl, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkyloxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, amino(alkyl), alkanoylaminoalkyl, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl, or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein:
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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, 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; 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 R 5 containing between four and twenty atoms.
59 . A composition as set forth in claim 58 comprising a first amount of said compound of Formula I and a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, an immunomodulator, an immunostimulant, and mixtures thereof,
wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.
60 . A composition a set forth in claim 58 further comprising a pharmaceutically acceptable, carrier, diluent or excipient.
61 . A pharmaceutical composition as set forth in claim 58 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 R 5 .
62 . A pharmaceutical composition as set forth in claim 61 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
63 . A salt of an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound and an antiviral compound selected from the group consisting of a nucleoside having an acid moiety and a nucleotide, said N-substitutted-1,5-dideoxy-1,5-imino-D-glucitol compound corresponding to Formula I:
Formula I
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, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkyloxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, alkanoylaminoalkyl, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein:
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene, or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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, 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; 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 R 5 containing between four and twenty atoms.
64 . A pharmaceutical composition comprising a antiviral effective amount of the salt of claim 63 .
65 . A pharmaceutical composition comprising the salt of claim 63 further comprising a pharmaceutically acceptable carrier, diluent or excipient.
66 . A method as set forth in claim 63 wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl or R 5 .
67 . A salt as set forth in claim 66 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
68 . A pharmaceutical composition comprising N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof:
Formula I
wherein:
R is aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 is independently oxygen, sulfur, sulfoxide or sulfone;
m, n and p are independently 0, 1, 2, or 3;
(m+n+p)≦3; and
(m+n+p)≧1;
when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen;
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 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 R 5 containing between four and twenty atoms; and
a pharmaceutically acceptable carrier, diluent, or excipient.
69 . A method for treating a hepatitis virus infection in a mammal, comprising administering to said mammal a first amount of at least one 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, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkyloxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyal-kylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, alkanoylaminoalkyl, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl,
alkoxycarbonylalkyl, perhaloalkylaralkyl or R 5 , wherein
R 5 ═R 1 X 1 (R 2 X 2 )×m(R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein:
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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, 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; and
the main chain of R 5 containing between four and twenty atoms; and
a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, an immunomodulator, an immunostimulant, and mixtures thereof,
wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.
70 . A method as set forth in claim 69 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 R 5 .
71 . A method as set forth in claim 70 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
72 . A method as set forth in claim 69 wherein said compound of Formula I wherein R is selected from the group consisting of:
73 . A method as set forth in claim 69 wherein said nucleoside or nucleotide antiviral compound is selected from the group consisting of:
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
(−)-2′-deoxy-3′-thiocytidine-5′-triphosphate (3TC);
(−)-cis-5-fluoro-1-[2-(hydroxy-methyl)-1,3-oxathiolan-5-yl]cytosine (FTC);
(−)2′,3′, dideoxy-3′-thiacytidine [(−)-SddC];
1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC);
1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine triphosphate (FIACTP);
1-(2′-deoxy-2′-fluoro-beta-D-arabinofuranosyl)-5-methyluracil (FMAU);
1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide; 2′,3′-dideoxy-3′-fluoro-5-methyl-dexocytidine (FddMeCyt);
2′,3′-dideoxy-3′-chloro-5-methyl-dexocytidine (ClddMeCyt);
2′,3′-dideoxy-3′-amino-5-methyl-dexocytidine (AddMeCyt);
2′,3′-dideoxy-3′-fluoro-5-methyl-cytidine (FddMeCyt);
2′,3′-dideoxy-3′-chloro-5-methyl-cytidine (ClddMeCyt); 2′,3′-dideoxy-3′-amino-5-methyl-cytidine (AddMeCyt);
2′,3′-dideoxy-3′-fluorothymidine (FddThd);
2′,3′-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC);
2′,3′-dideoxy-beta-L-5-thiacytidine;
2′,3′-dideoxy-beta-L-5-cytidine (beta-L-ddC);
9-(1,3-dihydroxy-2-propoxymethyl)guanine;
2′-deoxy-3′-thia-5-fluorocytosine;
3′-amino-5-methyl-dexocytidine (AddMeCyt);
2-amino-1,9-[(2-hydroxymethyl-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one (gancyclovir);
2-[2-(2-amino-9H-purin-9y)ethyl]-1,3-propandil diacetate (famciclovir);
2-amino-1,9-dihydro-9-[(2-hydroxy-ethoxy)methyl]6H-purin-6-one (acyclovir);
9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine (penciclovir);
9-(4-hydroxy-3-hydroxymethyl-but-1-yl)-6-deoxy-guanine, diacetate (famciclovir);
3′-azido-3′-deoxythymidine (AZT);
3′-chloro-5-methyl-dexocytidine (ClddMeCyt);
9-(2-phosphonyl-methoxyethyl)-2′,6′-diaminopurine-2′,3′-dideoxyriboside;
9-(2-phosphonylmethoxyethyl)adenine (PMEA);
acyclovir triphosphate (ACVTP);
D-carbocyclic-2′-deoxyguanosine (CdG);
dideoxy-cytidine;
dideoxy-cytosine (ddC);
dideoxy-guanine (ddG);
dideoxy-inosine (ddI);
E-5-(2-bromovinyl)-2′-deoxyuridine triphosphate;
fluoro-arabinofuranosyl-iodouracil;
1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-iodo-uracil (FIAU);
stavudine;
9-beta-D-arabinofuranosyl-9H-purine-6-amine monohydrate (Ara-A);
9-beta-D-arabinofuranosyl-9H-purine-6-amine-5′-monophosphate monohydrate (Ara-AMP);
2-deoxy-3′-thia-5-fluorocytidine; 2′,3′-dideoxy-guanine; and
2′,3′-dideoxy-guanosine.
74 . A method as set forth in claim 69 comprising administering to said mammal from about 0.1 mg/kg/day to about 100 mg/kg/day of at least one N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I or a pharmaceutically acceptable salt thereof; and
from about 0.1 mg/person/day to about 500 mg/person/day of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and a mixture thereof.
75 . A method as set forth in claim 74 comprising administering between about 0.1 mg/person/day and about 500 mg/person/day of (−)-2′-deoxy-3′-thiocytidine-5′-triphosphate.
76 . A method as set forth in claim 69 comprising treating a hepatitis B virus infection comprising administering to said mammal an anti-hepatitis B 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.
77 . A method as set forth in claim 68 comprising treating a hepatitis C virus infection comprising administering to said mammal an anti-hepatitis C 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.
78 . A method as set forth in claim 68 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, perhaloalkylaralkyl or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independentlv oxyqen, sulfur, sulfoxide or sulfone;
X 4 is independently oxygen, sulfur, sulfoxide or sulfone;
m, n and p are independently 0, 1, 2, or 3; and
m+n+p≦3,
wherein the main chain in R contains between one and twenty atoms;
the main chain of R 5 containing between four and twenty atoms.
79 . A pharmaceutical composition comprising an anti-hepatitis effective amount of an 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, heteroarylakenyl, heteroarylalkynyl, aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkenyl, dihydroxyalkenyl, hydroxyalkynyl, haloalkyloxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, carbonyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonylalkyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl, alkanoyloxyalkyl, aryloxyalkoxyalkyl, aroyloxyalkyl, aminoalkyl, amino(alkyl), alkanoylaminoalkyl, aminocarbonylalkyl, hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, perhaloalkylaralkyl or R 5 , wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 —, wherein:
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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, 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; 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 R 5 containing between four and twenty atoms; and
a pharmaceutically acceptable carrier, diluent or excipient.
80 . A pharmaceutical composition as set forth in claim 79 wherein R is selected from the group consisting of aryloxyalkyl, monohaloalkyl, haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl, aryioxyalkyicarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, perhaloalkylaralkyl or R 5 .
81 . A pharmaceutical composition as set forth in claim 80 wherein when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen: (m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl, or not all of any R 2 , R 3 , and R 4 groups are unsubstituted alkylene.
82 . A pharmaceutical composition as set forth in claim 79 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 R 5 .
83 . 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 R 5 carbonyl wherein:
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 — wherein
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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 X 1 , X 2 , X 3 , and X 4 linkages are oxygen;
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 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 R 5 containing between four and twenty atoms;
when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen; and
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 groups are unsubstituted alkylene.
84 . 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 83 and a pharmaceutically acceptable carrier, diluent or excipient.
85 . 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 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 R 5 carbonyl wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 — wherein
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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 X 1 , X 2 , X 3 , and X 4 linkages are oxygen;
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 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 R 5 containing between four and twenty atoms;
when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen; and
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 groups are unsubstituted alkylene.
86 . 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 1 and a pharmaceutically acceptable carrier, diluent or excipient.
87 . 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 aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, cycloalkylalkylcarbonyl, aryloxyalkoxyalkylcarbonyl, arylcarbonyloxyalkylcarbonyl, aminoalkylcarbonyl, alkylcarbonylaminoalkylcarbonyl, arylcarbonylaminoalkylcarbonyl, alkoxycarbonylaminoalkylcarbonyl, aminocarbonylaminoalkylcarbonyl, aminothiocarbonylaminoalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, aminothiocarbonylalkylcarbonyl, aminosulfonealkylcarbonyl, arylalkynylcarbonyl, heterocycloalkylcarbonyl, heteroarylalkylcarbonyl, heteroaryloxyalkylcarbonyl, heteroarylthiavcarbonyl, heterocyclooxyalkylcarbonyl, heterocyclothiaalkylcarbonyl, arylthiaalkylcarbonyl, monohaloalkylcarbonyl, haloalkyloxyalkylcarbonyl or cycloalkylalkyloxyalkylcarbonyl wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 — wherein
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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 X 1 , X 2 , X 3 , and X 4 linkages are oxygen;
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 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 R 5 containing between four and twenty atoms;
when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen; and
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 groups are unsubstituted alkylene.
88 . 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 87 and a pharmaceutically acceptable carrier, diluent or excipient.
89 . 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:
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 R 5 carbonyl wherein
R 5 =R 1 X 1 (R 2 X 2 ) m (R 3 X 3 ) n (R 4 X 4 ) p R 6 — wherein
R 1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or haloalkyl;
R 2 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 3 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 4 is independently alkylene, alkenylene, alkynylene or haloalkylene;
R 6 is independently alkylene, alkenylene, alkynylene or haloalkylene;
X 1 is independently oxygen, sulfur, sulfoxide or sulfone;
X 2 is independently oxygen, sulfur, sulfoxide or sulfone;
X 3 is independently oxygen, sulfur, sulfoxide or sulfone;
X 4 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 X 1 , X 2 , X 3 , and X 4 linkages are oxygen;
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 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 R 5 containing between four and twenty atoms;
when all of any X 1 , X 2 , X 3 , and X 4 linkages are oxygen; and
(m+n+p)≧2; and R 1 is not hydrogen or unsubstituted alkyl; or not all of any R 2 , R 3 and R 4 groups are unsubstituted alkylene.
90 . 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 89 and a pharmaceutically acceptable carrier, diluent or excipient.Join the waitlist — get patent alerts
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