Methods of treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-D- glucuitol compounds in combination therapy

• US 20060106065A1
• Filed: 12/15/2005
• Published: 05/18/2006
• Est. Priority Date: 02/14/1997
• Status: Abandoned Application

• Current Assignee: Gary S. Jacob, Raymond A. Dwek, Timothy M Block
• Original Assignee: Gary S. Jacob, Raymond A. Dwek, Timothy M Block
• Inventors: Dwek, Raymond A., Jacob, Gary S., Block, Timothy M.
• Application Number:
  US11/300,463
• Publication Number:
  US 20060106065A1
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4

Abstract

Provided are methods and compositions for treating hepatitis virus infections in mammals, especially humans. The methods comprise (1) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/immunostimulating agents, or (2) administering N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/immunostimulating agents.

Claims

1-69. -69. (canceled)

70. A method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal a 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 arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C₁ to C₂₀, and

W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl;

2) an antiviral compound selected from the group consisting of nucleoside antiviral compounds, nucleotide antiviral compounds, and mixtures thereof,

3) an immunostimulating or immunomodulating compound selected from the group consisting of immunomodulating agents, immunostimulating agents, and mixtures thereof, wherein the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound, the antiviral compound and the immunostimulating/immunomodulating compound form an anti-hepatitis virus effective amount of said compounds.

71. The method of claim 70, wherein R is a branched or straight chain alkyl having a chain length of C₁ to C₂₀, and W, X, Y, and Z are each hydrogen.

72. The method of claim 71, wherein R is a straight chain alkyl having a chain length of C₂ to C₁₄.

73. The method of claim 72, wherein R is butyl or nonyl.

74. The method of claim 70, wherein the 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-methyluarcil (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);

2′

,3-deoxy-3′

-thia-5-fluorocytosine;

3′

-amino-5-methyl-dexocytidine (AddMeCyt);

3′

-azido-3′

-deoxythymidine (AZT);

3′

-chloro-5-methyl-dexocytidine (ClddMeCyt);

9-(2-phosphonylmethoxyethyl)-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;

stavudine;

2-deoxy-3′

-thia-5-fluorocytidine;

2′

,3′

-dideoxy-guanine; and

2′

,3′

-dideoxy-guanosine.

75. The method of claim 74, wherein the antiviral compound is 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide.

76. The method of claim 70, wherein the immunostimulating or immunomodulating compound is selected from the group consisting of AA-2G;

adamantylamide dipeptide;

adenosine deaminase;

an adjuvant agelasphin-11;

AIDS therapy;

algal glucan;

algammulin, Anutech;

Anginlyc;

anticellular factors, Yeda;

Anticort;

antigastrin-17 immunogen, Ap;

antigen delivery system, Vac;

antigen formulation, IDBC;

antiGnRH immunogen, Aphton;

Antiherpin;

Arbidol;

Aviron;

chemokine inhibitors, ICOS;

CMV peptides, City of Hope;

CN-5888;

cytokine-releasing agent, St;

DHEAS, Paradigm;

DISC TA-HSV;

J07B;

I01A;

I01Z;

ditiocarb sodium;

ECA-10-142;

ELS-1;

endotoxin, Novartis;

FCE-20696;

FCE-24089;

FCE-24578;

FLT-3 ligand, Immunex;

FR-900483;

FR-900494;

FR-901235;

FTS-Zn;

G-proteins, Cadus;

gludapcin;

glutaurine;

glycophosphopeptical;

GM-2;

GM-53;

GMDP;

factor vaccine, EntreM;

H-BIG, NABI;

H-CIG, NABI;

HAB-439;

Helicobacter pylori vaccine, herpes-specific immune factor;

HIV therapy, United Biomed;

HyperGAM+CF;

ImmuMax;

Immun BCG;

immune therapy, Connective;

immunomodulator, Evans;

immunomodulators, Novacell;

imreg-1;

imreg-2;

Indomune;

inosine pranobex;

interferon, Dong-A (alpha2);

interferon, Genentech (gamma);

interferon, Novartis (alpha);

interleukin-12, Genetics Ins;

interleukin-15, Immunex;

interleukin-16, Research Cor;

ISCAR-1;

J005X;

L-644257;

licomarasminic acid;

LipoTher;

LK-409;

LK-410;

LP-2307;

LT (R1926);

LW-50020;

MAF, Shionogi;

MDP derivatives, Merck;

met-enkephalin, TNI;

methylfurylbutyrolactones;

MIMP;

mirimostim;

mixed bacterial vaccine, Tem;

MM-1;

moniliastat;

MPLA, Ribi;

MS-705;

murabutide;

murabutide, Vacsyn;

muramyl dipeptide derivative;

muramyl peptide derivatives;

myelopid;

N-563;

NACOS-6;

NH-765;

NISV, Proteus;

NPT-16416;

NT-002;

PA-485;

PEFA-814;

peptides, Scios;

peptidoglycan, Pliva;

Perthon, Advanced Plant;

PGM derivative, Pliva;

Pharmaprojects No. 1099;

Pharmaprojects No. 1426;

Pharmaprojects No. 1549;

Pharmaprojects No. 1585;

Pharmaprojects No. 1607;

Pharmaprojects No. 1710;

Pharmaprojects No. 1779;

Pharmaprojects No. 2002;

Pharmaprojects No. 2060;

Pharmaprojects No. 2795;

Pharmaprojects No. 3088;

Pharmaprojects No. 3111;

Pharmaprojects No. 3345;

Pharmaprojects No. 3467;

Pharmaprojects No. 3668;

Pharmaprojects No. 3998;

Pharmaprojects No. 3999;

Pharmaprojects No. 4089;

Pharmaprojects No. 4188;

Pharmaprojects No. 4451;

Pharmaprojects No. 4500;

Pharmaprojects No. 4689;

Pharmaprojects No. 4833;

Pharmaprojects No. 494;

Pharmaprojects No. 5217;

Pharmaprojects No. 530;

pidotimod;

pimelautide;

pinafide;

PMD-589;

podophyllotoxin, Conpharm;

POL-509;

poly-ICLC;

poly-ICLC, Yamasa Shoyu;

PolyA-PolyU;

Polysaccharide A;

protein A, Berlox Bioscience;

PS34WO;

pseudomonas MAbs, Teijin;

Psomaglobin;

PTL-78419;

Pyrexol;

pyriferone;

Retrogen;

Retropep;

RG-003;

Rhinostat;

rifamaxil;

RM-06;

Rollin;

romurtide;

RU-40555;

RU-41821;

rubella antibodies, ResCo;

S-27609;

SB-73;

SDZ-280-636;

SDZ-MRL-953;

SK&

F-107647;

SL04;

SL05;

SM-4333;

Solutein;

SR1-62-834;

SRL-172;

ST-570;

ST-789;

staphage lysate;

Stimulon;

suppressin;

T-150R1;

T-LCEF;

tabilautide;

temurtide;

Theradigm-HBV;

Theradigm-HPV;

Theradigm-HSV;

THF, Pharm &

Upjohn;

THF, Yeda;

thymalfasin;

thymic hormone fractions;

thymocartin;

thymolymphotropin;

thymopentin;

thymopentin analogues;

thymopentin, Peptech;

thymosin fraction 5, Alpha;

thymostimulin;

thymotrinan;

TMD-232;

TO-115;

transfer factor, Viragen;

tuftsin, Selavo;

ubenimex;

Ulsastat;

ANGG−

;

CD-4+;

Collag+;

COLSF+;

COM+;

DA-A+;

GAST−

;

GF-TH+;

GP-120−

;

IF+;

IF-A+;

IF-A-2+;

IF-B+;

IF-G+;

IF-G-1B+;

JL-2+;

IL-12+;

IL-15+;

IM+;

LHRH−

;

LIPCOR+;

LYM-B+;

LYM-NK+;

LYM-T+;

OPI+;

PEP+;

PHG-MA+;

RNA-SYN−

;

SY-CW−

;

TH-A-1+;

TH-5+;

TNF+ and UN.

77. The method of claim 76, wherein the immunostimulating or immunomodulating compound is interferon alpha.

78. The method of claim 70, wherein the hepatitis infection is hepatitis B.

79. The method of claim 70, wherein the hepatitis infection is hepatitis C.

80. The method of claim 70, wherein the hepatitis infection is hepatitis C;

wherein R is butyl, W, X, Y, and Z are each hydrogen, wherein the antiviral compound is 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and the immunostimulating or immunomodulating compound is interferon alpha.

81. The method of claim 70, wherein the hepatitis infection is hepatitis C;

wherein R is nonyl, W, X, Y, and Z are each hydrogen, wherein the antiviral compound is 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and the immunostimulating or immunomodulating compound is interferon alpha.