U.S. patent application number 11/472542 was filed with the patent office on 2006-11-23 for use of substituted-1, 5-dideoxy-1, 5-imino-d-glucitol compounds for treating hepatitis virus infections.
This patent application is currently assigned to United Therapeutics Corporation. Invention is credited to Martin L. Bryant, Richard A. Mueller, Richard A. Partis.
Application Number | 20060264468 11/472542 |
Document ID | / |
Family ID | 26817632 |
Filed Date | 2006-11-23 |
United States Patent
Application |
20060264468 |
Kind Code |
A1 |
Mueller; Richard A. ; et
al. |
November 23, 2006 |
Use of substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for
treating hepatitis virus infections
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 agents selected from among
nucleosides, nucleotides, immunomodulators, immunostimulants or
various combinations of such other agents.
Inventors: |
Mueller; Richard A.;
(Glenco, IL) ; Bryant; Martin L.; (Carlisle,
MA) ; Partis; Richard A.; (Evanston, IL) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
United Therapeutics
Corporation
|
Family ID: |
26817632 |
Appl. No.: |
11/472542 |
Filed: |
June 22, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10341717 |
Jan 14, 2003 |
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11472542 |
Jun 22, 2006 |
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09503945 |
Feb 14, 2000 |
6545021 |
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10341717 |
Jan 14, 2003 |
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60119722 |
Feb 12, 1999 |
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60119856 |
Feb 12, 1999 |
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Current U.S.
Class: |
514/317 ;
514/326; 514/327 |
Current CPC
Class: |
A61P 31/20 20180101;
A61K 31/445 20130101; Y10S 514/885 20130101; A61K 31/454 20130101;
A61P 31/14 20180101; A61K 31/444 20130101; A61K 45/06 20130101;
A61K 31/4545 20130101; A61P 1/16 20180101; A61K 31/5377 20130101;
A61K 31/4535 20130101; A61K 31/436 20130101 |
Class at
Publication: |
514/317 ;
514/326; 514/327 |
International
Class: |
A61K 31/445 20060101
A61K031/445; A61K 31/454 20060101 A61K031/454 |
Claims
1-90. (canceled)
91. A pharmaceutical composition comprising a salt of a basic
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound and an
antiviral compound, wherein said antiviral compound is a
biologically active acid selected from the group consisting of a
nucleoside containing a carboxylic acid moiety and a nucleotide,
said N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound
corresponding to Formula I: ##STR317## 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.sup.5, wherein
R.sup.5.dbd.R.sup.1X.sup.1(R.sup.2X.sup.2).sub.m(R.sup.3X.sup.3).sub.n(R.-
sup.4X.sup.4).sub.pR.sup.6--, wherein: R.sup.1 is alkyl, aryl,
alkenyl, alkynyl, hydrogen or haloalkyl; R.sup.2 is independently
alkylene, alkenylene, alkynylene or haloalkylene; R.sup.3 is
independently alkylene, alkenylene, alkynylene or haloalkylene;
R.sup.4 is independently alkylene, alkenylene, alkynylene or
haloalkylene; R.sup.6 is independently alkylene, alkenylene,
alknylene or haloalkylene; X.sup.1 is independently oxygen, sulfur,
sulfoxide or sulfone; X.sup.2 is independently oxygen, sulfur,
sulfoxide or sulfone; X.sup.3 is independently oxygen, sulfur,
sulfoxide or sulfone; X.sup.4 is independently oxygen, sulfur,
sulfoxide or sulfone; m, n and p are independently 0, 1, 2, or 3;
and m+n+p.ltoreq.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.sup.5
contains between four and twenty atoms.
92. The pharmaceutical composition of claim 91 further comprising a
pharmaceutically acceptable carrier, diluent or excipient.
93. The pharmaceutical composition of claim 91 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.sup.5.
94. The pharmaceutical composition of claim 91 wherein all of any
X.sup.1, X.sup.2, X.sup.3, and X.sup.4 linkages are oxygen:
(m+n+p).gtoreq.2; and R.sup.1 is not hydrogen or unsubstituted
alkyl; or not all of any R.sup.2, R.sup.3, and R.sup.4 groups are
unsubstituted alkylene.
95. The pharmaceutical composition of claim 91 wherein the
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol is
N-(8,8,8-trifluorooctyl)-1,5-dideoxy-1,5-imino-D-glucitol.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to methods and compositions
for treating hepatitis virus infections, especially hepatitis virus
infections, particularly hepatitis B and hepatitis C, in mammals,
especially humans. The methods comprise administering
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in
combination with nucleoside antiviral agents, nucleotide antiviral
agents, mixtures thereof, or, alternatively, in combination with
immunomodulating/-immunostimulating agents. Administration of
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds in
combination with both a nucleoside and/or nucleotide type antiviral
agent and an immunomodulating/immunostimulating agent or agents is
also contemplated. Combinations of anti-hepatitis viral agents show
unexpected efficacy in inhibiting replication and secretion of
hepatitis viruses in cells of mammals infected with these
viruses.
[0003] 2. Background of Invention
[0004] Over half the biologically important proteins are
glycosylated and that glycosylation may vary with disease. Based
upon this information, the use of drugs to control glycosylation
patterns, glycoforms, changes or rates of change will have a
biochemical effect, and may provide a beneficial therapeutic
result. Control of glycolipid and glycoprotein sugar patterns as
well as their synthesis and degradation leads to basic
physiological effects on mammals including humans, agricultural
animals and pets. Possibly, this is through influences on, for
example, N-linked glycans, O-linked glycans, glucosoaminoglycans,
glycosphingolipids, glycophospholipids, lectins, immuneoglobulin
molecules, antibodies, glycoproteins and their biochemical
intermediates or conversion products. Modification of glycosalation
site occupancy influences receptor and enzyme binding site
specificity, selectivity, capacity, protein folding, enzyme
activity, kinetics and energetics. Glycosidase and
glycosyltransferase systems are two biochemical mechanisms that are
suggested to affect such systems (Dwek, Raymond A., Glycobiology:
Toward Understanding the Function of Sugars, Chemical Reviews, 96,
683-720 (1996).
[0005] Other hepatitis viruses significant as agents of human
disease include Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis
Delta, Hepatitis E, Hepatitis F, and Hepatitis G (Coates, J. A. V.,
et. al., Exp. Opin. Ther. Patents (1995) 5(8):747-756). Hepatitis C
infection is also on the increase and effective treatments are
needed. In addition, there are animal hepatitis viruses that are
species-specific, but serves as excellent models for the human
disease. These include, for example, those infecting ducks,
woodchucks, cattle and mice.
1,5-dideoxy-1,5-imino-D-glucitol Compounds
[0006] 1,5-dideoxy-1,5-imino-D-glucitol (also known as
1-deoxynojirimycin, DNJ) and its N-alkyl derivatives (together,
"imino sugars") are known inhibitors of the N-linked
oligosaccharide processing enzymes alpha glucosidase I and II
(Saunier et al., J. Biol. Chem. (1982) 257:14155-14161 (1982);
Elbein, Ann. Rev. Biochem. (1987) 56:497-534). As glucose analogs,
they also have potential to inhibit glucose-transport,
glucosyl-transferases, and/or glycolipid synthesis (Newbrun et al.,
Arch. Oral Biol. (1983) 28: 516-536; Wang et al., Tetrahedron Lett.
(1993) 34:403-406). Their inhibitory activity against glucosidases
has led to the development of these compounds as anti-hyperglycemic
agents and antiviral agents. See, for example, PCT International
Publication WO 87/03903 and U.S. Pat. Nos. 4,065,562; 4,182,767;
4,533,668; 4,639,436; 4,849,430; 4,957,926; 5,011,829; and
5,030,638.
[0007] Glucosidase inhibitors such as
N-alkyl-1,5-dideoxy-1,5-imino-D-glucitol compounds wherein the
alkyl group contains between three and six carbon atoms have been
shown to be effective in the treatment of Hepatitis B infection
(PCT International Publication WO 95/19172). For example,
N-(n-butyl)-deoxynojirimycin (N-butyl-DNJ;
N-(n-butyl)-1-5-dideoxy-1,5-imino-D-glucitol) is effective for this
purpose (Block, T. M., Proc. Natl. Acad. Sci. USA (1994)
91:2235-2239; Ganem, B. Chemtracts: Organic Chemistry (1994) 7(2),
106-107). N-butyl-DNJ has also been tested as an anti-HIV-1 agent
in HIV infected patients, and is known to be well tolerated.
Another alpha glucosidase inhibitor, deoxynojirimycin (DNJ), has
been suggested as an antiviral agent for use in combination with
N-(phosphonoacetyl)-L-aspartic acid (PALA) (WO 93/18763). However,
combinations of N-substituted-imino-D-glucitol derivatives and
other antiviral agents for the treatment of hepatitis virus
infections have not been previously disclosed or suggested. From
results obtained in a woodchuck animal model of hepatitis virus
infection, Block et al. ((1998) Nature Medicine 4(5):610-614)
suggested that glucosidase inhibitors such as N-nonyl DNJ, which
interfere with specific steps in the N-linked glycosylation pathway
of hepatitis virus glycoproteins, may be useful in targeting
glycosylation processing as a therapeutic intervention for
hepatitis B virus.
[0008] Compounds such as N-butyl-DNJ N-butyl-deoxynojirimycin) and
N-butyl-DGNJ (N-butyl-desoxynogalactonojirimycin) are reported as
treatments of lysosomal storage diseases such as Tay-Sachs disease,
Gauchers disease and related ailments. In addition, treatment of
cholera has been reported (U.S. Pat. No. 5,399,567) via inhibition
of the synthesis of glycolipids (U.S. Pat. No. 5,472,969). It has
been reported that inhibition of glycosyl transferase or
glycosidase enzymes affects the catabolism and metabolism of
phopholipids, sphingolipids, cerebrosides, gangliosides by or and
within mammalian cells or interferes with such biochemical
processes as attachment to cells, penetration of cells and/or
release from cells. In any event, treatments for these diseases are
badly needed since "With rare exceptions a treatment of these often
lethal diseases is not possible to date." (Kolter, T and Sandhoff,
K, Inhibitors of Glycosphingolipid Biosynthesis, Chemical Society
Reviews, 371-381 (1996), WO 98/02161.
[0009] The use of N-butyl-1,5-dideoxy-1,5-imino-D-glucose and
certain other imino-glucose compounds for the treatment of diseases
caused or induced by human immunodeficiency virus (HIV),
cytomeglovirus CMV), hepatitis virus, respiratory syncytial virus
(RSV) and herpes virus (HSV) infection has been reported.
[0010] Nucleoside and Nucleotide Antiviral Agents
[0011] Reverse transcriptase inhibitors, including the class of
nucleoside and nucleotide analogs, were first developed as drugs
for the treatment of retroviruses such as human immunodeficiency
virus (HIV), the causative agent of AIDS. Increasingly, these
compounds have found use against other viruses, including both RNA
and DNA viruses, via viral screening and chemical modification
strategies. Nucleoside and nucleotide analogs exert their antiviral
activities by inhibiting the corresponding DNA and RNA polymerases
responsible for synthesis of viral DNA and RNA, respectively.
Because viruses contain different forms of polymerases, the same
nucleoside/nucleotide compound can have a dramatically different
effect against different viruses. For example, lamivudine (3TC)
appears to be useful against HBV infection, whereas zidovudine
(AZT) appears to have little use against the same virus (Gish, R.
G., et al., Exp. Opin. Invest. Drugs (1995) 4(2):95-115).
[0012] AZT is an example of a nucleoside/nucleotide analog that can
effect glycosylation processes at clinically achievable
concentrations rather than interfere with DNA replication or
protein synthesis (Yan, J., et al., J. Biol. Chem., 270, 22836
(1995).
[0013] Toxicity has been significant with some nucleoside analog
antivirals. For example, clinical tests on the use of the
nucleoside analog fialuridine (FIAU) for treatment of chronic
hepatitis B were suspended recently due to drug-related liver
failure leading to death in some patients. Consequently, there is
still a need for safer drug regimens for the treatment of hepatitis
B infections and hepatitis (Mutchnick, M. G., et. al., Antiviral
Research (1994) 24:245-257).
[0014] Immunomodulators and Immunostimulants
[0015] Immunomodulators/immunostimulators such as interferon alpha
and other cytokines have been used for the treatment of HBV
infection with promising results. Unfortunately, the response rates
are lower than desired. Interferon treatment is currently approved
by the FDA for the treatment of Hepatitis B. Other immune
system-affecting drug candidates are presently being investigated.
These include thymic peptides for use in the treatment of chronic
hepatitis B (CHB), isoprinosine, steroids, Schiff base-forming
salicylaldehyde derivatives such as Tucaresol, levamisol, and the
like (Gish, R. G., et al., Exp. Opin. Invest. Drugs (1995)
4(2):95-115; Coates, J. A. V., et al., Exp. Opin. Ther. Patents
(1995) 5(8):747-765).
SUMMARY OF THE INVENTION
[0016] As noted above, the use of the substituted-imino-D-glucitol
compounds and derivatives thereof disclosed herein alone, or in
combination with other anti-hepatitis virus compounds has, to the
present inventor's knowledge, neither been suggested nor disclosed.
The use of two or more anti-viral agents to provide improved
therapy for the treatment of hepatitis B virus and hepatitis C
virus infections is desirable due to the morbidity and mortality of
the disease. Combination therapy is also desirable since it can
reduce toxicity in patients as it enables the physician to
administer lower doses of one or more of the drugs being given to a
patient. Combination therapy can also help to prevent the
development of drug resistance in patients (Wiltink, E. H. H.,
Pharmaceutish Weekblads Scientific Edition (1992) 14(4A):268-274).
The result of an improved efficacy configuration combined with a
relative lack of toxicity and development of resistance would
provide a much improved drug treatment profile.
[0017] Substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds
disclosed herein are effective in treating hepatitis virus
infections. The use of these compounds in combination with
nucleoside or nucleotide antiviral compounds, or combinations
thereof, and/or immunomodulators/immunostimulants, is especially
effective against hepatitis viruses.
[0018] Accordingly, in a first aspect, the present invention
provides a method of treating a hepatitis virus infection in a
mammal, comprising administering to said mammal an anti-hepatitis
virus effective amount of at least one
substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I
or a pharmaceutically acceptable salt thereof: ##STR1##
[0019] 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, aryloxyalkyl, aminoalkyl,
alkanoylaminoalkyl, amino)alkyl, aminocarbonylalkyl,
hydroxysulfonealkyl, aminosulfonealkyl, aminocarbonylaminoalkyl,
aroylaminoalkyl, alkoxycarbonylaminoalkyl, carboxyalkyl,
alkoxycarbonylalkyl or R.sup.5, wherein
R.sup.5.dbd.R.sup.1X.sup.1(R.sup.2X.sup.2).sub.m(R.sup.3X.sup.3).sub.n(R.-
sup.4X.sup.4).sub.pR.sup.6-- wherein:
[0020] R.sup.1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or
haloalkyl;
[0021] R.sup.2 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0022] R.sup.3 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0023] R.sup.4 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0024] R.sup.6 is alkylene, alkenylene, alkynylene, or
haloaldylene;
[0025] X.sup.1 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0026] X.sup.2 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0027] X.sup.3 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0028] X.sup.4 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0029] m, n and p are independently 0, 1, 2, or 3; and
[0030] m+n+p.ltoreq.3
[0031] A, B, C, and D are independently hydrido, lower alkyl,
lowerhaloalkyl or acyl;
[0032] D and R taken together may form a five or six membered ring
when R is carbonyl or alkylcarbonyl;
[0033] A and B taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0034] B and C taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring; and
[0035] C and D taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0036] wherein the main chain in R contains between one and twenty
atoms; and
[0037] the main chain of R.sup.5 containing between four and twenty
atoms.
[0038] In a second aspect, the present invention provides a method
for treating a hepatitis virus infection in a mammal, comprising
administering to said mammal an antiviral composition consisting
essentially of an antiviral effective amount of at least one
substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I
as defined above, or a pharmaceutically acceptable salt
thereof.
[0039] In a third aspect, the present invention provides a method
for treating a hepatitis virus infection in a mammal, comprising
administering to said mammal an antiviral composition containing an
antiviral effective amount of at least one
substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I,
as defined above or a pharmaceutically acceptable salt thereof, as
above, substantially exclusive of the administration of any
antiviral agent comprising a nucleoside, a nucleotide, an
immunomodulator, or an immunostimulant.
[0040] In a fourth aspect, the present invention provides a method
for treating a hepatitis virus infection in a mammal, consisting
essentially of administering to said mammal an antiviral
composition comprising an antiviral effective amount of at least
one substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of
Formula I, as defined above, or a pharmaceutically acceptable salt
thereof, as above. In this method, the antiviral composition can
consist essentially of an antiviral effective amount of the
substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I,
or a pharmaceutically acceptable salt thereof.
[0041] In a fifth aspect, the present invention provides a method
of 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,
as defined above, or a pharmaceutically acceptable salt thereof 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.
[0042] In a sixth aspect the invention is directed to a method for
treating a hepatitis virus infection in a mammal, 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.
[0043] In a seventh aspect, the invention is directed to a method
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.
[0044] In another aspect, the present invention provides a method
of treating a hepatitis virus infection in a mammal, comprising
administering to said mammal from about 0.1 mg/kg/day to about 100
mg/kg/day of at least one
substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I,
as above, 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.
[0045] In another aspect, the present invention provides a
pharmaceutical composition, consisting essentially of an antiviral
effective amount of at least one
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula
I, as defined above, or a pharmaceutically acceptable salt thereof,
as above and a pharmaceutically acceptable carrier, excipient, or
diluent.
[0046] In another aspect, the present invention provides a
pharmaceutical composition, containing an antiviral effective
amount of at least one substituted-1,5-dideoxy-1,5-imino-D-glucitol
compound of Formula I or a pharmaceutically acceptable salt
thereof, as above, substantially exclusive of any antiviral agent
comprising a nucleoside, a nucleotide, an immunomodulator, or an
immunostimulant and a pharmaceutically acceptable carrier, diluent,
or excipient.
[0047] In another aspect, the present invention provides a
composition, comprising at least one
substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula I,
as above, and an antiviral compound selected from the group
consisting of a nucleoside antiviral compound, a nucleotide
antiviral compound, an immunomodulator, an immunostimulant, and
mixtures thereof.
[0048] In another aspect, the present invention provides a
pharmaceutical composition, comprising a first amount of at least
one substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of
Formula I, as above, a second amount of an antiviral compound
selected from the group consisting of a nucleoside antiviral
compound, a nucleotide antiviral compound, an immunomodulator, and
immunostimulant, and mixtures thereof, and a pharmaceutically
acceptable carrier, diluent, or excipient, wherein said first and
second amounts of said compounds together comprise an antiviral
effective amount of said compounds.
[0049] In yet a further aspect, the present invention provides a
pharmaceutical composition for treating a hepatitis B virus
infection in a mammal, comprising from about 0.1 mg to about 100 mg
of at least one substituted-1,5-dideoxy-1,5-imino-D-glucitol
compound of Formula I, as above, and from about 0.1 mg to about 500
mg of a compound selected from the group consisting of a nucleoside
antiviral compound, a nucleotide antiviral, and mixtures thereof,
and a pharmaceutically acceptable carrier, diluent, or
excipient.
[0050] Also provided is a pharmaceutical composition for treating a
hepatitis virus infection in a human patient, comprising from about
0.1 mg to about 100 mg of
(n-nonenyl)-1,5-dideoxy-1,5-imino-D-glucitol, from about 0.1 mg to
about 500 mg of (-)-2'-deoxy-3'-thiocytidine-5'-triphosphate, and a
pharmaceutically acceptable carrier, diluent, or excipient.
[0051] In another aspect, nucleosides and nucleotides and analogs
such as AZT that inhibit sugar processing in addition to or instead
of interfering with DNA or RNA are of special interest for use in
combination therapy with iminosugars of this invention and for us
in pharmaceutical formulations with the iminosugars disclosed
herein. We intend that compounds such as AZT are useful in
combination with the iminosugars disclosed herein for the treatment
of diseases described with regard to the various aspects of this
invention.
[0052] Each of the methods of the invention as described
hereinabove is effective for treating various forms of infectious
hepatitis. Forms of hepatitis which can be treated by
administration of the above-described imino sugars include
hepatitis B, hepatitis C, hepatitis delta, hepatitis E, hepatitis F
and hepatitis G. The methods of the invention, as detailed
hereinbelow, are particularly suited and preferred for the
treatment of hepatitis B and hepatitis C.
[0053] In another aspect, the present invention provides
intermediates useful for the preparation of
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds or a salt
thereof used alone or in combination in the treatment of Hepatitis
B infection.
[0054] Also provided is a salt, comprising an anti-hepatitis
effective amount of an
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of Formula
I, as described above, and a nucleoside having an acidic moiety or
a nucleotide.
[0055] Also provided is a compound, comprising an
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound selected
from: ##STR2##
[0056] wherein:
[0057] R is aryloxyalkyl, monooalkyl, haloalkyloxyalkyl,
cycloalkyloxyalkyl, cycloalkylalkyloxy-alkyl, alkenylcarbonyl,
alkynylcarbonyl, arylalkylcarbonyl, arylalkyloxycarbonyl,
aryloxyalkylcarbonyl, haloalkylcarbonyl, hydroxyalkylcarbonyl,
haloalkyloxyalkylcarbonyl, cycloalkyloxyalkylcarbonyl,
alkoxyalkylcarbonyl, or R.sup.5, wherein
R.sup.5.dbd.R.sup.1X.sup.1(R.sup.2X.sup.2).sub.m(R.sup.3X.sup.3).sub.n(R.-
sup.4X.sup.4).sub.pR.sup.6-- or hydrido;
[0058] R.sup.1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or
haloalkyl;
[0059] R.sup.2 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0060] R.sup.3 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0061] R.sup.4 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0062] R.sup.6 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0063] X.sup.1 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0064] X.sup.2 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0065] X.sup.3 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0066] X.sup.4 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0067] m, n and p are independently 0, 1, 2, or 3;
[0068] (m+n+p).gtoreq.3; and
[0069] (m+n+p).gtoreq.2 and not all of R.sup.2, R.sup.3, and
R.sup.4 are alkylene when all of X.sup.1, X.sup.2, X.sup.3, and
X.sup.4 are oxygen;
[0070] A, B, C, and D are independently hydrido, lower alkyl,
lowerhaloalkyl or acyl;
[0071] A and B taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0072] B and C taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0073] C and D taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0074] wherein the main chain in R contains between one and twenty
atoms; and
[0075] the main chain of R.sup.5 containing between four and twenty
atoms.
[0076] Also provided is a chemical preparation intermediate
selected from the group consisting of: ##STR3## R 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.sup.5 carbonyl wherein R.sup.5 is as defined hereinabove.
[0077] Further scope of the present invention will become apparent
from the detailed description and drawings provided below. However,
it should be understood that the following detailed description and
examples, while indicating preferred embodiments of the invention,
are given by way of illustration only since various changes and
modifications within the spirit and scope of the invention will
become apparent to those skilled in the art from this detailed
description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0078] The above and other objects, features, and advantages of the
present invention will be better understood from the following
detailed description taken in conjunction with the accompanying
drawings, all of which are given by way of illustration only, and
are not limitative of the present invention, in which:
[0079] FIG. 1 shows the anti-hepatitis B virus activity of
(-)-2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) alone and in
combination with N-nonyl-DNJ in vitro.
[0080] FIG. 2 shows the plasma concentration of N-nonyl-DNJ versus
dose of N-nonyl-DNJ for each animal in Example 5, from samples
taken during dosing. Animals are indicated by unique letters, and a
small amount of random noise has been added to the dose value so
that overlapping values can be distinguished.
[0081] FIG. 3 shows the slope of Log-(IPDNA+10) to week versus
dose. A distinct letter is used for each animal. The fitted line is
from a four parameter logistic model. The parameters of the fitted
curve and their approximate standard errors are shown on the
plot.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The following detailed description is provided to aid those
skilled in the art in practicing the present invention. Even so,
this detailed description should not be construed to unduly limit
the present invention as modifications and variations in the
embodiments discussed herein can be made by those of ordinary skill
in the art without departing from the spirit or scope of the
present inventive discovery.
[0083] The contents of each of the patent documents and other
references cited herein, including the contents of the references
cited within these primary references, are herein incorporated by
reference in their entirety.
[0084] It has been discovered that the use of
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds is effective
when such compounds are used alone for treating hepatitis virus
infections. In accordance with the present invention, it has
additionally been discovered that combinations of
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds with
anti-hepatitis virus nucleosides or nucleotides, and/or
immunomodulators/immunostimulants, are also effective for this
purpose.
[0085] The present invention thus provides pharmaceutical
compositions and methods of treating hepatitis virus infections,
especially hepatitis B and C virus infections, in humans, other
mammals, and cells using
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or in
combination with either an antiviral nucleoside, an antiviral
nucleotide, mixtures thereof, and/or an immunomodulating or
immunostimulating agent. The
substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds may have
basic nitrogen atoms and may be used in the form of a
pharmaceutically acceptable salt. Nucleosides and nucleotides
useful in the present invention are substituted purine or
pyrimidine heterocycles further substituted with R.sup.1 in
Formulas II-VI at the 9 position in the case of purines or with
R.sup.1 at the 1 position in the case of pyrimidines. The
immunomodulating and immunostimulating agents useful in the present
invention include those that stimulate immune responses effective
in controlling or eliminating viruses or other infectious agents.
Non-limiting examples of such immunomodulating and
immunostimulating agents include cytokines, peptide agonists,
steroids, and classic drugs such as tetramisole (levamisole). The
drug combinations of this invention may be provided to a cell or
cells, or to a human or other mammalian patient, either in separate
pharmaceutically acceptable formulations administered
simultaneously or sequentially, formulations containing more than
one therapeutic agent, or by an assortment of single agent and
multiple agent formulations. However administered, these drug
combinations form an anti-hepatitis virus effective amount of
components.
[0086] As used herein, the term "anti-hepatitis-virus effective
amount" refers to an amount of an
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound that is
effective when used alone in treating hepatitis virus infection, or
a combined amount of an
N-substituted-1,5,-dideoxy-1,5-imino-D-glucitol and another
antiviral agent that is effective in such treatment. The combined
amounts of antiviral agent can be provided via combinations of: (1)
an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound with
either an antiviral nucleoside, an antiviral nucleotide, or a
mixture of an antiviral nucleoside and an antiviral nucleotide; (2)
an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound with an
immunomodulating/-immunostimulating agent (or mixtures thereof), or
(3) an N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound with
an antiviral nucleoside, an antiviral nucleotide, or a mixture
thereof, plus an immunomodulating/-immunostimulating agent (or
mixtures thereof). The antiviral effectiveness of the
aforementioned combinations may involve a variety of different
phenomena associated with viral replication and assembly. These may
include, for example, blocking hepatitis viral DNA synthesis;
blocking viral transcription; blocking virion assembly; blocking
virion release or secretion from infected cells; blocking or
altering viral protein function, including the function of viral
envelope protein(s); and/or the production of immature or otherwise
non-functional virions. The overall effect is an inhibition of
viral replication and infection of additional cells, and therefore
inhibition of the progress of infection in the patient.
Substituted-1,5-dideoxy-1,5-imino-D-glucose compounds
[0087] Substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds
useful in the present invention are represented by structure I
below or salts thereof: ##STR4##
[0088] R is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,
cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl,
bicycloalkenylalkyl, tricycloalkenylalkyl, tetracycloalkenylalkyl,
bicycloalkenoxyalkyl, tricycloalkenoxyalkyl,
tetracycloalkenyloxyalkyl, cycloalkylalkenyl, cycloalkylalkynyl,
aralkenyl, aralkynyl, substituted aralkyl, aralkoxyalkyl,
aralkoxyalkenyl, aralkoxyalknyl, 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, substituted arylalkylcarbonyl,
arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,
hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,
cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl, alkyloxycarbonyl,
alkanoyloxyalkyl, aryloxyalkoxyalkyl, aryloxyalkyl, aminoalkyl,
alkanoylaminoalkyl, aminocarbonylalkyl, hydroxysulfonealkyl,
aminosulfonealkyl, aminocarbonylaminoalkyl, aroylaminoalkyl,
alkoxycarbonylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl or
R.sup.5, wherein
R.sup.5.dbd.R.sup.1X.sup.1(R.sup.2X.sup.2).sub.m(R.sup.3X.sup.3)-
.sub.n(R.sup.4X.sup.4).sub.pR.sup.6-- wherein:
[0089] R.sup.1 is alkyl, aryl, alkenyl, alkynyl, hydrogen or
haloalkyl;
[0090] R.sup.2 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0091] R.sup.3 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0092] R.sup.4 is alkylene, alkenylene, alkynylene or
haloalkylene;
[0093] R.sup.6 is alkylene, alkenylene, alkynylene, or
haloalkylene;
[0094] X.sup.1 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0095] X.sup.2 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0096] X.sup.3 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0097] X.sup.4 is independently oxygen, sulfur, sulfoxide or
sulfone;
[0098] m, n and p are independently 0, 1, 2, or 3; and
[0099] m+n+p.ltoreq.3
[0100] A, B, C, and D are independently hydrido, lower alkyl,
lowerhaloalkyl or acyl;
[0101] D and R taken together may form a five or six membered ring
when R is carbonyl or alkylcarbonyl;
[0102] A and B taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0103] B and C taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring; and
[0104] C and D taken together with the atoms to which they are
attached may form a five or six membered heterocyclic ring;
[0105] wherein the main chain in R contains between one and twenty
atoms; and
[0106] the main chain of R.sup.5 containing between four and twenty
atoms.
[0107] As utilized herein, the term "alkyl", alone or in
combination, means a straight-chain or branched-chain alkyl radical
containing from 1 to and including 20 carbon atoms. Substituted
alkyl, alone or in combination, means an alkyl radical which is
optionally substituted as defined herein with respect to the
definitions of aryl and heterocyclo. Alkylene means a saturated
aliphatic hydrocarbon moiety attached at two or more positions such
as methylene (--CH.sub.2--). Examples of alkyl radicals include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
[0108] The term "lower alkyl", alone or in combination, means alkyl
containing from 1 to and including 6 carbon atoms.
[0109] The phrase "in the main chain" means the longest contiguous
or adjacent chain of carbon atoms starting at the point of
attachment of a group to the compounds of this invention.
[0110] The phrase "linear chain of atoms" means the longest
straight chain of atoms independently selected from carbon,
nitrogen, oxygen and sulfur.
[0111] The term "hydrido" means a hydrogen substituent, i.e.,
--H.
[0112] The term "alkenyl", alone or in combination, means a
straight-chain or branched-chain hydrocarbon radical having one or
more double bonds and containing from 2 to 20 carbon atoms.
Substituted alkenyl, alone or in combination, means an alkyl
radical which is optionally substituted as defined herein with
respect to the definitions of aryl and heterocyclo. Alkenylene
means a carbon-carbon double bond system attached at two or more
positions such as ethenylene (--CH.dbd.CH--). Examples of suitable
alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl,
1,4-butadienyl and the like.
[0113] The term lower "alkenyl", alone or in combination, means
alkenyl containing from 2 to and including 6 carbon atoms.
[0114] The term "alkynyl", alone or in combination, means a
straight-chain or branched chain hydrocarbon radical having one or
more triple bonds and containing preferably from 2 to 20 carbon
atoms. Substituted alkynyl, alone or in combination, means an alkyl
radical which is optionally substituted as defined herein with
respect to the definitions of aryl and heterocyclo. Alkynylene
means a carbon-carbon triple-bond attached at two positions such as
ethynylene (--C:::C--). Examples of alkynyl radicals include
ethynyl, propynyl (propargyl), butynyl and the like.
[0115] The term lower "alkynyl", alone or in combination, means
alkynyl containing from 2 to and including 6 carbon atoms.
[0116] The term "alkoxy", alone or in combination, means an alkyl
ether radical wherein the term alkyl is as defined above. Examples
of suitable alkyl ether radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy, ethoxyethoxy, methoxypropoxyethoxy,
ethoxypentoxyethoxyethoxy and the like.
[0117] The term "cycloalkyl", alone or in combination, means a
saturated or partially saturated monocyclic, bicyclic or tricyclic
alkyl radical wherein each cyclic moiety contains preferably from 3
to 10 carbon atom ring members and which may optionally be a benzo
fused ring system which is optionally substituted as defined herein
with respect to the definition of aryl. Examples of such cycloalkyl
radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl
and the like.
[0118] The term "cycloalkylalkyl" means an alkyl radical as defined
above which is substituted by a cycloalkyl radical as defined
above. Examples of such-cycloalkylalkyl radicals include
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,
2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl,
cyclopentylpropyl, cyclohexylbutyl and the like.
[0119] The term "benzo", alone or in combination, means the
divalent radical C.sub.6H.sub.4.dbd. derived from benzene.
[0120] The term "aryl", alone or in combination, or "ara" or" "ar"
in combination, means a phenyl or naphthyl radical which is
optionally substituted with one or more substituents selected from
the group consisting of alkyl, alkylcarbonyl, alkoxy, halogen,
hydroxy, amino, nitro, cyano, haloalkyl, haloalkylthio,
haloalkyloxy, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo,
alkylcarbonylamino, aminoalkanoyl, amido, aminocarbonyl,
arylcarbonyl, arylcarbonylamino, aryl, aryloxy, alkyloxycarbonyl,
arylalkyloxycarbonyl, alkoxycarbonylamino, substituted amino,
disubstituted amino, substituted aminocarbonyl, disubstituted
aminocarbonyl, substituted amido, disubstituted amido,
aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, arylthio,
arylsulfinyl, arylsulfonyl, alkylsulfinylamino, alkylsulfonylamino,
haloalkylsulfinylamino, haloalkylsulfonylamino, arylsulfinylamino,
arylsulfonylamino, heterocyclo, sulfonate, sulfonic acid,
trisubstitutedsilyl and the like. It is intended to include both
fused ring systems, such as naphthyl and .beta.-carbolinyl, and
substituted ring systems, such as biphenyl, phenylpyridyl, naphthyl
and diphenylpiperazinyl. Examples of aryl radicals are phenyl,
p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,
3-methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl,
3-nitrophenyl, 3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,
2-methyl-3-acetamidophenyl, 4-CF.sub.3-phenyl,
2-methyl-3-aminophenyl, 4-CF.sub.3O-phenyl, 3-methyl-4-aminophenyl,
2-amino-3-methylphenyl, 2,4-dimethyl-3-aminophenyl,
4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,
3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,
6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl, piperazinylphenyl and
the like.
[0121] The terms "aralkyl" and "aralkoxy", alone or in combination,
means an alkyl or alkoxy radical as defined above in which at least
one hydrogen atom is replaced by an aryl radical as defined above.
Thus, "aryl" includes substituents such as benzyl, 2-phenylethyl,
dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, and
diphenylmethyl, and "aryloxy" includes substituents such as
benzyloxy, diphenylmethoxy, 4-methoxyphenylmethoxy and the
like.
[0122] The term "aralkoxycarbonyl", alone or in combination, means
a radical of the formula aralkyl-O--C(O)-- in which the term
"aralkyl" has the significance given above. Examples of an
aralkoxycarbonyl radical are benzyloxycarbonyl and
4-methoxyphenylmethoxycarbonyl.
[0123] The term "aryloxy" means a radical of the formula aryl-O--
in which the term aryl has the significance given above.
[0124] The term "alkanoyl", alone or in combination, means an acyl
radical derived from an alkanecarboxylic acid, examples of which
include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and
the like.
[0125] The term "alkylcarbonyl" means alkanoyl.
[0126] The term "cycloalkylcarbonyl", means an acyl radical of the
formula cycloalkyl-C(O)-- in which the term "cycloalkyl" has the
significance give above, such as cyclopropylcarbonyl,
cyclohexylcarbonyl, adamantylcarbonyl,
1,2,3,4-tetrahydro-2-naphthoyl,
2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl,
1-hydroxy-1,2,3,4-tetrahydro-6-naphthoyl and the like.
[0127] The term "aralkanoyl" means an acyl radical derived from an
aryl-substituted alkanecarboxylic acid such as benzoyl,
phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,
(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,
4-methoxyhydrocinnamoyl, and the like. The term "aroyl" means an
acyl radical derived from an arylcarboxylic acid, "aryl" having the
meaning given above. Examples of such aroyl radicals include
substituted and unsubstituted benzoyl or napthoyl such as benzoyl,
4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl,
1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl,
6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,
3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the
like.
[0128] The term "arylcarbonyl" is aroyl.
[0129] Where substituents are recited without qualification as to
substitution, both substituted and unsubstituted forms are
encompassed. Where a substituent is qualified as "substituted," the
substituted form is specifically intended.
[0130] The term "substituted", when used in combination and not
otherwise defined in this paragraph, means one to four substituents
attached that are independently selected from the group comprising
alkyl, alkylcarbonyl, alkoxy, halogen, hydroxy, amino, nitro,
cyano, thiol, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl,
heterocyclo, alkanoylamino, aminoalkanoyl, amido, aminocarbonyl,
arylcarbonyl, aryl, aryloxy, alkyloxycarbonyl,
arylalkyloxycarbonyl, alkoxycarbonylamino, substituted amino,
disubstituted amino, substituted aminocarbonyl, disubstituted
aminocarbonyl, substituted amido, disubstituted amido,
aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
arylthio, arylsulfinyl, arylsulfonyl, heterocyclo, sulfonate,
sulfonic acid and trisubstitutedsilyl. Still other substituents may
be contemplated by the term "substituted," including the various
substituents for aryl moieties as described hereinabove, some of
which may suitably be substituted onto non-aromatic carbons and
other sites on the molecule.
[0131] The term "carbonyl", alone includes formyl {--(C.dbd.O)--H]
and in combination is a --C.dbd.O-- group.
[0132] The term "thiocarbonyl", alone includes thioformyl
{--(C.dbd.S)--H] and in combination is a --C.dbd.S-- group.
[0133] The term "oxy" means a --O-- group.
[0134] The term "carboxy" is --COOH or the corresponding
"carboxylate" anion such as is in a carboxylic acid salt.
[0135] The term "heterocyclo," alone or in combination, means a
saturated or partially unsaturated monocyclic, bicyclic or
tricyclic heterocycle radical containing at least one, preferably 1
to 4, more preferably 1 to 2, nitrogen, oxygen or sulfur atom ring
members and having preferably 3 to 8 ring members in each ring,
more preferably 3 to 7 ring members in each ring and most
preferably 5 to 6 ring members in each ring. "Heterocyclo" is
intended to include sulfones, sulfoxides, N-oxides of tertiary
nitrogen ring members, and carbocyclic fused and benzo fused ring
systems. Such heterocyclo radicals may be optionally substituted on
at least one, preferably 1 to 4, more-preferably 1 to 2, carbon
atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl,
heteroaryl, heteroaralkyl, amidino, N-alkylamidino,
alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a
secondary nitrogen atom (i.e., --NH--) by hydroxy, alkyl,
aralkoxycarbonyl, alkanoyl, heteroaralkyl, phenyl or phenylalkyl,
and/or on a tertiary nitrogen atom (i.e., .dbd.N--) by oxido.
[0136] The term "heterocycloalkyl" means an alkyl radical as
defined above in which at least one hydrogen atom is replaced by a
heterocyclo radical as defined above, such as pyrrolidinylmethyl,
tetrahydrothienylmethyl, pyridylmethyl and the like.
[0137] The term "heteroaryl", alone or in combination, means an
aromatic heterocyclo radical as defined above, which is optionally
substituted as defined above with respect to the definitions of
aryl and heterocyclo. Examples of such heterocyclo and heteroaryl
groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl,
1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, (e.g.,
2-(1-piperidinyl)pyridyl and 2-(4-benzyl
piperazin-1-yl-1-pyridinyl, etc.), pyrazinyl, pyrimidinyl, furyl,
tetrahydrofuryl, thienyl, tetrahydrothienyl and its sulfoxide and
sulfone derivatives, triazolyl, oxazolyl, thiazolyl, indolyl (e.g.,
2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,
1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,
3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,
1,2,3,4-tetrahydro-2-quinolyl, etc.),
1,2,3,4-tetrahydroisoquinolinyl (e.g.,
1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,
1-carbolinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or 5-benzimidazolyl,
methylenedioxyphen-4-yl, methylenedioxyphen-5-yl,
ethylenedioxyphenyl, benzothiazolyl, benzopyranyl, benzofuryl,
2,3-dihydrobenzofuryl, benzoxazolyl, thiophenyl and the like.
[0138] The term "cycloalkylalkoxycarbonyl" means an acyl group
derived from a cycloalkylalkoxycarboxylic acid of the formula
cycloalkylalkyl-O--COOH wherein cycloalkylalkyl has the meaning
given above.
[0139] The term "aryloxyalkanoyl" means an acyl radical of the
formula aryl-O-alkanoyl wherein aryl and alkanoyl have the meaning
given above.
[0140] The term "heterocycloalkoxycarbonyl" means an acyl group
derived from heterocycloalkyl-O--COOH wherein heterocycloalkyl is
as defined above.
[0141] The term "heterocycloalkanoyl" is an acyl radical derived
from a heterocycloalkylcarboxylic acid wherein heterocyclo has the
meaning given above.
[0142] The term "heterocycloalkanoyl" is an acyl radical derived
from a heterocycloalkylcarboxylic acid wherein heterocyclo has the
meaning given above.
[0143] The term "heterocycloalkoxycarbonyl" means an acyl radical
derived from a heterocycloalkyl-O--COOH wherein heterocyclo has the
meaning given above.
[0144] The term "heteroaryloxycarbonyl" means an acyl radical
derived from a carboxylic acid represented by heteroaryl-O--COOH
wherein heteroaryl has the meaning given above.
[0145] The term "trisubstitutedsilyl", alone or in combination,
means a silicone group substituted at its three free valences with
groups as listed herein under the definition of substituted amino.
Examples include trimethysilyl, tert-butyldimethylsilyl,
triphenylsilyl and the like. The terms "sulfonate", "sulfonic acid"
and "sulfonic", alone or in combination, mean the --SO.sub.3H group
and its anion as the sulfonic acid is used in salt formation.
[0146] The term "aminocarbonyl" alone or in combination, means an
amino-substituted carbonyl (carbamoyl) group wherein the amino
group can be a primary, secondary or tertiary amino group
containing substituents selected from alkyl, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl radicals and the like.
[0147] The term "amido", alone or in combination, means the product
of the combination of a carboxylic acid with an amine as defined
herein.
[0148] The term "amino", alone or in combination, means an --N.dbd.
group wherein the amino group can be a primary, secondary or
tertiary amino group containing substituents selected from alkyl,
aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
Primary amino has two free valences as hydrogen, i.e., --NH.sub.2.
Secondary amino, which is also mono-substituted amino or
N-substituted amino, has one free valence substituted as above.
Tertiary amino, which is also disubstituted amino or
N,N-disubstituted amino, has two free valences substituted as
above. For example, --NH.sub.2 is unsubstituted amino,
--N(H)(CH.sub.3) is mono-substituted amino (N-methylamino) and
--N(CH3)(CH.sub.2phenyl) is disubstituted amino
(N-methyl-N-benzylamino).
[0149] The term "aminoalkanoyl" means an acyl group derived from an
amino-substituted alkylcarboxylic acid wherein the amino group can
be a primary, secondary or tertiary amino group containing
substituents selected from alkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl radicals and the like.
[0150] The term "halogen" means fluorine, chlorine, bromine or
iodine.
[0151] The term "haloalkyl", alone or in combination, means an
alkyl radical having the meaning as defined above wherein one or
more hydrogens are replaced with a halogen. Haloalkylene means a
halohydrocarbyl group attached at two or more positions. Examples
include fluoromethylene (--CFH--), difluoromethylene
(--CF.sub.2--), chloromethylene (--CHCl--) and the like. Examples
of such haloalkyl radicals include chloromethyl, 1-bromoethyl,
fluoromethyl, difluoromethyl, trifluoromethyl,
1,1,1-trifluoroethyl, perfluorodecyl and the like.
[0152] The term "lowerhaloalkyl", alone or in combination, means
haloalkyl containing from 1 to and including 6 carbon atoms.
[0153] The terms "thia" and "thio", alone or in combination, mean a
--S-- group or an ether wherein the oxygen is replaced with a
sulfur. The oxidized derivatives of the thio function are included.
Examples include alkylthia groups such as methylthia and oxidation
products such as the sulfoxide [--(S--O)--] and sulfone
[--(S--O.sub.2)--] derivatives.
[0154] The term "thiol" means an --SH group.
[0155] The term "leaving group" (L or W) generally refers to groups
readily displaceable by a nucleophile, such as an amine, a thiol or
an alcohol nucleophile. Such leaving groups are well known in the
art. Examples of such leaving groups include, but are not limited
to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides,
triflates, tosylates and the like. Preferred leaving groups are
indicated herein where appropriate.
[0156] The definitions above are applied except where exceptions
are specified. For example, monohaloalkyl specifically means an
alkyl group with one halogen substituent.
[0157] Compounds disclosed herein are those expected to be
sufficiently stable to be used as presented herein or to be used in
the preparation of the materials shown herein. This specifically
includes temporary or transient intermediates in chemical reactions
and compounds that may exist in different forms depending upon
their environment. It is well known in the art that stability is
partially defined in relation to use. For illustration, aldehydes
may be hydrated when in an aqueous system but not hydrated in a
non-aqueous system and various solvates may be used in
pharmaceutical compositions rather than an anhydrous compound. The
pharmaceutical chloral is a material wherein the soporific is
conveniently administered as the hydrate (chloral hydrate) whereas
the anhydrous form (trichloroacetaldehyde) is conveniently used (or
made in situ) as a reagent or substrate in synthetic reactions such
Wittig reactions.
[0158] The present invention comprises any tautomeric forms of
compounds of Formula I. The present invention also comprises
compounds of Formula I having one or more asymmetric carbons. It is
known to those skilled in the art that those imino sugars of the
present invention having asymmetric carbon atoms may exist in
diastereomeric, racemic, or optically active forms. All of these
forms are contemplated within the scope of this invention. More
specifically, the present invention includes enantiomers,
diastereomers, racemic mixtures, and other mixtures thereof.
[0159] Representative N-substituted-imino-D-glucitol compounds
useful in the present invention include, but are not limited to
compounds in the Tables: TABLE-US-00001 TABLE 1 ##STR5## R 1.
##STR6## 2. ##STR7## 3. ##STR8## 4. ##STR9## 5. ##STR10## 6.
##STR11## 7. ##STR12## 8. ##STR13## 9. --(CH.sub.2).sub.8CF.sub.3
10. --(CH.sub.2).sub.7CF.sub.3 11. --(CH.sub.2).sub.9CF.sub.3 12.
--(CH.sub.2).sub.8CH.sub.3 13. --(CH.sub.2).sub.9CH.sub.3 14.
##STR14## 15. ##STR15## 16. ##STR16## 17. ##STR17## 18. ##STR18##
19. ##STR19## 20. ##STR20## 21. ##STR21## 22.
--(CH.sub.2).sub.8SO.sub.2CF.sub.3 23.
--(CH.sub.2NH(CH.sub.2).sub.4SO.sub.2CF.sub.3 24.
--(CH.sub.2).sub.9NHSO.sub.2CF.sub.3 25.
--(CH.sub.2).sub.8SO.sub.2NHC.sub.6H.sub.5 26. ##STR22##
[0160] TABLE-US-00002 TABLE 2 ##STR23## R 1. ##STR24## 2. ##STR25##
3. ##STR26## 4. ##STR27## 5. ##STR28## 6. ##STR29## 7. ##STR30## 8.
##STR31## 9. --(CH.sub.2).sub.8CF.sub.3 10.
--(CH.sub.2).sub.7CF.sub.3 11. --(CH.sub.2).sub.9CF.sub.3 12.
--(CH.sub.2).sub.8CH.sub.3 13. --(CH.sub.2).sub.9CH.sub.3 14.
##STR32## 15. ##STR33## 16. ##STR34## 17. ##STR35## 18. ##STR36##
19. ##STR37## 20. ##STR38## 21. ##STR39## 22.
--(CH.sub.2).sub.8SO.sub.2CF.sub.3 23.
--(CH.sub.2NH(CH.sub.2).sub.4SO.sub.2CF.sub.3 24.
--(CH.sub.2).sub.9NHSO.sub.2CF.sub.3 25.
--(CH.sub.2).sub.8SO.sub.2NHC.sub.6H.sub.5 26. ##STR40##
[0161] TABLE-US-00003 TABLE 3 ##STR41## R 1. ##STR42## 2. ##STR43##
3. ##STR44## 4. ##STR45## 5. ##STR46## 6. ##STR47## 7. ##STR48## 8.
##STR49## 9. --(CH.sub.2).sub.8CF.sub.3 10.
--(CH.sub.2).sub.7CF.sub.3 11. --(CH.sub.2).sub.9CF.sub.3 12.
--(CH.sub.2).sub.8CH.sub.3 13. --(CH.sub.2).sub.9CH.sub.3 14.
##STR50## 15. ##STR51## 16. ##STR52## 17. ##STR53## 18. ##STR54##
19. ##STR55## 20. ##STR56## 21. ##STR57## 22.
--(CH.sub.2).sub.8SO.sub.2CF.sub.3 23.
--(CH.sub.2NH(CH.sub.2).sub.4SO.sub.2CF.sub.3 24.
--(CH.sub.2).sub.9NHSO.sub.2CF.sub.3 25.
--(CH.sub.2).sub.8SO.sub.2NHC.sub.6H.sub.5 26. ##STR58##
[0162] TABLE-US-00004 TABLE 4 ##STR59## R 1.
--(CH.sub.2).sub.2O(CH.sub.2).sub.6CF.sub.3 2.
--(CH.sub.2).sub.6O(CH.sub.2).sub.6CF.sub.3 3.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 4.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 5.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 6.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 7.
##STR60## 8. ##STR61## 9.
--(CH.sub.2).sub.6S(CH.sub.2).sub.2CF.sub.3 10.
--(CH.sub.2).sub.4S(CH.sub.2).sub.2CF.sub.3 11. ##STR62## 12.
--(CH.sub.2).sub.2S(CH.sub.2).sub.4NHCH.sub.2CF.sub.3 13.
--(CH.sub.2).sub.3NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 14.
--(CH.sub.2).sub.2NH(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 15.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 16.
--(CH.sub.2).sub.2S(CH.sub.2).sub.2O(CH.sub.2).sub.3CF.sub.3 17.
--(CH.sub.2).sub.2N(CH.sub.3)(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.-
3 18. ##STR63## 19. ##STR64## 20.
--(CH.sub.2).sub.6N(CH.sub.2C.sub.6H.sub.5)(CH.sub.2).sub.2CF.sub.3
22. ##STR65## 22. ##STR66##
[0163] TABLE-US-00005 TABLE 5 ##STR67## R 1.
--(CH.sub.2).sub.2O(CH.sub.2).sub.6CF.sub.3 2.
--(CH.sub.2).sub.6O(CH.sub.2).sub.6CF.sub.3 3.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 4.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 5.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 6.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 7.
##STR68## 8. ##STR69## 9.
--(CH.sub.2).sub.6S(CH.sub.2).sub.2CF.sub.3 10.
--(CH.sub.2).sub.4S(CH.sub.2).sub.2CF.sub.3 11. ##STR70## 12.
--(CH.sub.2).sub.2S(CH.sub.2).sub.4NHCH.sub.2CF.sub.3 13.
--(CH.sub.2).sub.3NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 14.
--(CH.sub.2).sub.2NH(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 15.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 16.
--(CH.sub.2).sub.2S(CH.sub.2).sub.2O(CH.sub.2).sub.3CF.sub.3 17.
--(CH.sub.2).sub.2N(CH.sub.3)(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.-
3 18. ##STR71## 19. ##STR72## 20.
--(CH.sub.2).sub.6N(CH.sub.2C.sub.6H.sub.5)(CH.sub.2).sub.2CF.sub.3
22. ##STR73## 22. ##STR74##
[0164] TABLE-US-00006 TABLE 6 ##STR75## R 1.
--(CH.sub.2).sub.2O(CH.sub.2).sub.6CF.sub.3 2.
--(CH.sub.2).sub.6O(CH.sub.2).sub.6CF.sub.3 3.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 4.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 5.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 6.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 7.
##STR76## 8. ##STR77## 9.
--(CH.sub.2).sub.6S(CH.sub.2).sub.2CF.sub.3 10.
--(CH.sub.2).sub.4S(CH.sub.2).sub.2CF.sub.3 11. ##STR78## 12.
--(CH.sub.2).sub.2S(CH.sub.2).sub.4NHCH.sub.2CF.sub.3 13.
--(CH.sub.2).sub.3NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 14.
--(CH.sub.2).sub.2NH(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 15.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 16.
--(CH.sub.2).sub.2S(CH.sub.2).sub.2O(CH.sub.2).sub.3CF.sub.3 17.
--(CH.sub.2).sub.2N(CH.sub.3)(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.-
3 18. ##STR79## 19. ##STR80## 20.
--(CH.sub.2).sub.6N(CH.sub.2C.sub.6H.sub.5)(CH.sub.2).sub.2CF.sub.3
22. ##STR81## 22. ##STR82##
[0165] TABLE-US-00007 TABLE 7 ##STR83## R 1.
--(CH.sub.2).sub.2O(CH.sub.2).sub.6CF.sub.3 2.
--(CH.sub.2).sub.6O(CH.sub.2).sub.6CF.sub.3 3.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 4.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 5.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 6.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 7.
##STR84## 8. ##STR85## 9.
--(CH.sub.2).sub.6S(CH.sub.2).sub.2CF.sub.3 10.
--(CH.sub.2).sub.4S(CH.sub.2).sub.2CF.sub.3 11. ##STR86## 12.
--(CH.sub.2).sub.2S(CH.sub.2).sub.4NHCH.sub.2CF.sub.3 13.
--(CH.sub.2).sub.3NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 14.
--(CH.sub.2).sub.2NH(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 15.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 16.
--(CH.sub.2).sub.2S(CH.sub.2).sub.2O(CH.sub.2).sub.3CF.sub.3 17.
--(CH.sub.2).sub.2N(CH.sub.3)(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.-
3 18. ##STR87## 19. ##STR88## 20.
--(CH.sub.2).sub.6N(CH.sub.2C.sub.6H.sub.5)(CH.sub.2).sub.2CF.sub.3
22. ##STR89## 22. ##STR90##
[0166] TABLE-US-00008 TABLE 8 ##STR91## R 1.
--(CH.sub.2).sub.2O(CH.sub.2).sub.6CF.sub.3 2.
--(CH.sub.2).sub.6O(CH.sub.2).sub.6CF.sub.3 3.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 4.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 5.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 6.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 7.
##STR92## 8. ##STR93## 9.
--(CH.sub.2).sub.6S(CH.sub.2).sub.2CF.sub.3 10.
--(CH.sub.2).sub.4S(CH.sub.2).sub.2CF.sub.3 11. ##STR94## 12.
--(CH.sub.2).sub.2S(CH.sub.2).sub.4NHCH.sub.2CF.sub.3 13.
--(CH.sub.2).sub.3NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 14.
--(CH.sub.2).sub.2NH(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 15.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 16.
--(CH.sub.2).sub.2S(CH.sub.2).sub.2O(CH.sub.2).sub.3CF.sub.3 17.
--(CH.sub.2).sub.2N(CH.sub.3)(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.-
3 18. ##STR95## 19. ##STR96## 20.
--(CH.sub.2).sub.6N(CH.sub.2C.sub.6H.sub.5)(CH.sub.2).sub.2CF.sub.3
22. ##STR97## 22. ##STR98##
[0167] TABLE-US-00009 TABLE 9 ##STR99## R 1.
--(CH.sub.2).sub.2O(CH.sub.2).sub.6CF.sub.3 2.
--(CH.sub.2).sub.6O(CH.sub.2).sub.6CF.sub.3 3.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 4.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 5.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OCF.sub.3 6.
--(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 7.
##STR100## 8. ##STR101## 9.
--(CH.sub.2).sub.6S(CH.sub.2).sub.2CF.sub.3 10.
--(CH.sub.2).sub.4S(CH.sub.2).sub.2CF.sub.3 11. ##STR102## 12.
--(CH.sub.2).sub.2S(CH.sub.2).sub.4NHCH.sub.2CF.sub.3 13.
--(CH.sub.2).sub.3NH(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.3 14.
--(CH.sub.2).sub.2NH(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 15.
--(CH.sub.2).sub.6O(CH.sub.2).sub.2S(CH.sub.2).sub.2OCF.sub.3 16.
--(CH.sub.2).sub.2S(CH.sub.2).sub.2O(CH.sub.2).sub.3CF.sub.3 17.
--(CH.sub.2).sub.2N(CH.sub.3)(CH.sub.2).sub.2O(CH.sub.2).sub.2CF.sub.-
3 18. ##STR103## 19. ##STR104## 20.
--(CH.sub.2).sub.6N(CH.sub.2C.sub.6H.sub.5)(CH.sub.2).sub.2CF.sub.3
22. ##STR105## 22. ##STR106##
[0168] TABLE-US-00010 TABLE 10 ##STR107## R 1.
--(CH.sub.2).sub.11CF.sub.3 2.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCH.sub.2CF.sub.3 3.
--(CH.sub.2).sub.4O(CH.sub.2).sub.4CF.sub.3 4. ##STR108## 5.
##STR109## 6. ##STR110## 7. ##STR111## 8. ##STR112## 9. ##STR113##
10. ##STR114## 11. ##STR115## 12.
--(CH.sub.2).sub.8(CF.sub.2).sub.3CF.sub.3 13.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCF.sub.2CF.sub.3 14.
--(CH.sub.2).sub.4O(CH.sub.2).sub.2(CF.sub.2).sub.2CF.sub.3 15.
##STR116## 16. ##STR117## 17. ##STR118## 18. ##STR119## 19.
##STR120## 20. ##STR121## 21. ##STR122## 22. ##STR123##
[0169] TABLE-US-00011 TABLE 11 ##STR124## R 1.
--(CH.sub.2).sub.11CF.sub.3 2.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCH.sub.2CF.sub.3 3.
--(CH.sub.2).sub.4O(CH.sub.2).sub.4CF.sub.3 4. ##STR125## 5.
##STR126## 6. ##STR127## 7. ##STR128## 8. ##STR129## 9. ##STR130##
10. ##STR131## 11. ##STR132## 12.
--(CH.sub.2).sub.8(CF.sub.2).sub.3CF.sub.3 13.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCF.sub.2CF.sub.3 14.
--(CH.sub.2).sub.4O(CH.sub.2).sub.2(CF.sub.2).sub.2CF.sub.3 15.
##STR133## 16. ##STR134## 17. ##STR135## 18. ##STR136## 19.
##STR137## 20. ##STR138## 21. ##STR139## 22. ##STR140##
[0170] TABLE-US-00012 TABLE 12 ##STR141## R 1.
--(CH.sub.2).sub.11CF.sub.3 2.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCH.sub.2CF.sub.3 3.
--(CH.sub.2).sub.4O(CH.sub.2).sub.4CF.sub.3 4. ##STR142## 5.
##STR143## 6. ##STR144## 7. ##STR145## 8. ##STR146## 9. ##STR147##
10. ##STR148## 11. ##STR149## 12.
--(CH.sub.2).sub.8(CF.sub.2).sub.3CF.sub.3 13.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCF.sub.2CF.sub.3 14.
--(CH.sub.2).sub.4O(CH.sub.2).sub.2(CF.sub.2).sub.2CF.sub.3 15.
##STR150## 16. ##STR151## 17. ##STR152## 18. ##STR153## 19.
##STR154## 20. ##STR155## 21. ##STR156## 22. ##STR157##
[0171] TABLE-US-00013 TABLE 13 ##STR158## R 1.
--(CH.sub.2).sub.11CF.sub.3 2.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCH.sub.2CF.sub.3 3.
--(CH.sub.2).sub.4O(CH.sub.2).sub.4CF.sub.3 4. ##STR159## 5.
##STR160## 6. ##STR161## 7. ##STR162## 8. ##STR163## 9. ##STR164##
10. ##STR165## 11. ##STR166## 12.
--(CH.sub.2).sub.8(CF.sub.2).sub.3CF.sub.3 13.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCF.sub.2CF.sub.3 14.
--(CH.sub.2).sub.4O(CH.sub.2).sub.2(CF.sub.2).sub.2CF.sub.3 15.
##STR167## 16. ##STR168## 17. ##STR169## 18. ##STR170## 19.
##STR171## 20. ##STR172## 21. ##STR173## 22. ##STR174##
[0172] TABLE-US-00014 TABLE 14 ##STR175## R 1.
--(CH.sub.2).sub.11CF.sub.3 2.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCH.sub.2CF.sub.3 3.
--(CH.sub.2).sub.4O(CH.sub.2).sub.4CF.sub.3 4. ##STR176## 5.
##STR177## 6. ##STR178## 7. ##STR179## 8. ##STR180## 9. ##STR181##
10. ##STR182## 11. ##STR183## 12.
--(CH.sub.2).sub.8(CF.sub.2).sub.3CF.sub.3 13.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCF.sub.2CF.sub.3 14.
--(CH.sub.2).sub.4O(CH.sub.2).sub.2(CF.sub.2).sub.2CF.sub.3 15.
##STR184## 16. ##STR185## 17. ##STR186## 18. ##STR187## 19.
##STR188## 20. ##STR189## 21. ##STR190## 22. ##STR191##
[0173] TABLE-US-00015 TABLE 15 ##STR192## R 1.
--(CH.sub.2).sub.11CF.sub.3 2.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCH.sub.2CF.sub.3 3.
--(CH.sub.2).sub.4O(CH.sub.2).sub.4CF.sub.3 4. ##STR193## 5.
##STR194## 6. ##STR195## 7. ##STR196## 8. ##STR197## 9. ##STR198##
10. ##STR199## 11. ##STR200## 12.
--(CH.sub.2).sub.8(CF.sub.2).sub.3CF.sub.3 13.
--(CH.sub.2).sub.7O(CH.sub.2).sub.2OCF.sub.2CF.sub.3 14.
--(CH.sub.2).sub.4O(CH.sub.2).sub.2(CF.sub.2).sub.2CF.sub.3 15.
##STR201## 16. ##STR202## 17. ##STR203## 18. ##STR204## 19.
##STR205## 20. ##STR206## 21. ##STR207## 22. ##STR208##
[0174] TABLE-US-00016 TABLE 16 ##STR209## R 1. ##STR210## 2.
##STR211## 3. ##STR212## 4. ##STR213## 5. ##STR214## 6. ##STR215##
7. ##STR216## 8. ##STR217## 9. ##STR218## 10. ##STR219## 11.
##STR220## 12. ##STR221## 13. ##STR222## 14. ##STR223## 15.
##STR224## 16. ##STR225##
[0175] TABLE-US-00017 TABLE 17 ##STR226## R 1. ##STR227## 2.
##STR228## 3. ##STR229## 4. ##STR230## 5. ##STR231## 6. ##STR232##
7. ##STR233## 8. ##STR234## 9. ##STR235## 10. ##STR236## 11.
##STR237## 12. ##STR238## 13. ##STR239## 14. ##STR240## 15.
##STR241## 16. ##STR242##
[0176] TABLE-US-00018 TABLE 18 ##STR243## R 1. ##STR244## 2.
##STR245## 3. ##STR246## 4. ##STR247## 5. ##STR248## 6. ##STR249##
7. ##STR250## 8. ##STR251## 9. ##STR252## 10. ##STR253## 11.
##STR254## 12. ##STR255## 13. ##STR256## 14. ##STR257## 15.
##STR258## 16. ##STR259##
[0177] TABLE-US-00019 TABLE 19 ##STR260## R 1. ##STR261## 2.
##STR262## 3. ##STR263## 4. ##STR264## 5. ##STR265## 6. ##STR266##
7. ##STR267## 8. ##STR268## 9. ##STR269## 10. ##STR270## 11.
##STR271## 12. ##STR272## 13. ##STR273## 14. ##STR274## 15.
##STR275## 16. ##STR276##
[0178] TABLE-US-00020 TABLE 20 ##STR277## R 1. ##STR278## 2.
##STR279## 3. ##STR280## 4. ##STR281## 5. ##STR282## 6. ##STR283##
7. ##STR284## 8. ##STR285## 9. ##STR286## 10. ##STR287## 11.
##STR288## 12. ##STR289## 13. ##STR290## 14. ##STR291## 15.
##STR292## 16. ##STR293##
[0179] TABLE-US-00021 TABLE 21 ##STR294## R 1. ##STR295## 2.
##STR296## 3. ##STR297## 4. ##STR298## 5. ##STR299## 6. ##STR300##
7. ##STR301## 8. ##STR302## 9. ##STR303## 10. ##STR304## 11.
##STR305## 12. ##STR306## 13. ##STR307## 14. ##STR308## 15.
##STR309## 16. ##STR310##
[0180] Among the substituents that may constitute R in the
compounds of Formula I, certain classes are preferred. For example,
to provide a compound which in its free base form is relatively
strongly alkaline, it is advantageous for R to be selected from
among: TABLE-US-00022 TABLE 22 aryloxyalkoxyalkyl
aminothiocarbonylalkyl alkylcarbonyloxyalkyl aminosulfonealkyl
substituted alkyl arylalkynyl arylcarbonyloxyalkyl heterocycloalkyl
alkylcarbonylaminoalkyl heteroarylalkyl arylcarbonylaminoalkyl
heteroaryloxyalkyl alkoxycarbonylaminoalkyl heteroarylthiaalkyl
aminothiocarbonyl- heterocyclooxyalkyl aminothiocarbonyl-
heterocyclothiaalkyl aminoalkyl aryloxyalkyl alkenyl arylthiaalkyl
arylalkenyl monohaloalkyl carboxyalkyl haloalkyloxyalkyl
alkoxycarbonylalkyl cycloalkyloxyalkyl aminocarbonylalkyl
cycloalkylalkyloxyalky perhaloalkylaralkyl
[0181] Salts of such compounds with strong pharmaceutically
acceptable acids provide highly dissociable compounds that are
effective in the method of the invention. More preferably, R may be
selected from among: aryl, arylcarbonylaminoalkyl,
aminocarbonylaminoalkyl, alkenyl, arylalkenyl, arylalkynyl,
heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,
heterocyclooxyalkyl, aryloxyalkyl, arylthiaalkyl,
haloalkyloxyalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl and
perhaloalkylaralkyl; of which alkyl, alkenyl, arylalkenyl,
heterocycloalkyl, heteroarylalkyl, heteroaryloxyalkyl,
heterocyclooxyalkyl, aryloxyalkyl, haloalkyloxyalkyl and
perhaloalkylaralkyl are particularly preferred, and alkenyl,
arylalkenyl, heterocycloalkyl, heteroarylalkyl, aryloxyalkyl
haloalkyloxyalkyl, perhaloalkylaralkyl and cycloalkyloxyalkyl are
most preferred.
[0182] However, amidoglucitol compounds of Formula I and
pharmaceutically acceptable salts thereof are also useful in the
treatment of hepatitis infections, or alternatively in the
synthesis of other compounds of Formula I that are effective for
such treatment. Thus, members of the following group of amido and
other substituents may also serve effectively as the N-substituent
(R) in the compounds of Formula I: TABLE-US-00023 TABLE 23 carbonyl
alkylcarbonyloxyalkylcarbonyl alkenylcarbonyl
arylcarbonyloxyalkylcarbonyl alkynylcarbonyl aminoalkylcarbonyl
arylalkylcarbonyl alkylcarbonylaminoalkylcarbonyl
aryloxyalkylcarbonyl arylcarbonylaminoalkylcarbonyl
haloalkylcarbonyl alkoxycarbonylaminoalkylcarbonyl
hydroxyalkylcarbonyl aminocarbonylaminoalkylcarbonyl
haloalkyloxyalkylcarbonyl aminothiocarbonylaminoalkylcarbonyl
cycloalkyloxyalkylcarbonyl arylalkenylcarbonyl alkoxyalkylcarbonyl
carboxyalkylcarbonyl cycloalkylalkylcarbonyl
alkoxycarbonylalkylcarbonyl alkoxycarbonyl substituted
alkylcarbonyl aryloxyalkoxyalkylcarbonyl carbonyl
aminocarbonylalkylcarbonyl aminothiocarbonylalkylcarbonyl
aminosulfonealkylcarbonyl arylalkynylcarbonyl
heterocycloalkylcarbonyl heteroarylalkylcarbonyl
heteroaryloxyalkylcarbonyl heteroarylthiaalkylcarbonyl
heterocyclooxyalkylcarbonyl hetercyclothiaalkylcarbonyl
arylthiaalkylcarbonyl monohaloalkylcarbonyl
haloalkyloxyalkylcarbonyl cycloalkylalkyloxyalkyl-
More preferably, R may be selected from among: alkenylcarbonyl,
arylalkylcarbonyl, haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,
cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,
cycloalkylalkylcarbonyl, alkylcarbonyl, aminoalkylcarbonyl,
arylalkenylcarbonyl, aminosulfonalkylcarbonyl, arylalkylcarbonyl,
heterocycloalkylcarbony, heteroarylalkylcarbonyl,
heteroaryloxyalkylcarbonyl, heterocyclooxyalkylcarbonyl,
arylthiaalkylcarbonyl, haloalkyloxyalkylcarbonyl,
cycloalkylalkyloxyalky; of which alkenylcarbonyl,
arylalkylcarbonyl, haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,
cycloalkyloxyalkylcarbonyl, alkoxyalkylcarbonyl,
cycloalkylalkylcarbonyl, alkylcarbonyl, aminoalkylcarbonyl,
arylalkenylcarbonyl, heterocycloalkylcarbony,
heteroarylalkylcarbonyl, heteroaryloxyalkylcarbonyl and
haloalkyloxyalkylcarbonyl are particularly preferred, and
arylalkylcarbonyl, haloalkylcarbonyl, haloalkyloxyalkylcarbonyl,
cycloalkylalkylcarbonyl, aminoalkylcarbonyl and
haloalkyloxycarbonyl are most preferred either as antiviral
compounds or as intermediates from which such compounds are
prepared.
[0183] N-substituents which may be preferred for purposes of
potency, efficacy, formulation ability, toxicity and/or cost
include: TABLE-US-00024 TABLE 24 aryloxyalkoxyalkyl
heterocycloalkyl substituted alkyl heteroarylalkyl aminoalkyl
heteroaryloxyalkyl arylcarbonylaminoalkyl heteroarylthiaalkyl
alkoxycarbonylaminoalkyl heterocyclooxyalkyl
aminocarbonylaminoalkyl heterocyclothiaalkyl alkenyl aryloxyalkyl
arylalkenyl arylthiaalkyl aminocarbonylalkyl monohaloalkyl
aminosulfonealkyl haloalkyloxyalkyl arylalkynyl cycloalkyloxyalkyl
cycloalkylalkyloxyalkyl
[0184] Certain compounds of Formula I are novel compounds of this
invention. Novel compounds of Formula I include compounds in which
R is among the following: TABLE-US-00025 TABLE 25 aryloxyalkyl
arylalkyloxycarbonyl substituted- aryloxyalkylcarbonyl aryloxyalkyl
substituted aryloxyalkylcarbonyl monohaloalkyl haloalkylcarbonyl
haloalkyloxyalkyl hydroxyalkylcarbonyl carbonyl
haloalkyloxyalkylcarbonyl cycloalkyloxyalkyl
cycloalkyloxyalkylcarbonyl cycloalkylalkyloxyalkyl
alkoxyalkylcarbonyl alkenylcarbonyl alkynylcarbonyl
arylalkylcarbonyl substituted- arylalkylcarbonyl
Of the compounds of Table 25, the substituted alkyls are basic
compounds which are advantageous in forming stable, water soluble,
non-volatile pharmaceutically acceptable salts, preferably with
strong acids. The carbonyl compounds of Table 25, like those of
Table 23, are adapted for use either as antiviral therapeutic
compounds or as intermediates for the preparation of other
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of the
invention and/or useful in the methods thereof. Of the carbonyl
compounds of Table 25, arylalkylcarbonyl, aryloxyalkylcarbonyl,
haloalkylcarbonyl, haloalkyloxyalkylcarbonyl, and
cycloalkyloxyalkylcarbonyl are the more preferred.
[0185] Another identifiable class of particularly preferred
compounds are those in which R is R.sup.5, and especially compounds
wherein R is selected from among aryloxyalkyl, monooalkyl,
haloalkyloxyalkyl, cycloalkyloxyalkyl, and
cycloalkylalkyloxyalkyl.
[0186] In another useful group of compounds, R is selected from
among alkenylcarbonyl, alkynylcarbonyl, arylalkylcarbonyl,
arylalkyloxycarbonyl, aryloxyalkylcarbonyl, haloalkylcarbonyl,
hydroxyalkylcarbonyl, haloalkyloxyalkylcarbonyl,
cycloalkyloxyalkylcarbonyl, and alkoxyalkylcarbonyl.
[0187] Compounds in which R is R.sup.5 are highly preferred,
especially the ethers (where each of any of X.sup.1 through X.sup.4
are oxygen or sulfur, preferably oxygen), R.sup.1 is alkyl or
haloalkyl, and each of any of R.sup.2 through R.sup.4 and R.sup.6
is independently alkylene or haloalkylene. The di- and triethers
are particularly preferred, as are the R.sup.5 substituents in
which R.sup.1 is trifluoroalkyl.
[0188] Compounds in which A, B, C, and D are hydrido are
particularly preferred for administration in the treatment of
hepatitis infections. However, compounds with other combinations of
A, B, C and D substituents and configurations (including ring
structures as described hereinabove) are useful as therapeutic
agents and as intermediates for the synthesis of other compounds of
Formula I. Where used as therapeutic agents, many of these
substituted imino sugars, especially the esters and ethers,
function as prodrugs.
[0189] Particular advantageous combinations of A, B, C, and D
include those in which, for example: (i) A, B and C are hydrido and
D and R taken together may form a five membered ring when R is
carbonyl or a six membered ring when R is alkylcarbonyl; (ii) A and
B taken together with the atoms to which they are attached form a
five or six membered heterocyclic ring and C and D are hydrido;
(iii) A and B are hydrido, lower alkyl, lower haloalkyl or acyl,
and C and D taken together with the atoms to which they are
attached form a five or six membered heterocyclic ring.
[0190] Advantageous properties as intermediates, direct action
pharmaceuticals, and/or prodrugs are provided by compounds which
combine a substituent from each of the preferred groups which may
constitute R, as defined in R.sup.5 and/or Tables 1 through 4, with
each of the configurations of A, B, C and D as outlined in
enumerated combinations (i) through (iii) above.
[0191] The substituted-imino-D-glucitol compounds, including
pro-drugs, useful in the present invention, can be prepared by
methods well known in the art. U.S. Pat. No. 4,260,622 discloses
the preparation of numerous compounds and U.S. Pat. No. 5,401,645
shows the preparation of glucamine precursers of iminosugars and
their conversion into substituted iminosugars. Additional documents
relevant to the preparation of substituted-imino-D-glucitol
compounds and pro-drugs include U.S. Pat. Nos. 4,182,767,
4,260,622, 4,611,058, 4,639,436, and 5,003,072, 5,411,970,
5,806,650 and 5,151,519; PCT International Publication WO 95/19172;
and Tan et al. (1991) Journal of Biological Chemistry
266(22):14504-14510; and the references cited therein. Methods for
introducing oxygen into alkyl side chains are disclosed in Tan et
al., (1994) Glycobiology 4(2):141-149, and van den Broek et al.
(1994) Recl. Trav. Chim. Pays-Bas 113:107-116 discloses the
preparation of ether oxygen-containing DNJ compounds. Starting
material such as DNJ (deoxynojirimycin) are also commercially
available (Sigma Chemical Co (1989) catalog number D-1282.
[0192] Non-limiting illustrative preparation procedures are
presented below in Examples 1 and 2 and Scheme 1 through and
including Scheme 5. ##STR311## ##STR312## ##STR313## ##STR314##
##STR315##
[0193] Procedures are provided in the discussion and schemes that
follow of exemplary chemical transformations that can be useful for
the preparation of compounds of this invention. R, A, B, C and D
are as defined hereinabove. P is a protecting group and L is a
leaving group both of which are as defined and in the book by Green
referenced below. These syntheses, as with all of the reactions
discussed herein, can be carried out under a dry inert atmosphere
such a nitrogen or argon if desired. Selected reactions known to
those skilled in the art, can be carried out under a dry atmosphere
such as dry air whereas other synthetic steps, for example, aqueous
acid or base ester or amide hydrolyses, can be carried out under
ambient air.
[0194] In general, the choices of starting material and reaction
conditions can vary as is well know to those skilled in the art.
Usually, no single set of conditions is limiting because variations
can be applied as required and selected by one skilled in the art.
Conditions will also will be selected as desired to suit a specific
purpose such as small scale preparations or large scale
preparations. In either case, the use of less safe or less
environmentally sound materials or reagents will usually be
minimized. Examples of such less desirable materials are
diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide,
some halogenated solvents, benzene and the like. In addition, many
starting materials can be obtained from commercial sources from
catalogs or through other arrangements.
[0195] Reaction media can be comprised of a single solvent, mixed
solvents of the same or different classes or serve as a reagent in
a single or mixed solvent system. The solvents can be protic,
non-protic or dipolar aprotic. Non-limiting examples of protic
solvents include water, methanol (MeOH), denatured or pure 95% or
absolute ethanol, isopropanol and the like.
[0196] Typical non-protic solvents include acetone,
tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl
ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl
acetate, methyl acetate, butyl acetate, trichloroethane, methylene
chloride, ethylenedichloride (EDC), hexane, heptane, isooctane,
cyclohexane and the like.
[0197] Dipolar aprotic solvents include compounds such as
dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile,
nitromethane, tetramethylurea, N-methylpyrrolidone and the
like.
[0198] Non-limiting examples of reagents that can be used as
solvents or as part of a mixed solvent system include organic or
inorganic mono- or multi-protic acids or bases such as hydrochloric
acid, phosphoric acid, sulfuric acid, acetic acid, formic acid,
citric acid, succinic acid, triethylamine, morpholine,
N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine,
potassium hydroxide, sodium hydroxide, alcohols or amines for
making esters or amides or thiols for making the products of this
invention.
[0199] Room temperature or less or moderate warming (-10.degree. C.
to 60.degree. C.) are the preferred temperatures of the synthesis
and/or transformations of the compounds of this invention. If
desired, the reaction temperature can range from about -78.degree.
C. to the reflux point of the reaction solvent or solvents. Colder
temperatures such as that of liquid nitrogen may be desired on
occasion especially if improved selectivity is required. Higher
temperatures may also be used preferably in a pressure container
system, i.e., a pressure bomb.
[0200] Examples of bases that can be used include, for example,
metal hydroxides such as sodium, potassium, lithium or magnesium
hydroxide, oxides such as those of sodium, potassium, lithium,
calcium or magnesium, metal carbonates such as those of sodium,
potassium, lithium, calcium or magnesium, metal bicarbonates such
as sodium bicarbonate or potassium bicarbonate, primary
(I.degree.), secondary (II.degree.) or tertiary (III.degree.)
organic amines such as alkyl amines, arylalkyl amines,
alkylarylalkyl amines, heterocyclic amines or heteroaryl amines,
ammonium hydroxides or quaternary ammonium hydroxides. As
non-limiting examples, such amines can include triethyl amine,
trimethyl amine, diisopropyl amine, methyldiisopropyl amine,
diazabicyclononane, tribenzyl amine, dimethylbenzyl amine,
morpholine, N-methylmorpholine, N,N'-dimethylpiperazine,
N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine,
dimethylaminopyridine, pyridine, quinoline,
tetramethylethylenediamine and the like.
[0201] Non-limiting examples of ammonium hydroxides, usually made
from amines and water, can include ammonium hydroxide, triethyl
ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl
ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl
ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium
hydroxide, N,N'-dimethylpiperazinium hydroxide, N-ethylpiperidinium
hydroxide, and the like. As non-limiting examples, quaternary
ammonium hydroxides can include tetraethyl ammonium hydroxide,
tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium
hydroxide, benzymethyldiisopropyl ammonium hydroxide,
methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl
ammonium hydroxide, N,N-dimethylmorpholinium hydroxide,
N,N,N',N',-tetramethylpiperazenium hydroxide, and
N-ethyl-N'-hexylpiperidinium hydroxide and the like. Metal
hydrides, amide or alcoholates such as calcium hydride, sodium
hydride, potassium hydride, lithium hydride, sodium methoxide,
potassium tert-butoxide, calcium ethoxide, magnesium ethoxide,
sodium amide, potassium diisopropyl amide and the like can also be
suitable reagents. Organometallic deprotonating agents such as
alkyl or aryl lithium reagents such as methyl, phenyl, butyl,
iso-butyl, sec-butyl or tert-butyl lithium, sodium or potassium
salts of dimethylsulfoxide, Grignard reagents such as
methylmagnesium bromide or methymagnesium chloride, organocadium
reagents such as dimethylcadium and the like can also serve as
bases for causing salt formation or catalyzing the reaction.
Quaternary ammonium hydroxides or mixed salts are also useful for
aiding phase transfer couplings or serving as phase transfer
reagents. Preferred base for use in the alkylation reaction is
lithium diisopropyl amide as mentioned above.
[0202] A further use of bases is for the preparation of
pharmaceutically acceptable salts discussed herein. These include
those listed above with metal carbonates, bicarbonates, amines,
quaternary amines, hydroxides and various polymeric bases being
preferred.
[0203] Acids are used in many reactions during various synthesis
and for the preparation of pharmaceutical salts. The Schemes as
well as this discussion illustrate the use of acid for the removal
of the THP protecting group, removal of a tert-butoxy carbonyl
group, amine/ester exchange and the like. Acid hydrolysis of
carboxylic acid protecting groups or derivatives is well known in
the art. These methods, as is well known in the art, can use acid
or acidic catalysts. The acid can be mono-, di- or tri-protic
organic or inorganic acids. Examples of acids include hydrochloric
acid, phosphoric acid, sulfuric acid, acetic acid, formic acid,
citric acid, succinic acid, hydrobromic acid, hydrofluoric acid,
carbonic acid, phosphorus acid, p-toluene sulfonic acid,
trifluoromethane sulfonic acid, trifluoroacetic acid,
difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene
sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic
acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid,
and the like. They can also be Lewis acids such as aluminum
chloride, borontrifluoride, antimony pentafluoride and the
like.
[0204] Salts of the compounds or intermediates of this invention
are prepared in the normal manner wherein acidic compounds are
reacted with bases such as those discussed above to produce metal
or nitrogen containing cation salts. Basic compounds such as amines
can be treated with an acid to form an amine salt. If the acid
component of the salt is a weaker acid it is preferred that the
base component be a stronger base. If the base component of the
salt is with a weaker base it is preferred that the acid component
be a stronger acid. Thus, the salts preferably are prepared from an
acid having a relatively low pKa, preferably less than about 4.5.
Most preferred are salts of relatively strongly basic imino sugars
with strong acids. Pharmaceutically acceptable acids and bases for
forming salts are well known in the art. Salts of the iminosugars
of this invention and anti-viral and anti-cancer
nucleosides/nucleotides are pharmaceutically acceptable salts.
[0205] Treatment of an amine substrate such as 1, 6, 11 or 16 (see
reaction schemes as set forth above) with an aldehyde or ketone
under reducing conditions will produce a tertiary amine of this
invention such as 2. Preferred solvents include, depending on the
reducing agent, alcohols or tetrahydrofurane (THF). An inert
atmosphere or dry atmosphere is used again depending upon the
reactivity of the reducing agent. Hydrogen gas is the usual
atmosphere for catalytic reductions. These reducing agents are well
known in the art.
[0206] Reductive alkylation is carried out by adding R--CHO or a
ketone to an amine such as DNJ and treating with a reducing agent
such as sodium cyanoborohydride or carrying out a catalytic
reduction with, for example, a metal catalyst and hydrogen gas.
Such reducing agents are well known in the art and include such
reagents as borane, borane:THF, borane:pyridine, lithium aluminum
hydride, aluminum hydride, lithium borohydride, sodium borohydride
potassium triacetylborohydride and the like. Alternatively,
reductive alkylation can be carried out under hydrogenation
conditions in the presence of a metal catalyst. Catalysts, hydrogen
pressures and temperatures are discussed and are well known in the
art. A desirable "hydride type" reductive alkylation catalyst is
borane:pyridine complex. Reductive alkylation or hydrogenation can
be carried out at atmospheric pressure and higher pressures can be
used if desired. Catalysts include, for example, Pd, Pd on Carbon,
Pt, PtO.sub.2 and the like. Less robust catalysts (deactivated)
include such thing as Pd on BaCO.sub.3 or Pd with quinoline or/and
sulfur can be used in situations wherein selectivity is
desired.
[0207] Acylation of substrates 1, 6, 11 or 16, as shown in the
reaction schemes set out above, can be carried out in standard
fashion wherein the amine is treated with a carbonyl compound with
a leaving group attached as is discussed in textbooks of organic
chemistry. The leaving group is designated as "L" in the Schemes
and may be different in the case of, for example, carboxylic acid
derivatives, SN.sub.2 substrates and SN.sub.1 substrates and the
addition-elimination process with carbonyl type compounds. Well
know acylating groups including those with leaving groups include
halides, anhydrides, mixed anhydrides, ketenes as well as
exchangeable groups such as ester groups. Coupling with an
activated ester synthesized in situ is also a useful process for
preparing amides and it is discussed below. For example, compound
1, 6, 11 or 16 is treated with an acid chloride in the presence of,
preferably, a tertiary amine base under an inert atmosphere at
between about -10.degree. C. and 0.degree. C. The product of this
reaction is an amide 3 or 8 of this invention. A preferred acid
activating group (L) is the chloride prepared by, for example,
reaction of an acid with oxalyl chloride, phosphorus trichloride
and the like. These carboxylic acids can be derivatized with
protecting group or hydrolyzed to the acid as required.
[0208] Compounds 3 or 8 are reduced to produce 4 or 9,
respectively, as a products of this invention. The reduction is
carried out using procedures and reagents as discussed hereinabove
and other methods as indicated. Reduction of amides is well known
in the art.
[0209] Amides such as 3, 8, 13 or 18 can be hydrolyzed if desired.
Base hydrolysis or acid hydrolysis methods are well known and the
choice of systems will depend upon factors determined by the
chemist. For example, the presence of base labile substituents
might cause a scientist to select an acid hydrolysis process. Bases
that can be used are listed herein. Acids are also discussed above
and hydrogen chloride, toluenesulfonic acid and trifluoroacetic
acid being preferred. Acid catalyzed exchange processes are also
useful for converting compound 3 or 8 into other analogs or into
1.
[0210] Compounds 1, 6, 11 or 16 are also able to be protected as is
shown by the preparation of 5, 10, 15 and 20, respectively. The
group P in, for example, 5, 10, 15 and 20, is a special case of R
wherein the group may be useful for treating disease and also
useful for the preparation of other compounds of this invention.
Protecting groups, P, are well know in organic chemistry along with
protection/deprotection processes. They are frequently used to
control reaction sites, reaction selectivities, help with
resolutions such as optical resolutions, aid in purification
processes and prevent over reaction in preparation processes. It
should be noted that protection of groups other than nitrogen is
common in the art with non-limiting examples being hydroxyl groups,
thiol groups, carbonyl groups, phosphorus groups, silicon groups
and the like and that P is used to indicate protecting groups in
these cases also. It should also be noted that protecting groups
and protection/deprotection reaction sequences are well know in the
art of natural product chemistry including sugar chemistry- and
amino acid/peptide chemistry; Editions of the books by Thedora
Green, e.g., Green, T., Protecting Groups in Organic Chemistry,
Second ed., John Wiley & Sons, New York (1991), are useful in
this regard and are incorporated herein by reference.
[0211] As mentioned above, contemplated compounds can include
compounds wherein a nitrogen of an amine is acylated to provide,
for example, amino acid carbamates. Non-limiting examples of these
carbamates are the carbobenzoxycarbonyl (Z, CBZ,
benzyloxycarbonyl), iso-butoxycarbonyl and tert-butoxycarbonyl
(BOC, t-BOC) compounds. The materials can be made at various stages
in the synthesis based on the needs and decisions made by a person
skilled in the art-using methods well know in the art.
[0212] Useful synthetic techniques and reagents for the preparation
of the compounds of this invention include those used in protein,
peptide and amino acid synthesis, coupling and transformation
chemistry. The use of the tert-butoxycarbonyl (BOC) and
benzyloxycarbonyl (Z) as will as their synthesis and removal are
examples of such protection or synthesis schemes. This includes,
for example, active ester or mixed anhydride couplings wherein
preferred bases, if required, are tertiary amines such as
N-methylmorpholine. Reagents for protection of the amine group of
the protected amino acids include carbobenzoxy chloride,
iso-butylchloroformate, tert-butoxycarbonyl chloride, di-tert-butyl
dicarbonate and the like which are reacted with the amine in
non-protic or dipolar aprotic solvents such as DMF or THF or
mixtures of solvents.
[0213] Removal of protecting groups on nitrogen, oxygen, sulfur or
other groups such as carbamates, silyl groups, THP ethers, enol
ethers, ketals, acetals, hemiacetals, hemiketals, methoxymethyl
ethers, benzyl, p-methoxybenzyl, or other substituted benzyl
groups, acyl or aroyl groups or diphenylmethyl (benzhydryl) or
triphenylmethyl (trityl) can be carried out at different stages in
the synthesis of the compounds of this invention as required by
methods selected by one skilled in the art. These methods are well
known in the art including the amino acid, amino acid coupling,
peptide synthesis, peptide mimetic synthesis art. Removal methods
can include catalytic hydrogenation, base hydrolysis, carbonyl
addition reactions, acid hydrolysis, exchange and the like. Both
the preparation and removal of protecting groups, for example,
carbamates, trifluoroacetate groups, benzyl groups and/or
substituted arylalkyl groups is discussed in Green, T., Protecting
Groups in Organic Chemistry, Second ed., John Wiley & Sons, New
York (1991) as discussed above. A preferred method of removal of a
BOC group is HCl gas in methylene chloride which, following normal
workup, provides directly an HCl salt of an amine of this
invention, i.e., an ammoniun salt. A preferred method of removing a
Z group is catalytic reduction.
[0214] Alkylation of amines such as 1, 6, 11 or 16 is accomplished
by methods well known in the art and discussed in textbooks of
organic chemistry. The process is via SN.sub.2 or SN.sub.1
displacement of a leaving group, L, on a substrate by the amine.
The amine is treated in a solvent such as those discussed above
like DMSO, DMF, methanol, ethanol, THF, acetone and the like.
Leaving groups can include halides, sulfonic acid esters such as
tosylates, mesylates, triflates, trifluoroacetates and the like.
The reaction can be carried out under an inert atmosphere or dry,
non-oxidative conditions. An inert atmosphere is preferred.
[0215] Scheme 2 illustrates the application of the methods
discussed for the preparation of compounds wherein A, B, C and D
are hydrogen. It is to be noted that the syntheses may proceed in
the presence of the hydroxyl groups thus the chemist has options in
selecting the compound to be synthesized as well as the synthetic
route to the compound.
[0216] Scheme 3 and Scheme 4 illustrate the preparation of open
chain sugars containing amines 12, 14, 17 and 19, amides 13 and 18
or protected amines 15 and 20. The reductive alkylation,
hydrolysis, reduction, protection, deprotection, and alkylation
processes have been discussed above. These open chain compounds are
useful as intermediates for the preparation of 2 and its analogs by
the methods of Scheme 5. Derivatization 15 or 20 to produce 11 or
16 illustrates that protected amines can be converted and
interconverted into compounds wherein A, B, C and D are as defined
herein above. For example, hydroxyl groups can be alkyated,
acylated by processed discussed above and well know in the art.
Treatment with an aldehyde, aldimine, ketone or ketimine under, for
example, acid conditions in a non-protic or dipolar aprotic
solvent, produces heterocycles such as those presented above.
[0217] Scheme 5 illustrates the used of glucose, sorbose other open
chain sugars and their derivatives in the preparation of 2. For
example, glucose is reacted with a primary amine R--NH.sub.2 or a
derivative of the R group in R--NH.sub.2 to produce a putative
imine derivative 22. R is as defined above and preferably not
connected via a carbonyl carbon. Reaction can be with or without
heating and with oreithout a catalyls such as an acid catalyst.
Removal of water during imine formation from the putative open
chain aldehyde intermediate is possible if desired. Reduction using
methods discussed above including metal catalyzed hydrogenations
produce the open chain compound 23. Microbial fermentation of the
5-hydroxy compound 23 (sugar nomenclature) leads to ketones 24
which is in equiliberium with the carbinolamine 25. The 24-25
compounds can be novel intermediates. Reduction of the 24-25
ring-chain tautomer pair produce 2.
[0218] Compounds of the present invention can possess one or more
asymmetric carbon atoms and are thus capable of existing in the
form of optical isomers such as enantiomers, racemates and
diastereoisomers as well as in the form of racemic or nonracemic
mixtures thereof. The optical isomers can be obtained by resolution
of the racemic mixtures according to conventional processes well
known in the art, for example by formation of diastereoisomeric
salts by treatment with an optically active acid or base.
[0219] Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, natural
aminoacids and camphorsulfonic acid and then separation of the
mixture of diastereoisomers by crystallization followed by
liberation of the optically active bases from these salts. A
different process for separation of optical isomers involves the
use of a chiral chromatography column optimally chosen to maximize
the separation of the enantiomers.
[0220] Still another available method involves synthesis of
covalent diastereoisomeric molecules, e.g., esters, amides,
acetals, ketals, and the like, by reacting compounds of Formula I
with an optically active acid in an activated form, a optically
active diol or an optically active isocyanate. The synthesized
diastereoisomers can be separated by conventional means such as
chromatography, distillation, crystallization or sublimation, and
then hydrolyzed to deliver the enantiomericaly pure compound. In
some cases hydrolysis to the parent optically active drug is not
necessary prior to dosing the patient since the compound can behave
as a prodrug. The optically active compounds of Formula I can
likewise be obtained by utilizing optically active starting
materials.
[0221] In addition to the optical isomers or potentially optical
isomers discussed above, other types of isomers are specifically
intended to be included in this discussion and in this invention.
Examples include cis isomers, trans isomers, E isomers, Z isomers,
syn-isomers, anti-isomers, tautomers, rotamers and the like. Aryl,
heterocyclo or heteroaryl tautomers, heteroatom isomers,
heterocyclo or heteroaryl heteroatom isomers and ortho, meta or
para substitution isomers are also included as isomers as are
multicyclic isomers such as those of the phenanthrene/anthracene
type and the multicyclic saturated or partially unsaturated type.
The latter type of isomer is exemplified in general by
bicyclo[2,2,2]octane and bicyclo[3,2,1]octane. Solvates or solvent
addition compounds such as hydrates or alcoholates are also
specifically included both as chemicals of this invention and in,
for example, formulations or pharmaceutical compositions for drug
delivery.
[0222] Where a substituent is designated as, or can be, a hydrogen,
the exact chemical nature of a substituent which is other than
hydrogen at that position, e.g., a hydrocarbyl radical or a
halogen, hydroxy, amino and the like functional group, is not
critical so long as it does not adversely affect the overall
activity and/or synthesis procedure. For example, two hydroxyl
groups, two amino groups, two thiol groups or a mixture of two
hydrogen-heteroatom groups on the same carbon are known not to be
stable without protection or as a derivative.
[0223] The chemical reactions described above are generally
disclosed in terms of their broadest application to the preparation
of the compounds of this invention. Occasionally, the reactions can
not be applicable as described to each compound included within the
disclosed scope. The compounds for which this occurs will be
readily recognized by those skilled in the art. In all such cases,
either the reactions can be successfully performed by conventional
modifications known to those skilled in the art, e.g., by
appropriate protection of interfering groups, by changing to
alternative conventional reagents, by routine modification of
reaction conditions, and the like, or other reactions disclosed
herein or otherwise conventional, will be applicable to the
preparation of the corresponding compounds of this invention. In
all preparative methods, all starting materials are known or
readily preparable from known starting materials.
[0224] Other compounds of this invention that are acids can also
form salts. Examples include salts with alkali metals or alkaline
earth metals, such as sodium, potassium, calcium or magnesium or
with organic bases or basic quaternary ammonium salts.
[0225] In some cases, the salts can also be used as an aid in the
isolation, purification or resolution of the compounds of this
invention.
[0226] Prodrugs are drugs that can be chemically converted in vivo
or in vitro by biological systems into an active drug or drugs,
i.e., it is a pharmaceutically acceptable bioprecursor of a desired
pharmaceutical or pharmaceuticals. The prodrug can be a compound
having a structural formula different from the active compound but
which upon administration to a mammal or in vitro system is
converted into a compound of this invention. Such prodrugs are also
compounds of this invention useful for the treatment of human,
agricultural and general veterinary diseases.
[0227] In treating hepatitis B virus or hepatitis C virus
infections, one can use the present
substitututed-1,5-dideoxy-1,5-imino-D-glucitol compounds alone or
in combination in the form of salts derived from inorganic or
organic acids. These salts include but are not limited to the
following: 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.
[0228] The basic nitrogen-containing groups can be quaternized with
agents such as lower alkyl halides, such as methyl, ethyl, propyl,
and butyl chloride, bromides, and iodides; dialkyl sulfates such as
dimethyl, diethyl, dibuytl, and diamyl sulfates; long chain halides
such as decyl, lauryl, myristyl, and stearyl chlorides, bromides,
and iodides; aralkyl halides such as benzyl and phenethyl bromides,
and others. Water- or oil-soluble or dispersible products are
thereby obtained as desired. The salts are formed by combining the
basic compounds with the desired acid.
[0229] Nucleosides and Nucleotides
[0230] Nucleosides and nucleotides useful in the present invention
are purine (II) base compounds or pyrimidine (III) base compounds,
or analogs such as compounds IV, V or VI. ##STR316##
[0231] Position numbering for purines and pyrmidines is as shown in
structures II and III. R.sup.1 can be selected from hydroxyalkyl,
hydroxyalkenyl, carboxyalkyl, carboxyalkenyl, thiolalkyl,
alkylthioalkyl, alkoxyalkyl, alkoxyalkenyl, heterocycle,
heterocyclo-alkyl, hydroxyalkylalkoxyalkyl, alkoxyalkylalkoxyalkyl,
and cycloalkylalkyl. The purine compounds can be further
substituted at positions 1, 2, 3, 6, 7, or 8 of the purine
heterocycle, and the pyrimidine compounds can be substituted at
positions 2, 3, 4, 5, or 6 of the pyrimidine heterocycle. Such
substituents can be selected from hydroxy, alkoxy, halo, thiol,
amino, carboxyl, mono-substituted amino, di-substituted amino, and
alkyl.
[0232] The following definitions are applicable only to the
structures of Formulas II, III, IV, V and VI of this invention.
When used in combination with another radical when referring to the
purines and pyrimidines useful in the present invention, the term
"alkyl" means a straight or branched chain hydrocarbon radical
containing from 1 to 8 carbon atoms, preferably 1 to 4 carbon
atoms. When used in combination with another radical, the term
"alkenyl" means a straight or branched chain hydrocarbon radical
having 1 or more double bonds, containing from 2 to 8 carbon atoms,
preferably 1 to 4 carbon atoms. When used alone when referring to
purines and pyrimidines useful in the present invention, the term
"alkyl" means a straight or branched chain alkyl radical containing
from six to 14 carbon atoms, preferably seven to 12 carbon atoms,
and most preferably eight to 11 carbon atoms. The term "aryl" alone
or in combination with another radical means a phenyl, naphthyl, or
indenyl ring, optionally substituted with one or more substituents
selected from alkyl, alkoxy, halogen, hydroxy, or nitro. "Alkanoyl"
means branched or straight chain alkanecarbonyl having a chain
length of C.sub.1 to C.sub.20, preferably C.sub.2 to C.sub.14, more
preferably C.sub.4 to C.sub.10; "aroyl" means arylcarbonyl; and
"trifluoroalkanoyl" means alkyl containing three fluoro
substituents. "Halogen" means fluorine, chlorine, bromine, or
iodine. "Thiol" means sulfur substituted with hydrogen (--SH).
"Amino" means nitrogen with two hydrogen atoms; "monosubstituted
amino" and "disubstituted amino" mean amino groups further
independently substituted with one or more alkyl or arylalkyl
groups. "Hydroxyalkyl" means an alkyl group substituted with one or
more hydroxyl groups; "hydroxyalkenyl" means an alkenyl group
substituted with one or more hydroxyl groups; "thioalkyl" means an
alkyl substituted with one or more thiol (SH) groups; "alkoxyalkyl"
means an alkyl substituted with one or more alkyl ether groups;
"alkoxyalkenyl" means an alkenyl group substituted with one or more
alkyl ether groups; "hydroxyalkylalkoxyalkyl" means an alkoxyalkyl
group substituted with a hydroxyalkyl group;
"alkoxyalkyl-alkoxyalkyl" means an alkoxyalkyl group substituted
with an alkoxyalkyl group; "cycloalkylalkyl" means an alkyl group
substituted with a cycloalkyl group. The term "heterocycle," alone
or in combination, means a saturated or partially unsaturated 5 or
6-membered ring containing one or more oxygen, nitrogen, and/or
sulfur heteroatoms. Said heterocycle can further be substituted
with one to four substituents, which can be independently, hydroxy,
hydroxyalkyl, thiol, alkoxy, azido, nitro, a halogen atom, amino,
mono-substituted amino, or disubstituted amino. Heterocycloalkyl
means an alkyl group wherein one or more hydrogen atoms are
replaced by a substituted or unsubstituted heterocyclic ring.
[0233] Also included are the tautomers of the substituents on the
compounds of the invention. Non-limiting examples of tautomers are
ketone/enol tautomers, imino/amino tautomers, N-substituted
imino/N-substituted amino tautomers, thiol/thiacarbonyl tautomers,
and ring-chain tautomers such as the five and six membered ring
oxygen, nitrogen, sulfur, or oxygen- and sulfur-containing
heterocycles also containing substituents alpha to the heteroatoms.
Also specifically included in the present invention are enantiomers
and diastereomers, as well as racemates and isomeric mixtures of
the compounds discussed herein.
[0234] Representative nucleoside and nucleotide compounds useful in
the present invention include, but are not limited to: [0235]
(+)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine;
[0236] (-)-2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) [0237]
(-)-cis-5-fluoro-1-[2-(hydroxy-methyl)-[1,3-oxathiolan-5-yl]cytosine
(FTC); [0238] (-)2',3',dideoxy-3'-thiacytidine [(-)-SddC]; [0239]
1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine
(FIAC); [0240]
1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine
triphosphate (FIACTP); [0241]
1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluracil
(FMAU); [0242] 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide;
[0243] 2',3'-dideoxy-3'-fluoro-5-methyl-dexocytidine (FddMeCyt);
[0244] 2',3'-dideoxy-3'-chloro-5-methyl-dexocytidine (ClddMeCyt);
[0245] 2',3'-dideoxy-3'-amino-5-methyl-dexocytidine (AddMeCyt);
[0246] 2',3'-dideoxy-3'-fluoro-5-methyl-cytidine (FddMeCyt); [0247]
2',3'-dideoxy-3'-chloro-5-methyl-cytidine (ClddMeCyt); [0248]
2',3'-dideoxy-3'-amino-5-methyl-cytidine (AddMeCyt); [0249]
2',3'-dideoxy-3'-fluorothymidine (FddThd); [0250]
2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC); [0251]
2',3'-dideoxy-beta-L-5-thiacytidine; [0252]
2',3'-dideoxy-beta-L-5-cytidine (beta-L-ddC); [0253]
9-(1,3-dihydroxy-2-propoxymethyl)guanine; [0254]
2'-deoxy-3'-thia-5-fluorocytosine; [0255]
3'-amino-5-methyl-dexocytidine (AddMeCyt); [0256]
2-amino-1,9-[(2-hydroxymethyl-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6--
one (gancyclovir); [0257]
2-[2-(2-amino-9H-purin-9y)ethyl]-1,3-propandil diacetate
(famciclovir); [0258]
2-amino-1,9-dihydro-9-(2-hydroxy-ethoxy)methyl]6H-purin-6-one
(acyclovir); [0259] 9-(4-hydroxy-3-hydroxymethyl-but-1-yl)guanine
(penciclovir); [0260]
9-(4-hydroxy-3-hydroxymethyl-but-1-yl)-6-deoxy-guanine diacetate
(famciclovir); [0261] 3'-azido-3'-deoxythymidine (AZT); [0262]
3'-chloro-5-methyl-dexocytidine (ClddMeCyt); [0263]
9-(2-phosphonyl-methoxyethyl)-2',6'-diaminopurine-2',3'-dideoxyriboside;
[0264] 9-(2-phosphonylmethoxyethyl)adenine (PMEA); [0265] acyclovir
triphosphate (ACVTP); [0266] D-carbocyclic-2'-deoxyguanosine (CdG);
[0267] dideoxy-cytidine; [0268] dideoxy-cytosine (ddC); [0269]
dideoxy-guanine (ddG); [0270] dideoxy-inosine (ddI); [0271]
E-5-(2-bromovinyl)-2'-deoxyuridine triphosphate; [0272]
fluoro-arabinofuranosyl-iodouracil; [0273]
1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-iodo-uracil
(FIAU); [0274] stavudine; [0275]
9-beta-D-arabinofuranosyl-9H-purine-6-amine monohydrate (Ara-A);
[0276] 9-beta-D-arabinofuranosyl-9H-purine-6-amine-5'-monophosphate
monohydrate (Ara-AMP); [0277] 2-deoxy-3'-thia-5-fluorocytidine;
[0278] 2',3'-dideoxy-guanine; and [0279]
2',3'-dideoxy-guanosine.
[0280] A preferred compound is
(-)-2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC).
[0281] Synthetic methods for the preparation of nucleosides and
nucleotides useful in the present invention are likewise well known
in the art as disclosed in Acta Biochim. Pol., 43, 25-36 (1996);
Swed. Nucleosides Nucleotides 15, 361-378 (1996), Synthesis 12,
1465-1479 (1995), Carbohyd. Chem. 27, 242-276 (1995), Chem.
Nucleosides Nucleotides 3, 421-535 (1994), Ann. Reports in Med.
Chem., Academic Press; and Exp. Opin. Invest. Drugs 4, 95-115
(1995).
[0282] The chemical reactions described in the references cited
above are generally disclosed in terms of their broadest
application to the preparation of the compounds of this invention.
Occasionally, the reactions may not be applicable as described to
each compound included within the scope of compounds disclosed
herein. The compounds for which this occurs will be readily
recognized by those skilled in the art. In all such cases, either
the reactions can be successfully performed by conventional
modifications known to those skilled in the art, e.g., by
appropriate protection of interfering groups, by changing to
alternative conventional reagents, by routine modification of
reaction conditions, and the like, or other reactions disclosed
herein or otherwise conventional will be applicable to the
preparation of the corresponding compounds of this invention. In
all preparative methods, all starting materials are known or
readily preparable from known starting materials.
[0283] While nucleoside analogs are generally employed as antiviral
agents as is, nucleotides (nucleoside phosphates) must sometimes
have to be converted to nucleosides in order to facilitate their
transport across cell membranes. An example of a chemically
modified nucleotide capable of entering cells is
S-1-3-hydroxy-2-phosphonylmethoxypropyl cytosine (HPMPC, Gilead
Sciences).
[0284] Nucleoside and nucleotide compounds of this invention that
are acids can form salts. Examples include salts with alkali metals
or alkaline earth metals, such as sodium, potassium, calcium, or
magnesium, or with organic bases or basic quaternary ammonium
salts.
[0285] Immunomodulators and Inmuunostimulants
[0286] A large number of immunomodulators and immunostimulants that
can be used in the methods of the present invention are currently
available. A list of these compounds is provided in Table 1, below.
TABLE-US-00026 TABLE 1 AA-2G adamantylamide dipeptide adenosine
deaminase, Enzon adjuvant, Alliance adjuvants, Ribi adjuvants,
Vaxcel Adjuvax agelasphin-11 AIDS therapy, Chiron algal glucan, SRI
algammulin, Anutech Anginlyc anticellular factors, Yeda Anticort
antigastrin-17 immunogen, Ap antigen delivery system, Vac antigen
formulation, IDBC antiGnRH immunogen, Aphton Antiherpin Arbidol
azarole Bay-q-8939 Bay-r-1005 BCH-1393 Betafectin Biostim BL-001
BL-009 Broncostat Cantastim CDRI-84-246 cefodizime 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 growth 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- 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 SRI-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+ IL-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+ TN-5+ TNF+ UN
[0287] Dosages
[0288] The substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds
useful in the present invention can be administered to humans in an
amount in the range of from about 0.1 mg/kg/day to about 100
mg/kg/day, more preferably from about 1 mg/kg/day to about 75
mg/kg/day, and most preferably from about 5 mg/kg/day to about 50
mg/kg/day.
[0289] The nucleoside or nucleotide antiviral compound, or mixtures
thereof, can be administered to humans in an amount in the range of
from about 0.1 mg/person/day to about 500 mg/person/day, preferably
from about 10 mg/person/day to about 300 mg/person/day, more
preferably from about 25 mg/person/day to about 200 mg/person/day,
even more preferably from about 50 mg/person/day to about 150
mg/person/day, and most preferably in the range of from about 1
mg/person/day to about 50 mg/person/day.
[0290] Immunomodulators and immunostimulants useful in the present
invention can be administered in amounts lower than those
conventional in the art. For example, thymosin alpha 1 and thymosin
fraction 5 are typically administered to humans for the treatment
of HepB infections in an amount of about 900 g/m.sup.2, two times
per week (Hepatology (1988) 8:1270; Hepatology (1989) 10:575;
Hepatology (1991) 14:409; Gastroenterology (1995) 108:A1127). In
the methods and compositions of the present invention, this dose
can be in the range of from about 10 g/m.sup.2, two times per week
to about 750 g/m.sup.2, two times per week, more preferably from
about 100 g/m.sup.2, two times per week to about 600 g/m.sup.2, two
times per week, most preferably from about 200 g/m.sup.2, two times
per week to about 400 g/m.sup.2, two times per week. Interferon
alfa is typically administered to humans for the treatment of HepC
infections in an amount of from about 1.times.10.sup.6
units/person, three times per week to about 10.times.10.sup.6
units/person, three times per week (Simon et al., (1997) Hepatology
25:445-448). In the methods and compositions of the present
invention, this dose can be in the range of from about
0.1.times.10.sup.6 units/person, three times per week to about
7.5.times.10.sup.6 units/person, three times per week, more
preferably from about 0.5.times.10.sup.6 units/person, three times
per week to about 5.times.10.sup.6 units/person, three times per
week, most preferably from about 1.times.10.sup.6 units/person,
three times per week to about 3.times.10.sup.6 units/person, three
times per week.
[0291] Due to the enhanced hepatitis virus antiviral effectiveness
of these immunomodulators and immunostimulants in the presence of
the N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds useful
in the present invention, reduced amounts of other
immunomodulators/immunostimulants can be employed in the methods
and compositions disclosed herein. Such reduced amounts can be
determined by routine monitoring of hepatitis virus in infected
patients undergoing therapy. This can be carried out by, for
example, monitoring hepatitis viral DNA in patients' serum by
slot-blot, dot-blot, or PCR techniques, or by measurement of
hepatitis surface or other antigens, such as the e antigen, in
serum. Methods therefor are discussed in Hoofnagle et al., (1997)
New Engl. Jour. Med. 336(5):347-356, and F. B. Hollinger in Fields
Virology, Third Ed., Vol. 2 (1996), Bernard N. Fields et al., Eds.,
Chapter 86, "Hepatitis B Virus," pp. 2738-2807, Lippincott-Raven,
Philadelphia, Pa., and the references cited therein.
[0292] Patients can be similarly monitored during combination
therapy employing N-substituted-1,5-dideoxy-1,5-imino-D-glucitol
compounds and nucleoside and/or nucleotide antiviral agents to
determine the lowest effective doses of each.
[0293] The doses described above can be administered to a patient
in a single dose or in proportionate multiple subdoses. In the
latter case, dosage unit compositions can contain such amounts of
submultiples thereof to make up the daily dose. Multiple doses per
day can also increase the total daily dose should this be desired
by the person prescribing the drug.
[0294] Pharmaceutical Compositions
[0295] The compounds of the present invention can be formulated as
pharmaceutical compositions. Such compositions can be administered
orally, parenterally, by inhalation spray, rectally, intradermally,
transdermally, or topically in dosage unit formulations containing
conventional nontoxic pharmaceutically acceptable carriers,
adjuvants, and vehicles as desired. Topical administration may also
involve the use of transdermal administration such as transdermal
patches or iontophoresis devices. The term parenteral as used
herein includes subcutaneous, intravenous, intramuscular, or
intrasternal injection, or infusion techniques. Formulation of
drugs is discussed in, for example, Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975),
and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage
Forms, Marcel Decker, New York, N.Y. (1980).
[0296] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose, any bland fixed oil may be employed, including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are useful in the preparation of injectables. Dimethyl
acetamide, surfactants including ionic and non-ionic detergents,
and polyethylene glycols can be used. Mixtures of solvents and
wetting agents such as those discussed above are also useful.
[0297] Suppositories for rectal administration of the compounds
discussed herein cat be prepared by mixing the active agent with a
suitable non-irritating excipient such as cocoa butter, synthetic
mono-, di-, or triglycerides, fatty acids, or polyethylene glycols
which are solid at ordinary temperatures but liquid at the rectal
temperature, and which will therefore melt in the rectum and
release the drug.
[0298] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the compounds of this invention are ordinarily
combined with one or more adjuvants appropriate to the indicated
route of administration. If administered per os, the compounds can
be admixed with lactose, sucrose, starch powder, cellulose esters
of alkanoic acids, cellulose alkyl esters, talc, stearic acid,
magnesium stearate, magnesium oxide, sodium and calcium salts of
phosphoric and sulfuric acids, gelatin, acacia gum, sodium
alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then
tableted or encapsulated for convenient administration. Such
capsules or tablets can contain a controlled-release formulation as
can be provided in a dispersion of active compound in
hydroxypropylmethyl cellulose. In the case of capsules, tablets,
and pills, the dosage forms can also comprise buffering agents such
as sodium citrate, or magnesium or calcium carbonate or
bicarbonate. Tablets and pills can additionally be prepared with
enteric coatings.
[0299] For therapeutic purposes, formulations for parenteral
administration can be in the form of aqueous or non-aqueous
isotonic sterile injection solutions or suspensions. These
solutions and suspensions can be prepared from sterile powders or
granules having one or more of the carriers or diluents mentioned
for use in the formulations for oral administration. The compounds
can be dissolved in water, polyethylene glycol, propylene glycol,
ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl
alcohol, sodium chloride, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art.
[0300] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions can also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0301] The amount of active ingredient that can be combined with
the carrier materials to produce a single dosage form will vary
depending upon the patient and the particular mode of
administration.
[0302] Certain of the pharmaceutical compounds of this invention
which are administered in accordance with the methods of the
invention can serve as prodrugs to other compounds of this
invention. Prodrugs are drugs that can be chemically converted in
vivo or in vitro by biological systems into an active derivative or
derivatives. Prodrugs are administered in essentially the same
fashion as the other pharmaceutical compounds of the invention.
Non-limiting examples are the esters of the
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds of this
invention.
[0303] Compounds of the combinations of this invention, for example
N-(n-nonenyl)-1,5-dideoxy-1,5-imino-D-glucitol and various
nucleosides or nucleotides, may be acids or bases. As such, they
may be used to form salts with one another, Nucleosides are purine
or pyrimidine compounds lacking a phosphate ester. Compounds of
Formulas II, III, IV, V, or VI herein without a phosphate ester but
containing a carboxylic acid moiety could form a salt with an
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound of the
present invention. Nucleotides are purine or pyrimidine compounds
that are mono-, di-, or triphosphate esters. These phosphate esters
contain free --OH groups that are acidic, and that can form salts
with inorganic bases or organic bases. Salt formation with organic
bases depends on the pKa of the acid and base. Certain
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds disclosed
herein are basic and form pharmaceutically acceptable ammonium or
quaternary ammonium salts. In the present case, useful salts can be
formed not only with pharmaceutically acceptable acids, but also
with biologically active acids such as the nucelosides and
nucleotides disclosed herein. These salts can be prepared in the
conventional manner for preparing salts, as is well known in the
art. For example, one can treat the free base of an
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compound with a
nucleotide analog of Formula II, III, IV, V, or VI to form a salt.
This can be performed as a separate chemical reaction, or as part
of the formulation process. The limiting reagent in the salt
forming reaction is either the acid or base, as selected by the
artisan to obtain a suitable biological result. The formulation can
contain mixtures of different salts, acids, or free bases as
desired. For example, the phosphoric acid form of
(-)-2'-deoxy-3'-thiocytidine-5'-triphosphate will form a salt with
the base form of N-(n-nonenyl)-1,5-dideoxy-1,5-imino-D-glucitol or
N-(n-nonenyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate. This
type of salt can then be provided to the patient in a
pharmaceutically acceptable formulation, as a pure single salt, or
as part of a mixture. These acids and bases can be independantly
formulated and maintained in separate compartments in the same
formulation if desired.
[0304] In some cases, the salts can also be used as an aid in the
isolation, purification, or resolution of the compounds of this
invention.
[0305] Treatment Regimen
[0306] The regimen for treating a patient suffering from a
hepatitis virus infection with the compounds and/or compositions of
the present invention is selected in accordance with a variety of
factors, including the age, weight, sex, diet, and medical
condition of the patient, the severity of the infection, the route
of administration, pharmacological considerations such as the
activity, efficacy, pharmacokinetic, and toxicology profiles of the
particular compounds employed, and whether a drug-delivery system
is utilized.
[0307] Administration of the drug combinations disclosed herein
should generally be continued over a period of several weeks to
several months or years until virus titers reach acceptable levels,
indicating that infection has been controlled or eradicated. As
noted above, patients undergoing treatment with the drug
combinations disclosed herein can be routinely monitored by
measuring hepatitis viral DNA in patients' serum by slot-blot,
dot-blot, or PCR techniques, or by measurement of hepatitis
antigens, such as hepatitis B surface antigen (HBsAg) and hepatitis
B e antigen (HBeAg), in serum to determine the effectiveness of
therapy. In chronic hepatitis B, for example, remissions are
characterized by the disappearance of hepatitis B viral DNA, i.e.,
reduction to undetectable levels as measured by hybridization tests
capable of detecting levels 10.sup.5 genomes per ml of serum, and
HBeAg from serum despite the continued presence of HBsAg. These
serologic events are followed by improvement in the biochemical and
histologic features of the disease. The end point of successful
treatment in most trials of antiviral therapy is the disappearance
of HBeAg and viral DNA from serum. In patients in whom the e
antigen disappears, remission is usually sustained, and results in
an inactive HBsAg carrier state. Many patients eventually become
HBsAg-negative (see Hoofnagle et al., (1997) New Engl. Jour. Med.
336(5):347-356 for a review).
[0308] Continuous analysis of the data obtained by these methods
permits modification of the treatment regimen during therapy so
that optimal amounts of each component in the combination are
administered, and so that the duration of treatment can be
determined as well. Thus, the treatment regimen/dosing schedule can
be rationally modified over the course of therapy so that the
lowest amounts of each of the antiviral compounds used in
combination which together exhibit satisfactory anti-hepatitis
virus effectiveness are administered, and so that administration of
such antiviral compounds in combination is continued only so long
as is necessary to successfully treat the infection.
[0309] The following non-limiting examples serve to illustrate
various aspects of the present invention.
EXAMPLE 1
Preparation of 1,5-(butylimino)-1,5-dideoxy-D-glucitol
[0310] A solution of 1,5-dideoxy-1,5-imino-D-glucitol (5.14 g,
0.0315 mole), butyraldehyde (3.35 ml, 0.0380 mole) and Pd black (1
g) in 200 ml methanol was hydrogenated (60 psi/29C/21 hrs.). After
filtering the resulting mixture, the filtrate was concentrated in
vacuo to an oil. The title compound was crystallized from acetone,
and recrystallized from methanol/acetone, m.p. ca. 132C. The
structure assignment was supported by NMR, infrared spectra and
elemental analysis.
[0311] Analysis calcd. for C.sub.10H.sub.21NO.sub.4: C, 54.78; H,
9.65; N, 6.39. Found: C, 54.46; H, 9.33; N, 6.46.
EXAMPLE 2
Preparation of 1,5-(butylimino)-1,5-dideoxy-D-glucitol,
tetraacetate
[0312] Acetic anhydride (1.08 g, 0.0106 mole) was added to the
title compound of Example 1 (0.50 g, 0.0023 mole) in 5 ml pyridine
and stirred for 17 days at room temperature. The product was
evaporated under nitrogen gas. The resulting title compound was
purified by silica gel chromatography. Structure assignment was
supported by NMR, infrared spectra and elemental analysis.
[0313] Analysis calcd. for C.sub.18H.sub.29NO.sub.8: C, 55.80; H,
7.54; N, 3.62. Found: C, 55.42; H, 7.50; N, 3.72.
EXAMPLE 3
Anti-Hepatitis B Virus Activity of Various
N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds In
Vitro
[0314] The anti-hepatitis B virus activity and effect on cell
viability of a number of different
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds were
assessed using an in vitro assay employing chronically hepatitis B
virus secreting HepG2.2.15 cells. The method employed was
essentially that described in Block et al. (1994) Proc. Natl. Acad.
Sci. USA 91:2235-2239. The results are shown in Tables 2 and 3.
TABLE-US-00027 TABLE 2 Effect of
N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds on
Hepatitis B Virus Secretion and Viability of HepG2.2.15 Cells
Relative amount of HBV secreted Compound and % Viable As A %
[Concentration].sup.1 +/-1 S.D..sup.2,5 of Control.sup.3 Control 90
+/- 7 (n = 4) 100 NBDNJ[200] 94 +/- 6 (n = 10) 37.0 +/- 13 (n = 15)
NBDNJ[1000] 88 +/- 8 (n = 10) 3.2 +/- 5 (n = 15) 1 [200] 90 +/- 2
(n = 4) 85.0 +/- 5 (n = 8) 1 [1000] 87 +/- 3 (n = 4) 35.0 +/- 6 (n
= 8) 2 [200] 90 +/- 6 (n = 4) 107.0 +/- 12 (n = 3) 2 [1000] 89 +/-
4 (n = 4) 38.0 +/- 15 (n = 3) 3 [200] n.d..sup.4 45.0 +/- 30 (n =
3) 3 [1000] n.d..sup.4 5.0 +/- 20 (n = 3) 4 [200] 93 +/- 1 (n = 4)
60.0 (n = 2) 4 [1000] 91 +/- 3 (n = 4) 34.0 (n = 2) 5 [200] 88 +/-
6 (n = 4) 0.0 +/- 0 (n = 3) 5 [1000] 5 +/- 5 (n = 4) 0.0 +/- 0 (n =
3) 6 [200] n.d. 58.0 +/- 20 (n = 3) 6 [1000] n.d. 20.0 +/- 15 (n =
3) .sup.1Chronically HBV secreting 2.2.15 cells (approximately
500,000 per well) were incubated in the presence of indicated
compound for three days. .sup.2After 3 days of culture in the
absence or presence of compound, cells were removed by trypsin
treatment, incubated with trypan blue, and visually examined for
dye exclusion by microscopy. Values are the percentage, relative to
the total number of cells examined, of cells excluding trypan blue
(trypan blue exclusion was considered equivalent to viability).
.sup.3After 3 days of incubation in the absence or presence of
compound, secreted virions were immunoprecipitated from the culture
medium with monoclonal antibody specific for preS1 antigen (Meisel
et al. (1995) Intervirology 37: 330-339; Lu et al. (1995) Virology
213: 660-665). Viral DNA present in the immunoprecipitates was
detected by densitrometric quantification of the DNA fragment of
the correct size resulting from a polymerase chain reaction. The
amount of # DNA amplified from control (cells receiving no
compound) is assumed to be 100%. NBDNJ:
N-(n-butyl-)-1,5-dideoxy-1,5-imino-D-glucitol; N-butyl DNJ.
.sup.4Although trypan blue viability staining was not performed,
cells appeared unremarkable (healthy) by gross microscopic
examination. .sup.5S.D.: standard deviation. Compounds: 1:
N-(3-phenylpropyl)-1,5-dideoxy-1,5-imino-D-glucitol 2:
N-(n-butyl)-1,5-dideoxy-1,5-imino-D-glucitol, tetrabutyrate 3:
N-(2-ethylbutyl)-1,5-dideoxy-1,5-imino-D-glucitol 4:
N-(4,4,4-triflourobutyl)-1,5-dideoxy-1,5-imino-D-glucitol 5:
N-(8,8,8-triflourooctyl)-1,5-dideoxy-1,5-imino-D-glucitol 6:
N-(6,6,6-triflourohexyl)-1,5-dideoxy-1,5-imino-D-glucitol
[0315] TABLE-US-00028 TABLE 3 Effect of
N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds on
Hepatitis B Virus Secretion and Viability of HepG2.2.15 Cells
Compound [ ] for a 50% secretion reduction in inhibition.sup.1 [ ]
for 90% HBV MMT.sup.2 1 0.5-1.0* 100-200 2 >200*s* ND 3 200*
>200 4 200* >200 5 200* >200 6 >200** >200 7
>200** >200 8 >200** >200 9 >200** >200 10 -200
500 .sup.1in microgs per ml. and based upon duplicate PCR results.
.sup.2in microgs per ml.; MTT: .sup.3Not determined. *lowest
concentration tested. **there was no inhibition seen at the highest
concentration used (200 microgs/ml). Compounds: 1:
N-(n-nonyl)-1,5-dideoxy-1,5-imino-D-glucitol 2:
N-(n-butyl)-1,5-dideoxy-1,5-imino-D-glucitol, diacetate 3:
1,5-dideoxy-1,5-imino-D-glucitol, tetracetate 4:
N,O-(1,6-carbonyl)-1,5-dideoxy-1,5-imino-D-glucitol 5:
N-(n-butyl)-2,3-dimethoxy-1,5-dideoxy-1,5-imino-D-glucitol 6:
N-(n-hexyl)-4,6-benzylidine-1,5-dideoxy-1,5-imino-D-glucitol 7:
N-(n-butyl)-3-methoxy-1,5-dideoxy-1,5-imino-D-glucitol 8:
N-(4,4,4-triflourobutyl)-2,3-dimethoxy-1,5-dideoxy-1,5-imino-D-glucito-
l, tetracetate 9:
N,O-(1,6-methylenecarbonyl)-1,5-dideoxy-1,5-imino-D-glucitol 10:
N-(8,8,8-triflourooctyl)-1,5-dideoxy-1,5-imino-D-glucitol MMT:
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. The
MTT-based colorimetric assay is a measurement of cell viability
(Heo et al. (1990) Cancer Research 50:3681-3690).
EXAMPLE 4
Anti-Hepatitis B Virus Activity of
(-)-2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) Alone and in
Combination with N-nonyl-DNJ
[0316] The anti-hepatitis B virus effect of
(-)-2'-deoxy-3'-thiocytidine-5'-triphosphate (3TC) alone and in
combination with N-nonyl-DNJ was determined according to Korba
((1996) Antiviral Research 29(1):49-51), using the "combostat"
strategy (Comstat Program, Combostat Corp., Duluth, Minn.). The
combostat method involves serially diluting the IC-90 of each
compound. The IC-90 of N-nonyl-DNJ has been determined to be
between 4 and 10 g/ml (T. Block and G. Jacob, unpublished
observation). The accepted IC-90 for 3TC in HepG 2.2.15 (2.2.15)
cells is 300 nM to 50 nM (Doong et al. (1991) Proc. Natl. Acad.
Sci. USA 88:8495-8499).
[0317] 2.2.15 cells, described in Sells et al. (1987) Proc. Natl.
Acad. Sci. USA 84:1005-1009, were maintained in RPMI 1640 medium
(Gibco BRL, #31800-022) supplemented with 10% fetal bovine serum,
200 g/ml G418 (Gibco BRL 066-1811). Cells were seeded into 25
cm.sup.2 flasks at 80% confluency. Five days later, flasks in
triplicate received either no compound, serial dilutions of 3TC
alone, or serial dilutions of 3TC plus N-nonyl-DNJ. At 2, 4, and 6
days after addition of compound (with medium replacement on those
days), the amount of hepatitis B virus (HBV) DNA in the culture
medium was determined by PCR analysis of
polyethyleneglycol-sedimented particles. Thus, in these
experiments, enveloped particles were not distinguished from
nucleocapsids. PCR-amplified products were resolved by agarose gel
electrophoresis (1.5% agarose), and the 538 nucleotide fragment was
quantified by band scanning (HP Jet Imager). The amount of HBV
recovered from untreated cells is assumed to be 100%. Data from the
6-day time point are presented in FIG. 1 as the average values from
at least three separate flasks, and the standard error was never
greater than 20%, with an average error of 12%.
[0318] For each of the three time point series tested, the
combination of 3TC plus N-nonyl-DNJ was significantly more
effective in inhibiting HBV secretion than either compound alone.
Conclusions based upon PCR analysis alone make it difficult to
assign precise IC-50 values. The extreme sensitivity and delicate
nature of PCR, for example, may account for the inability to
achieve greater than 90% inhibition of HBV by 3TC alone, even at
300 nM. Every experiment included controls to assure that PCR was
performed in a range of concentrations of DNA in which the reaction
yields results proportional to the amount of DNA in the sample.
Resolution is approximately 3-fold, i.e., 3-fold differences in DNA
concentrations can be detected. The inability to consistently
detect less than 3-fold differences probably explains the failure
of 3TC alone to achieve 90% inhibition. This suggests that a very
high standard of inhibition must be met for the PCR to detect
inhibition. Consequently, the trend, over three separate time
points, is clear: the combined effect of 3TC plus N-nonyl-DNJ is
greater than that of either compound alone, or the additive
individual effects of each compound. These data suggest that the
IC-50 of 3TC has been moved from about 60 nM to about 0.48 nM when
0.016 g/ml N-nonyl-DNJ is present.
EXAMPLE 5
Anti-Hepatitis B Virus Effect of N-nonyl-DNJ Alone in a Woodchuck
Model
[0319] In order to evaluate the efficacy of N-nonyl-DNJ in
combination with 3TC (or other nucleoside or nucleotide analogs)
against Hepatitis B virus in a woodchuck animal model, an
monotherapy experiment using N-nonyl-DNJ alone was first conducted.
This was necessary to determine if N-nonyl-DNJ has any anti-HBV
effect in the woodchuck and, if N-nonyl-DNJ has a beneficial
effect, to design a combination study based on the dose-response
relationship of this drug alone.
[0320] Therefore, five groups of four animals each (all groups had
both sexes, all but the control had two of each sex) were assigned
to 0, 12.5, 25, 50, and 100 mg/kg/day with BID oral dosing. These
were lab-reared wild animals. All animals were infected with
woodchuck hepatitis virus (WHV) as neonates, and had been tested
positive on serological tests for WHV surface antigen. Blood
samples were drawn one week prior to dosing (-1 week), immediately
before dosing (0 weeks), weekly during dosing (1, 2, 3, and 4
weeks), and after the end of dosing (5, 6, 8, and 10 weeks).
[0321] There are two measures of drug efficacy: reduction in total
HBV DNA (measured by quantitative PCR), and reduction in HBV DNA
from capsids with intact surface glycoproteins, which is the active
form of the virus (measured by an ELISA-like immune precipitation
assay followed by quantitative PCR). Cell culture experiments with
N-nonyl-DNJ demonstrated little or no effect of this compound on
total HBV DNA, but a marked effect on the immune precipitated DNA
(IPDNA). Not surprisingly, the IPDNA assay is quite variable; as a
partial compensation for this, four assay runs were conducted, each
containing samples from all animals, but different subsets of the
study weeks.
[0322] To summarize the results, N-nonyl-DNJ had no effect on total
HBV DNA measurements, which were essentially constant for all dose
levels over the pre-dose and dosed portions of the study. On the
other hand, IPDNA levels were not constant over the study period.
The low dose animals tended to have increasing levels of IPDNA over
the dosing period (weeks 0-4), while high dose animals tended to
have decreasing levels of IPDNA over the same period. Fitting a
straight line to each animal's weekly responses gave a significant
difference in the slope of these lines due to either dose or plasma
level of drug. The plasma levels of drug were also quite variable:
animals with the lowest plasma levels in their dose group had lower
plasma levels than the animals with the highest plasma levels from
the next lower-dose group. There were-no differences between
responses of males and females on any of the measures.
[0323] Plasma Levels
[0324] There were no clear patterns in the changes in plasma levels
of N-nonyl-DNJ which could be related to week of dosing or time
since previous dose. Because the plasma levels within an animal
seemed reasonably consistent during dosing, the median plasma level
for each animal was used for subsequent modeling. The plasma levels
for each week of the dosing period are plotted for each animal vs.
dose (a small amount of random noise is added to the dose level so
points which would lie on top of each other on the plot can be
distinguished) (FIG. 2).
[0325] HBV DNA
[0326] The total HBV DNA levels were essentially constant over time
within each animal (data not shown). There was a faint hint of a
dose-response relationship with decreasing levels of virus with
increasing levels of drug, except that three animals at the highest
dose had very high virus levels. It is not possible to conclude
that there is any relationship between dose of N-nonyl-DNJ and
total HBV DNA. It is possible that there are two populations of
animals, responders (such as animal r) and non-responders (animals
i, m, and d), but more data would be required to permit a firm
conclusion on this point.
[0327] Immune Precipitated HBV DNA
[0328] Substantial variation existed in the IPDNA assay, both
between assay runs and within assay runs (data not shown). Even so,
it was possible to observe and model a slope over weeks 0-4 which
is generally increasing for low dose animals and decreasing for
high dose animals. This change in slope was statistically
significant (p<0.005).
[0329] Before models are fitted to the data, a log transform was
applied because: 1) the variation in IPDNA increases with
increasing IPDNA values; the log transformation gives values with a
nearly constant variation, and 2) it is expected that drug effects
will appear as a constant multiplier of the IPDNA level. Because
there are zero values of IPDNA, a small value (about 1/2 of the
smallest non-zero value) was added to all values before the log
transform.
[0330] Two approaches were used to model the changes in slope to
week with dose of N-nonyl-DNJ: a linear modeling approach and a
nonlinear model. Both approaches assume that the (linear) rate of
change of the Log(IPDNA) measure over the dosing period is the
"right" measure to reflect the effect of the drug on the virus.
Both approaches are fit in stages, and the first stage is common to
both approaches. First, a simple straight line regression model is
fit using, weeks 0-4 to predict log(IPDNA_+.sub.--10) separately
for each animal by run combination. In the second stage, the
response variable is the slope fitted in the first stage.
[0331] For the linear approach, a model is fit with slope to week
as the response where run is considered a block, dose has a
significant effect (almost all of this effect is due to a slope to
dose), and the relevant error for testing the effect of dose is the
variation among animals treated alike (after the adjustment for the
runs as blocks). This is similar to using the calibration data
within each run to first adjust each run's data to a common virus
DNA concentration; the difference is that here the data from the
woodchucks are used for the run adjustment rather than only the
calibration data.
[0332] For the nonlinear approach, a four parameter logistic model
is fit with the slope to week as the response and the dose as the
predictor. Again, run is considered a block, but because no run has
all weeks, it is not possible to fully reflect the blocking in the
nonlinear approach. Even so, the nonlinear model yields an EC50 of
7.88 mg/kg/BID dose. The average maximum slope observed was 2.71
additional Log(IPDNA g/mL)/week, or an increase of about 150%/week,
the average minimum slope observed with N-nonyl-DNJ is 0.31 fewer
Log(IPDNA g/mL)/week), or about a decrease of about 25%/week. The
slopes, the fitted model, the parameter estimates from the model,
and the approximate standard errors for these parameters are all
shown in FIG. 3. The data indicate an approximate effective
monotherapy dose of N-nonyl-DNJ in woodchucks of about 16
mg/kg/day. Whether in woodchucks or humans, the effective dose of
both the N-alkyl-DNJ and nucleoside or nucleotide antiviral agent
administered in combination therewith can be administered in two
equal daily subdoses (i.e., B.I.D.).
[0333] FIGS. 2 and 3 show letters to indicate animals. Table 4
shows two of the animal codes, the sex, and the dose.
TABLE-US-00029 TABLE 4 Animal Codes, Sex, and Dose Animal Number
Letter Code Sex Dose F95343 b F 0 M96364 n M 0 F96304 k F 0 F96301
j F 0 M96285 h M 6.25 F96283 g F 6.25 F96391 o F 6.25 M96305 l M
6.25 F96271 f F 12.5 M96256 e M 12.5 M96404 s M 12.5 F96392 p F
12.5 F96163 c F 25 M96414 t M 25 F96393 q F 25 M95322 a M 25 M96286
i M 50 F96231 d F 50 F96402 r F 50 M96363 m M 50
EXAMPLE 6
Antiviral Study to Test the Activity of N-nonyl-DNJ in Combination
with 3TC in a Woodchuck Model of Hepatitis B Virus Infection
[0334] The combined activity of N-nonyl-DNJ and the nucleoside
analog 3TC can be assessed using the woodchuck model of hepatitis B
virus infection. Twenty-eight woodchucks with persistent woodchuck
hepatitis virus (WHV) infection can be utilized. Groups of
woodchucks can be treated orally with 3TC alone (s.i.d.), with
N-nonyl-DNJ alone (b.i.d.), or with combinations of the two drugs.
The antiviral activity of the individual drugs and combinations can
be assessed by measuring serum WHV DNA during treatment, and
comparing the results of treated groups to placebo treated
controls.
[0335] Twenty-eight woodchucks with established persistent WHV
infection cam be used, all of which were experimentally infected
with WHV during the first week of life. All can be WHsAg positive
at the time the study is initiated.
[0336] A total of eight experimental groups can be used. Woodchucks
in each group can be stratified on the basis of gender, body
weight, and age. 3TC can be administered orally as an aqueous
suspension of Epivir (Glaxo-Wellcome) tablets one time per day.
N-nonyl DNJ can also be administered orally in aqueous solution, in
two divided doses. Treatment with both drugs can be followed by the
administration of 4 to 5 mls of semisynthetic liquid woodchuck diet
to insure complete ingestion of the drugs.
[0337] The experimental groups can be as follows: TABLE-US-00030
Group No. 3TC ID (mg/kg/day) (mg/kg/day) N-nonly-DNJ 1 4 0.0 0.0 2
3 3.0 0.0 3 3 9.0 0.0 4 3 0.0 4.0 5 3 0.0 12.0 6 4 1.5 2.0 7 4 4.5
6.0 8 4 9.0 12.0
[0338] Woodchucks can be anesthetized (50 mg/kg ketamine, 5 mg/kg
zylazine), weighed, and blood samples obtained prior to initial
treatment, at weekly intervals during the six week period of
treatment, and at 1, 2, and 4 weeks following treatment. Serum can
be harvested and divided into aliquots. One aliquot can be used for
analysis of WHV DNA by dot blot hybridization and for WHsAg by
ELISA. CBCs and clinical biochemical profiles can be obtained prior
to treatment and at the end of treatment. A second aliquot can be
maintained as an archive sample. Other aliquots of serum can be
used for drug analysis and special WHV DNA analyses.
EXAMPLE 7
Anti-Hepatitis B Virus Activity of
N-Substituted-1,5-Dideoxy-1,5-Imino-D-Glucitol Compounds In
Vitro
[0339] The anti-hepatitis B virus activity and effect on cell
viability of a number of different
N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds is
assessed using an in vitro assay employing chronically hepatitis B
virus secreting HepG2.2.15 cells. The method employed is
essentially that described in Block et al. (1994) Proc. Natl. Acad.
Sci. USA 91:2235-2239. The compounds are of Formula I where R is:
4-(4-trifluoromethylphenyl)-butyl,
4-(4-trifluoromethylphenyl)-butane-1-carbonyl,
4-(4-trifluoromethyloxyphenyl)-butyl,
4-(4-trifluoromethyloxyphenyl)-butane-1-carbonyl,
2-cyclohexylethyl, 2-(4-thiapyran)-ethyl, 5-(morpholinyl-pentyl,
4-(4-pyridineoxy)-butyl, 3-(3-pyridyl)-propyl,
4-(4-trifluoromethylthiaphenyl)-butyl,
7-(trifluoromethylsulfonyl)-heptyl,
4-(4-trifluoromethylthiaphenyl)-butyl,
8-(trifluoromethylsulfonylamino)-octyl,
12,12,12-trifluoro-6,8-dioxa-dodecyl,
10,10,10-trifluoro-5-oxa-decyl,
12,12,12,11,11-pentafluoro-6-oxa-dodecyl,
9,9,9-trifluoro-2-oxa-nonyl,
5-(4-trifluoromethylphenyl)-4-oxa-butyl,
4-(4-trifluoromethylphenyl)-3-oxa-propyl,
4-(4-trifluoromethylphenyl)-3-oxa-propanoyl-5-cyclohexyl-4-oxabutyl,
5-(4-trifluoromethoxyphenyl)-4-oxa-butyl and
5-(4-trifluoromethylthiaphenyl)-4-oxa-butyl.
[0340] The invention being thus described, it will be obvious that
the same can be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the present
invention, and all such modifications and equivalents as would be
obvious to one skilled in the art are intended to be included
within the scope of the following claims.
* * * * *