Note: Descriptions are shown in the official language in which they were submitted.
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
USE OF 17-KETOSTEROID COMPOUNDS AND DERIVATIVES,
METABOLTTES AND PRECURSORS THEREOF IN THE TREATMENT OF
HEPATITIS C VIRUS AND OTHER T'OGAVIRUSES
BACKGROUND OF THE INVENTION
The present invention relates to steroid compositions and methods to use them
to treat
- _ flavivirus and togavirus infections, such as human hepatitis C virus,
("HCV") infections.
The present invention is directed to the use of 17-ketosteroid compounds, as
well as
derivatives, metabolites and precursors of such compounds, and
pharmaceutically acceptable salts
of any of these compounds, collectively defined herein as the "compounds of
the present
invention", optionally together with one or more additional chemical agents
and/or treatment
methods (as described below) in the treatment of hepatitis C type virus and/or
hepatitis G type virus
in patients in need of such treatment. In addition, the present invention is
directed to methods of
treatment of togaviruses, including alphaviruses (also known as arboviruses,
group A), flaviviruses
(also known as arboviruses, group 13)(such as yellow fever, as well as
hepatitis C and hepatitis G),
rubiviruses (also known as rubella viruses)(such as rubella) and pestiviruses
(also known as
mucosal disease viruses)(such as bovine virus diarrhea virus (BVDV)).
There is an ongoing need for methods of treatment of hepatitis C virus, which
are safer
and/or more effective than known methods of treatment. As stated by C. Everett
Koop, former U.S.
Surgeon Gederal, "we stand at the precipice of a grave threat to our public
health... It affects people
from all walks of life, in every state, in every country. And unless we do
something about it soon, it
will kill more people than AIDS", Koop, Hepatitis C. - An Epidemic for Anyone.
As stated in
Maddrey, W.C. et al, "Beyond Monotherapy: Next Generation Therapies for
Chronic Hepatitis C",
unfortunately, the only therapy offered in the U.S. National Institutes of
Health Consensus
Development Statement on the Management of Hepatitis C, published in March,
1997, has proven
ineffective for the majority of patients-not only have a significant
proportion of patients failed to
respond to this treatment, but another sizable segment has relapsed or had
limited response.
Because not all patients with chronic hepatitis C virus infection respond to
standard treatment with
interferon alfa ("IFNa"), new therapeutic strategies are needed Di Bisceglie,
A.M., "Emerging
Therapies for Chronic Hepatitis C".
Hepatitis C virus infection is extremely common, with estimates of worldwide
prevalence
of chronic hepatitis ranging from 90 million up to over 200 million (2 % to 4
%). There is no
vaccine or candidate vaccine for pre-exposure prophylaxis and no effective
globulin for post-
exposure prophylaxis.
The major liability of HCV infection is the propensity to develop chronic
hepatitis in at
least 75 % of the cases; virtually all infected patients may be chronically
infected. It is theorized
that HCV-related liver injury is directly or indirectly related to cytotoxic
Tlympho~ytes (CTL)
CA 02352205 2001-05-23
WO 00132177 PCT/US99/28082
directed at viral peptides expressed on the hepatocyte membrane. These CTL are
localized within _
the liver, are present in small numbers, and are probably only transiently
effective since the virus is
so heterogeneous and mutates at such a rapid rate. In view of this, purely
antiviral compounds, such
as nucleoside analogues or enzyme inhibitors, are likely to be virostatic but
unlikely to eliminate
infection. In addition, immune directed therapies such as antibody
preparations or cellular immune
stimulants are Likely to be transiently effective due to changes or mutations
in the virus.
- _ Chronic hepatitis C is insidiously progressive. In general, infection
progresses to chronic
hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma over a
period of decades, not months
or years.
A reliable and effective cell culture for HCV does not exist. In addition, no
nonprimate
animal model exists. As a result, few agents have been tested against HCV. It
is known that
acyclovir, ribavirin, and corticosteroids are ineffective, and that
corticosteroids increase the level of
HCV replication.
Interferons have been used in the treatment of chronic hepatitis C.
Interferons are natural
glycoproteins produced by cells in response to infection by viruses.
Interferons inhibit the
replication of a wide spectrum of RNA and DNA viruses, including hepatitis
viruses. This occurs
via a variety of mechanisms including inhibition of virus attachment and
uncoating, induction of
intracellular proteins and ribonucleases which convey antiviral properties to
the cell, and
amplification of both specific (cytotoxic T-lymphocyte) and nonspecific
(natural killer cell)
immune response to viral proteins. The specific mechanism of interferon
activity in chronic
hepatitis C infection is not known.
Because of its known antiviral properties and the experience with interferon
in the
treatment of other forms of viral hepatitis, interferon was evaluated as a
potential treatment for
patients with non-A, non-B hepatitis before the hepatitis C virus was even
identified. Several
reports indicate that a response during interferon therapy can be expected in
about 40 % of chronic
hepatitis C patients, and this response generally occurs quickly. HCV RNA
levels fall dramatically
and become undetectable within 4 - 8 weeks in the majority of patients who
subsequently normalize
their serum aminotransferases.
Despite the prompt antiviral and biochemical response to treatment and the
inability to
detect residual HCV in either fiver or serum in responding patients,
biochemical normalization and
absence of detectable viremia in serum is maintained in only a minority of
patients ranging from 8 -
%. Relapse characterized by a rebound in serum ALT out of the normal range
occurs in 50 - 90
of "successfully" treated patients following the discontinuation of interferon
treatment.
At least half of patients with chronic hepatitis C who are treated with
interferon fail to
35 respond. Some patients who initially appear to respond to interferon by
normalizing serum ALT
levels will demonstrate a progressive rise in the serum ALT levels despitc
continuation of
intcrferon.
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WO 00/32177 PCT/US99/28082
A variety of factors have been examined for their relation to whether a
patient responded to
interferon, including age, gender, body mass, pre-treatment HCV-RNA level,
extent of loss of
HCV-RNA during the start of treatment, viral genotype, absence or presence of
fibrosis or cirrhosis,
dosage of interferon, serum ferritin levels and hepatic iron levels, but none
of these has been able to
predict accurately and consistently which HCV patients will respond to
interferon.
Furthermore, there are many cases where administering interferon alone for
treatment of
- _ hepatitis C appears to be detrimental to patients, and sometimes very
harmful to patients. For
example, use of interferon in patients with predominant autoimmune features
can intensify an
immune-mediated hepatocullular inflammation (see Shindo et al, "Acute
exacerbation of liver
disease during interferon alfa therapy for chronic hepatitis C"
Gastroenteroloey 1992; 102: 1406-
1408). Interferon can transform chronic viral hepatitis into an autoimmune
hepatitis (Silva et al,
"Interferon-induced chronic active hepatitis?" Gastroenterolorw 1991; 101: 840-
8-42).
Administering interferon can also induce production of a variety of
autoantibodies of uncertain
clinical significance (Mayet et al, "Treatment of chronic type B hepatitis
with recombinant alpha-
interferon induces autoantibodies, not specific for autoimmune chronic
hepatitis," Heoatoloay
1989;10:24-28), all of which are incorporated herein by reference. Interferon
causes an increase in
HLA display on membrane surfaces, impairs suppressor T cell function, enhances
autoantibody
production, stimulates natural killer cell function, affects cytokine release,
and activates
macrophages, making it capable of worsening an immune-mediated disease (Baron
et al., "The
interferons: mechanisms of action and clinical applications," JAMA 1991;
266:1375-1383, which is
incorporated herein by reference). In still other patients, such as those with
normal serum ALT
levels or decompensated disease, the advantages of therapy are unproved and
doubtful.
In addition, from studies of its use in other therapies, interferon has a
number of well-
known side effects, including fever, chills, flu like syndrome, fatigue,
anorexia, worsening in
performance status, nausea and vomiting, weight loss, leukopenia, anemia,
neurological symptoms,
psychological symptoms and dyspnea. See, e.g., Tsavaris, N. et al, "Treatment
of renal cell
carcinoma with escalating doses of alpha-interferon," Chemotherany, 1993 Sep-
Oct; 39 (5): 361-6.
In addition, interferon has been linked with the development of thyroid
disease in HCV patients.
Lisker-Melman M, et al., "Development of thyroid disease during therapy of
chronic viral hepatitis
with interferon alfa". Gastroenteroloev 1992 Jun;102(6):2155-60.
Ribavarin is a compound which is reported to have a broad spectrum of in vitro
activity
against both RNA and DNA viruses, including flaviviridae related to hepatitis
C. Pilot studies
reported reduction of both serum ALT and HCV RNA levels in patients with
chronic HCV
infection, but in a subsequent randomized controlled trial, the antiviral
effect of ribavirin alone .
could not be confirmed. Several subsequent small studies appear to demonstrate
a synergistic effect
of ribavirin and interferon in patients with hepatitis C infection, however,
the risks and side effects
of interferon monotherapy remain as important drawbacks.
3
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WO 00/32177 PCT/US99/28082
Several agents or maneuvers including ursodeoxycholic acid, indomethacin,
nacetyl- ,
cysteine, silymarin, several herbal preparations and phlebotomy have been
reported to be useful
adjuncts to interferon treatment, but none of these have been consistently
shown to be effective in
controlled trials.
Hepatitis G virus (HGV; also called hepatitis GB virus C or HGBV-C) was fully
characterized in early 1996. HGV is a flavivirus and a distant relative of
HCV. At this time, HGV
' infection can be identified only through PCR testing, which indicates
current infection. Such
testing is not readily available or standardized. An antibody test for HGV is
under development
and, when available, will elucidate the epidemiology of HGV infection more
fully than HGV RNA
testing can. It appears that once antibodies are found, HGV RNA is usually no
longer present.
Transmission of HGV through blood transfusion has been documented (the only
Canadian study indicated that infection may occur in 1 in 1500 transfusion
recipients and account
for 9% of post-transfusion hepatitis), and from mother to child in the
perinatal period. There is an
increased prevalence of HGV RNA among groups with frequent exposure to blood
or blood
products (e.g., persons with hemophilia or thalassemia, patients on
hemodialysis and injection drug
users). Othcr modes of transmission (e.g., sexual) are possible but have not
been well documented.
Coinfection with HBV, HCV, or both is common and likely represents similar
modes of
transmission. In 0.3% of cases of community-acquired acute viral hepatitis,
HGV is the only
identified agent.
A nr~mber of steroid compounds and their uses have been described. See, e.g.,
U.S. patent
numbers 4956355, 5859000, 4268441, 4666898, 5837269, 5827841, 5811418,
5824313, 5686438,
5635496, 5587369, 5583126, 5562910, 5532230, 5518725, 5736537, 5843932,
5837700, 5824671,
5807849, 5798347, 5780460, 5776923, 5728688, 5610150, 5593981, 5372996,
5110810, 5807848,
5707983, 5641766, 5585371, 5506223, 5424463, 5296481, 5292730, 5776921,
5641768, 5559107,
5478566, 5461042, 5407684, 5387583, 5277907, 5206008, 5077284, 5162198,
5660835, 5527789,
5756482, 5709878, 5804576, 5744462, 5714481, 5700793, 5696106, 5656621,
5175154, 5157031,
5028631, 5001 I 19, 4898694, 5824668, 5710143, 5795880, 5527788, 5591736,
5861390 and PCT
publication numbers WO 98/05338, WO 95/21617, WO 98/50040, WO 98/50041 and WO
97/48367, all of which are incorporated herein by reference.
A number of flavonoids, methods to obtain them and their uses have been
described. See,
e.g., J.A. Manthey and B.S. Buslig, editors, Flavonoids in the living system,
Advances in
experimental medicine and biology, volume 439, Plenum Press, New York, 1998,
chapter 15 (pages
191-225), chapter 16 (pages 227-235) and chapter 17 (pages 237-247), which are
incorporated
herein by reference.
SUMMARY OF THE INVENTION
A principal embodiment of the invention provides a method to treat or prevent
a togavirus
infection comprising administering to a subject an effective amount of a
compounds) of formula I,
4
- CA 02352205 2001-05-23
r
WO 00/32177 PCT/US99/28082
Rt ~'~ X _
. ,
R~ De
R ' '
12
R~ R~ R~ lI 13 17
2
Q3 14 15
,.--1 9
- _ Q4 2 10 g R~
\ R~
R2 3 5 7 R~ R~
4__. . 6 /A~
R1 R1
1
wherein
Q, is -C(R, )z- or -C(O)-; '
Qz is -C(R,)z-, -C(R,)(Y)-, -C(Y}- or -CHz-CHz-;
S Q3 is -H or -C(R,)3-;
Q4 is -C(R~)z-, -C(O~, hydroxyvinylidine (-CH(CH=CHOH)-) or methyl methylene (-
CH(CH)3-);
Qs is -C(Rl)z- or -C(O~;
X and Y independently are -OH, -H, lower alkyl (e.g., C,.~ alkyl), -O-C(O~Rs,
-C(O)-ORs,'halogen (i.e., -F, -Cl, -Br or -I) or ~;
each R, independently is -H, -F, -CI, -Br, -I, -OH, C,.~ alkoxy, or C,~ alkyl;
Rz is -H, -OH, -F, -CI, -Br, -I, C,~ alkyl, C,~ alkoxy, -OR3, an ester (e.g., -
O-C(O)-R, or -
C(O)-O-R4), a thioester (e.g., -O-C(S)-R, or -C(S)-O-R4), a thioacetal (e.g., -
S-C(O}-R, or -C(O)-S-
R4), a sulfate ester (e.g., -O-S(O)(O)-O-R4), a sulfonate ester (e.g., -O-S(O)-
O-R4) or a carbamate
(e.g., -O-C(O)-NH-R, or -M-I-C(O)-O-R,) or Rz, together with the R~ that is
bonded to the same
carbon atom is -0;
R3 is -S(O)(O)-OM, -S(O)(O)-O-CHz-CH(O-C(O)-R6)-CHz-O-C(O)-R6,
-P(O)(O)-O-CHz-CH(O-C(O)-R,)-CHz-O-C(O)-R,, a glucuronide group of structure
(A)
COOH
H3C O
OH
OH
CH3 (A),
or R3 is C,_,a alkyl, Cz_,e alkenyl, Cz_,8 alkynyl, a C,.,e ester or a C,_,8
thioester, where any of the.
foregoing C,_,8 or Cz.,B moieties are optionally substituted at one or more
hydrogen atoms with one
or more independently selected -ORPR, (including -OH), -rIHRPR, (including -
NHz) or -SRPR,
5
s
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WO 00/32177 PCT/US99/28082
(including -SH) groups, or R~ is a C,.,a fatty acid, Ci.,o alkynyl, (J),;
phenyl-C,_f-alkyl, (J)~ phenyl-
Cz.s-alkenyl;
R, is -H, a protecting group, optionally substituted C,.,B alkyl, optionally
substituted C,.,a
alkenyl, optionally substituted C,.~B alkynyl, optionally substituted aryl,
optionally substituted aryl-
s C,.~ alkyl, optionally substituted aryl-C2.6 aikenyl, optionally substituted
aryl-CZ.~ alkynyl,
optionally substituted heterocycle-C,.~ alkyl, optionally substituted C~~
alkenyl-heterocycie,
' _ optionally substituted CZ.~ alkynyl-heterocycle or an optionally
substituted heterocycle, where any
of the foregoing moieties are optionally substituted at one, two, three, four,
five or more carbon or
hydrogen atoms with one or more independently selected -O-, -S-, -NRpR-
(including -NH-), -NH-
C(O)-, -ORPR (including -OH), -NHRPR (including -NHi), -SRpR (including -SH),
=O, =S, =N-OH, -
CN, -NO2, -F, -CI, -Br or -I groups or atoms;
each RS independently is straight or branched Ci.~4 alkyl;
each R6 independently is straight or branched C~.,, alkyl;
each R~ independently is straight or branched C,.,4 alkyl or a giucuronide
group of structure
(A);
each RPR independently is -H or an independently selected protecting group;
n is 0, 1, 2 or 3;
each J independently is -F, -Cl, -Br, -I, C,~ alkyl, Cz.~ alkenyl, C,~ alkoxy,
carboxy, vitro,
sulfate, sutfonyl, a C,.~ carboxyl ester or a C,.~ sulfate ester,
M ig'hydrogen, sodium, -S(O)(O)-O-CHZ-CH(O-C(O)-R6~CH2-O-C(O~R6, -P(O)(O~O-
CHZ-CH(O-C(O)-R~~CH2-O-C(O)-R, or a glucuronide group of structure (A);
the dotted lines in formula 1 represent an optional double bond, provided that
there are not
double bonds at both the 4-S and 5-6 positions and provided that when a double
bond is present,
zero or 1 R, group is bonded to carbon atoms at the 1-, 2-, 4-, 5-, 6- or 17
positions so that these
carbon atoms are tetravalent; and
the salts, stereoisomers, positional isomers, metabolites, analogs,
precursors, hydrates,
tautomers, ionized forms and solvates thereof. The formula 1 compounds are
collectively referred
to herein as the "compounds of the invention" or "compounds of the present
invention".
Another invention embodiment comprises a method to treat or prevent a
togavirus infection
comprising administering to a subject a compound of the invention
simultaneously or sequentially
with a compound of formula 2A or 2B
6
CA 02352205 2001-05-23 '
WO 00!32177 PCT/US99/28082
F X
1
4
X.
2A
R~ c X
I
4
Re X;
2B
wherein a double or a single bond is present at the dotted line and, when a
double bond is present, ~ _
S (i) the optionally substituted phenyl ring at the 2- or 3-position is
present and the R8 that is bonded
to the carbon is absent, and (ii) one R8 at the adjacent 2- or 3-position is
absent;
X~ iS -O- or -C(R8}~-;
Xz is -C(O)- or -C(R~,)Z-;
each Re independently is -H, -OH, halogen, C,.~ alkyl, C,.~ alkoxy,
glucuronide, a C,_ZS fatty
acid, the residue of a formula 2A or 2B compound where a hydrogen atom is
removed to forth the
formula 2A or 2B compound radical, -CHzCH=C(CH3)2, glucoside, a group having
structure (B) or
(C),
HO 0 0~
HO
OH (B) or OH
(C)
R,o is C,.~ alkyl, C,~ alkoxy, neohesperidoside, apioglucoside, rutinoside,
glucoside,
galactoside, rhamnoside, arabinoside, or a stereoisomer, hydrate, analog,
derivative or metabolite of
any of these moieties, any of which are optionally independently substituted
at one or more
hydrogen atoms with -OH, halogen, C,~ alkyl, C,.~ alkoxy, glucuronide or a
C,_~s fatty acid or R,o is
-H, -OH or halogen;
each R" independently is -H, -OH, halogen, C,.~ alkyl, C,.~ alkoxy,
glucuronide, a C,.is
fatty acid, or both R" together aca =O; and
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WO 00/32177 PCT1US99/28082
the salts, stereoisomers, positional isomers, metabolites, analogs,
precursors, hydrates,
tautomers, ionized forms and solvates thereof.
Another embodiment of the invention is a method to treat or prevent a
togavirus infection,
' including one or more infections with alphaviruses, flaviviruses,
rubiviruses or pestiviruses,
comprising administering to a subject a compound of the invention ( a formula
1 compound) and a
macrophage stimulating factor and optionally also administering a formula 2A
or 2B compound.
A further invention embodiment is a method to treat or prevent a togavirus
infection,
including one or more infections with alphaviruses, flaviviruses, rubiviruses
or pestiviruses,
comprising administering to a subject a compound of formula 1 and (1)
administering an oxidation
agent or (2) using oxygen ventilation and optionally also administering a
macrophage stimulating
factors) and/or a formula 2A or 2B compound.
Another invention embodiment is a method to treat or prevent a togavirus
infection,
including one or more infections with alphaviruses, flaviviruses, rubiviruses
or pestivirusos,
comprising administering to a subject a compound of formula i and ribavirin
and/or aIFN and
l S optionally also using one or more of a formula 2A or 2B compound, a
macrophage stimulating
factor, an oxidation agent or oxygen ventilation.
DETAILED DESCRIPTION OF THE INVENTION
As used herein and unless otherwise stated or implied by context, the
following terms have
the meanings defined here.
A "~Satient" or "subject" means a human or animal. Usually the animal is a
vertebrate such
as a primate, rodent, domestic animal or game animal. Primates include
chimpanzees,
cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents
include mice, rats,
woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include
cows, horses, pigs,
deer, bison, buffalo, felines, e.g., domestic cat, canines, e.g., dog, avians,
e.g., chicken, emu,
ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject
includes any subset of the
foregoing, e.g., all of the above, but excluding one or more groups or species
such as humans,
primates or rodents.
"Alkyl" as used herein, unless stated to the contrary, is a C I-C I g
hydrocarbon containing 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in
the form of normal,
secondary, tertiary, cyclic or mixed structures. Examples are -CH3, -CH2CH3, -
CH2CH2CH3, -
CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CHg)CH2CH3, -C(CH3)3,
CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH(CH2CH3)2, -C(CH3)2CH2CH3, -
CH(CH3)CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH(CH3)CH2CH3, -CH2C(CH3)3, -
CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH(CH2CH3)(CH2CH2CH3),
C(CH3)2CH2CH2CH3, -CH(CH3)CH(CH3)CH2CH3, -CH(CH3)CH2CH(CH3)2,
C(CH3)(CH2CH3)2, -CH(CH2CH3)CH(CH3)2, -C(CH3)2CH(CH3)2, -CH(CH3)C(CH3)3,
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WO 00/32177 PCT/US99/28082
cyciopropyl, cyclobutyl, cyciopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-
cyclopropyl-1-ethyl,
2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyI, 1-cyclobutyl-1-ethyl, 2-
cyclobutyl-1-ethyl,
1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyI, 2-
cyclopropyl-2-propyl,
and 1-cyclopropyl-2-propyl.
"Alkenyl" as used herein, unless stated to the contrary, is C2-C 1 g
hydrocarbon comprising
l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or I8 carbon atoms
in the form of normal,
secondary, tertiary, cyclic or mixed structures and comprising 1, 2, 3 or more
double bonds between
adjacent carbon atoms. Examples are -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -
C(=CH2)(CH3),
-CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH~(CH3)2, -CH2C(=CH2)(CH3),
-C(=CH2)CH2CH3, -C(CH3)=CHCH3, -CH(CH3)CH=CH2, -C=CHCH2CH2CH3, -
CHCH=CHCH2CH3, -CHCH2CH=CHCH3, -CHCH2CH2CH=CH2, -C(=CH2)CH2CH2CH3,
C(CH3)=CH2CH2CH3, -CH(CH3)CH=CHCH3, -CH(CH3)CH2CH=CH2, -CH2CH=C(CH3)2, 1-
cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-
cyclohex-2-enyl,
and 1-cyclohex-3-enyl.
"Alkynyl" as used herein, unless stated to the contrary, is C2-C I g
hydrocarbon comprising
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, I 1, 12, 13, 14, 15, 16, 17 or 18 carbon atoms
in the form of normal,
secondary, ternary, cyclic or mixed structures and comprising 1, 2, 3 or more
triple bonds between
adjacent carbon atoms. Examples are -CCH, -CCCH3, -CH2CCH, -CCCH2CH3, -
CH2CCCH3, -
CH2CH2CCH, -CH(CH3)CCH, -CCCH2CH2CH3, -CH2CCCH2CH3, -CH2CH2CCCH3 and -
CH2CH2CH2CCH.
"Halogen" or "halo" means fluorine (-F7, chlorine (-Cl), bromine (-Br) or
iodine (-I) and if
more than one halogen is referred to (e.g., two or more variable groups may be
a halogen), each
halogen is independently selected.
"Steroid nucleus" means 4 fused rings having the formula 1 structure.
"PEG" means an ethylene glycol polymer that contains about 20 to about 2000000
linked
monomers, typically about 50-1000 linked monomers, usually about 100-300.
Polyethylene glycols
include PEGs containing various numbers of linked monomers, e.g., PEG20,
PEG30, PEG40,
PEG60, PEG80, PEGI00, PEG115, PEG 200, PEG 300, PEG400, PEG500, PEG600, PEG
1000,
PEG1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEGI
1000,
PEG 12000, PEG2000000 and any mixtures thereof.
An "excipient" or a "carrier" means a component or an ingredient that is
acceptable in the
sense of being compatible with the other ingredients of compositions or
formulations as disclosed
herein and not overly deleterious to the patient or animal to which the
formulation is to be
administered. As used here, excipients and carriers include liquids, including
benzyl benzoate,
cottonseed oil, N,N-dimethylacetamide, a CZ.,z alcohol (e.g., ethanol),
glycerol, peanut oil, a PEG,
vitamin E, poFpyseed oil, propylene glycol, safflower oil, sesame oil, soybean
oil and vegetable oil.
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Excipients, as used herein may exclude solvents such as olive oil, chloroform,
dioxane or DMSO.
Excipients comprise one or more components typically used in the
pharmaceutical formulation arts,
e.g., fillers, binders, disintegrants and lubricants.
Unless otherwise specified, expressions that refer to "a formula 1
compounds)", a
"compound of the invention", a "formula 2A or 2B compound", a "plasma
concentration-enhancing
compound" and the like mean compositions or methods, e.g., methods to treat a
togavirus infection
as disclosed herein, where one or more than one formula I or formula 2A or 2B
compound is
present, typically l, 2, 3 or 4, usually 1.
"Alcohol" as used herein, includes excipients, means an alcohol that comprises
a C~.iZ alkyl
moiety substituted at one or more hydrogen atoms with one or more hydroxyl
groups, usually one,
two or three. Alcohols include, e.g., ethanol, n-propanol, i-propanol, n-
butanol, i-butanol, s-
butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexanol, »-
heptanol, n-octanol, n-
nonanol, n-decanol and benzyl alcohol. The carbon atoms in alcohols can be
straight, branehed or
cyclic. Alcohol includes any subset of the foregoing, e.g., Cz.q alcohols
(alcohols !raving 2, 3 or 4
I S carbon atoms).
"Ester" means a moiety that comprises a -C(O)-O- structure. Typically, esters
as used here
comprise an organic moiety containing about I-50 carbon atoms (e.g., about 2-
I2 carbon atoms)
and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si),
where the organic
moiety is bonded to a formula 1 steroid nucleus at RZ through the -C(O~O-
structure, e.g., organic
moiety-C(O~-O-steroid or organic moiety-O-C(O)-steroid. The organic moiety
usually comprises
one or more of any of the organic groups described above, e.g., C,.zo alkyl
moieties, C~.zo alkenyl
moieties, Cz_~o alkynyl moieties, aryl moieties, Cz.9 heterocycles or
substituted derivatives of any of
these, e.g., comprising 1, 2, 3, 4 or more substituents, where each
substituent is independently
chosen. Typical substitutions for hydrogen or carbon atoms in these organic
groups include 1, 2, 3,
4 or more, usually 1, 2, or 3 -O-, -S-, -NRPR- (including -NH-), -C(O)-, =O,
=S, -N(RPR)z (including
-NHZ), -C(O)ORPA (including -C(O)OH), -OC(O)RPR (including -O-C(O)-H), -ORPR
(including -
OH), -SRPR (including -SH), -NOz, -CN, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -
O-A8, -S-A8, -
C(O)-A8, -OC(O)-A8, -C(O)O-A8, =N-, -N=, =N-OH, -OP03(R~R)i, -OS03HZ or
halogen moieties
or atoms, where each RPR is -H, an independently selected protecting group or
both RPR together
comprise a protecting group, and A8 is C,.g alkyl, Ci.e alkenyl, C2.8 alkynyl,
C,_a alkyl-aryl (e.g.,
benzyl), aryl (e.g. phenyl) or Co., alkyl-Cz.9 heterocycle. Substitutions are
independently chosen.
The organic moiety includes compounds defined by the R4 variable. The organic
moieties exclude
obviously unstable moieties, e.g., -O-O-, except where such unstable moieties
are transient species
that one can use to make a compound with sufficient chemical stability for the
one or more of the
uses described herein. The substitutions listed above are typically
substituents that one can use to
replace one or more carbon atoms, e.g., -O- or -C(O)r, or Qne or more hydrogen
atom, e.g., halogen,
-NHz, -OH or =O.
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"Thioester" means a moiety that comprises a -C(S~O- structure. Typically,
thioesters as
used here comprise an organic moiety containing about 1-50 carbon atoms (e.g.,
about 2-12 carbon
atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic
moiety-is bonded to a
formula 1 steroid nucleus at Rl through the -C(S~O- structure, e.g., organic
moiety-C(S}-O-steroid
or organic moiety-O-C(S)-steroid. The organic moiety usually comprises one or
more of any of the
organic groups described above, e.g., C,.zo alkyl moieties, C=.io~alkenyl
moieties, C2_ZO alkynyl
moieties, aryl moieties, Cz.9 heterocycles or substituted derivatives of any
of these, e.g., comprising
1, 2, 3, 4 or more substituents, where each substituent is independently
chosen. Typical
substitutions for hydrogen or carbon atoms in these organic groups include 1,
2, 3, 4 or more,
usually 1, 2, or 3 -O-, -S-, -NRPR- (including -NH-), -C(O)-, =O, =S, -N(RPR)2
(including -NHZ), -
C(O)ORpR (including -C(O)OH), -OC(O)RPR (including -O-C(O)-H), -ORPR
(including -OH), -SRPR
(including -SH), -NOz, -CN, -NHC(O~, -C(O)NH-, -OC(O~, -C(O)O-, -O-A8, -S-A8, -
C(O)-A8,
OC(O)-A8, -C(O)O-A8, =N-, -N=, =N-OH, -OP03(RpR)i, -OS03Hz or halogen moieties
oratoms,
where each RPR is -H, an independently selected protecting group or both R~
together comprise a
protecting group, and A8 is Cr.B alkyl, C,.~ alkenyl, C,.g alkynyl, Cr., alkyl-
aryl (e.g., benryl), aryl
(e.g. phenyl) or Co., alkyl-C2.9 heterocycle. Substitutions are independently
chosen. The organic
moiety includes compounds defined by the R4 variable. The organic moieties
exclude obviously
unstable moieties, e.g., -O-O-, except where such unstable moieties are
transient species that one
can use to make a compound with sufficient chemical stability for the one or
more of the uses
described hqcein. The substitutions listed above are typically substituents
that one can use to
replace one or more carbon atoms, e.g., -O- or -C(O)-, or one or more hydrogen
atom, e.g., halogen,
-NHZ or -OH.
"Thioacetal" means a moiety that comprises a -C(O)-S- structure. Typically,
thioacetals as
used here comprise an organic moiety containing about 1-50 carbon atoms (e.g.,
about 2-12 carbon
atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic
moiety is bonded to a
formula 1 steroid nucleus at R~ through the -C(O)-S- structure, e.g., organic
moiety-C(O}-S-steroid
or organic moiety-S-C(O)-steroid. The organic moiety is as described above for
thioesters.
"Carbamate" means an organic moiety as described for ester that comprises 1,
2, 3, 4 or
more -0-C(O)NR~R- structures where RrR is -I-I, a protecting group or an
organic moiety as
described for ester. Typically, carbamate groups as used here comprise an
organic moiety
containing about 1-SO carbon atoms (e.g., about 2-12 carbon atoms) and 0 to
about 10 heteroatoms
(e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1
steroid nucleus at RZ
through the -O-C(O)-NRPR- structure, e.g., organic moiety-NRpR-C(O)-O-steroid
or organic moiety-
O-C(O)-NRPR-steroid. The organic moiety is as described above for thioesters.
"Sulfate ester" means a moiety that comprises a -O-S(O)(O)-O- structure.
Typically,
sulfate esters as used here comprise an organic moiety containing about 1-50
carbon atoms (e.g.,
about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si),
where the organic
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moiety is bonded to a formula I steroid nucleus at R~ through the -O-S(O)(Or0-
stnteture, e.g.,
organic moiety-O-S(O)(O)-O-steroid. The organic moiety is as described above
for thioesters
"Sulfite ester" means a moiety that comprises a -O-S(O)-O- structure.
Typically, sulfite
esters as used here comprise an organic moiety containing about 1-50 carbon
atoms (e.g., about 2-
12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where
the organic moiety is
bonded to a formula I steroid nucleus at R2 through the -O-S(O)-O- structure,
e.g., organic moiety-
' O-S(O)-O-steroid. The organic moiety is as described above for thioesters.
The compositions disclosed herein optionally comprise salts of the formula 1
and 2
compounds that comprise an ionizable moiety or a polar moiety. As used herein,
"salts" include
complexes that comprise moieties of opposite charge. Ionizable moieties
include -O-S(O)(O)-OH
or an -NH2 group at Ri and polar moieties include -OH. Salts include
pharmaceutically acceptable
salts that comprise, for example, an uncharged moiety or a monovalent anion
moiety or a
monovalent cation moiety. Salts include compounds derived by combination of
appropriate anions
such as inorganic acids. Suitable acids include those having sufficient
acidity to form a stable salt,
preferably acids of low toxicity. For example, one may form invention salts
from acid addition of
certain inorganic acids, e.g., HF, HCI, HBr, HI, H2S04~ H3P04, to basic
centers, typically amines
that may be present in formula I, 2A or 2B compounds. Or one may use certain
organic acids, e.g.,
organic sulfonic acids, organic carboxylic acids in the same manner. Exemplary
organic sulfonic
acids include C6_16 aryl sulfonic acids, C6_16 heteroaryl sulfonic acids and
C1_16 alkyl sulfonic
acids such a~ phenyl, a-naphthyl, ~naphthyl, (,S~-camphor, methyl, ethyl, n-
propyl, i-propyl, n-
butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids. Exemplary
organic carboxylic acids
include C1-16 alkyl, C6_16 aryl carboxylic acids and C4_16 heteroaryl
carboxylic acids such as
acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric,
fumaric, succinic, malic, malefic,
hydroxymaleic, benzoic, hydroxybenzoic, phenyiacetic, cinnamic, salicylic and
2-phenoxybenzoic.
Salts also include the invention compound salts with one or more amino acids.
Many amino acids
are suitable, especially the naturally occurring amino acids found as protein
components, although
the amino acid typically is one bearing a side chain with a basic or acidic
group, e.g., lysine,
arginine or glutamic acid, or a neutral group such as glycine, serine,
threonine, alanine, isoleucine,
or Ieucine. Salts are usually biologically compatible or pharmaceutically
acceptable or non-toxic,
particularly for mammalian cells. Salts that are biologically toxic are
generally used as synthetic
intermediates for making other invention compounds.
The neohesperidoside, rutinoside and glucoside groups have the structures
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CH~OH '
CHZOH
O O-
OH
HO
OH , respectively
wherein .one or more of the hydrogen atoms are optionally independently
substituted with hydroxy,
halogen, C,_6 alkyl, C,.~ alkoxy, glucuronide or a C,.25 fatty acid.
Heterocvcle. "Heterocycle" or "heterocyclic" includes by way of example and
not.
limitation these heterocycles described in Paquette, Leo A.; "Principles of
Modern Heterocyclic
Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6,
7, and 9; "The
Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley &
Sons, New York,
1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am.
Chem. Soc. 1960,
82:5566; and U.S. patent 5763483, all of which are incorporated herein by
reference.
Examples of heterocycles include by way of example and not limitation pyridyl,
thiazolyl,
tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,
furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl,
indolenyl, quinolinyl,
isoquinolinyl, benzimidazolyl, piperidinyi, 4-piperidonyl, pyrrolidinyl, 2-
pyrrolidonyl, pyrrolinyl,
tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl,
1 S octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-
1,5,2dithiazinyl, thienyl,
thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl,
2H-pynrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indoiizinyl, isoindolyl, 3H-
indolyl, 1H-indazoly,
purinyl, 4H-quinolizinyl, phthalazinyi, naphthyridinyl, quinoxalinyl,
quinazolinyl, cinnolinyl,
pteridinyl, 4aH-carbazolyl, carbazolyl, (3-carbolinyl, phenanthridinyl,
acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl,
isochromanyl, chromanyl,
imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyi, piperazinyl,
indolinyl, isoindolinyl,
quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyt,
oxindolyl,
benzoxazolinyl, and isatinoyl.
By way of example and not limitation, carbon bonded heterocycles are bonded at
position
2S 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine,
position 2, 4, S, or 6 of a
pyrimidine, position 2, 3, S, or 6 of a pyrazine, position 2, 3, 4, or S of a
furan, tetrahydrofuran,
thiofuran, thiophene, pyrrole or tetrahydropyrrole, position,2, 4, or 5 of an
oxazole, imidazole or
thiazofe, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,
position 2 or 3 of an aziridine,
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WO 00/32177 PCT/US99/28082
position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a
quinoline or position 1, 3, 4, 5, 6,
7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles
include 2-pyridyl, 3-
pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, S-
pyridazinyl, 6-pyridazinyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-
pyrazinyl, 5-pyrazinyl,
6-pyrazinyl, 2-thiazolyl, 4-thiszolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded
at position
- _ 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-
pyrroline, imidazole, imidazolidine,
2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-
pyrazoline, piperidine,
piperazine, indole, indoline, 1 H-indazole, position 2 of a isoindole, or
isoindoline, position 4 of a
morpholine, and position 9 of a carbazole, or ~carbolinc. Typically, nitrogen
bonded heterocycles
include I-aziridyl, I-azetedyl, 1-pyrrolyl, I-imidazolyl, I-pyrazolyl, and 1-
piperidinyl.
"Heteroaryl" means an aromatic ring or two or more fused rings that contain
one or more
aromatic rings where the ring or fused rings comprise 1, 2, 3 or more
heteroatoms, usually'bxygen
(-O-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a protecting group or
C,~ alkyl, usually -H.
Examples are as described for heterocycle. ,
Protecting ltrouns. Various groups that the formula 1, 2A or 2B compounds may
comprise
include, e.g., substituted alkyl groups, substituted alkenyl groups, esters or
substituted heterocycles,
which can contain one or more reactive moieties such as hydroxyl, or thiol.
Intermediates used to
make formula 1 or formula 2A or 2B compounds may be protected as is apparent
in the art.
Noncyclic amid cyclic protecting groups and corresponding cleavage reactions
are described in
"Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley &
Sons, Inc., New
York, 1991, ISBN 0-471-62301-6) (hereafter "Greene"). In the context of the
present invention,
these protecting groups are groups that can be removed from the molecule of
the invention without
irreversibly changing the covalent bond structure or oxidationlreduction state
of the remainder of
the molecule. For example, the protecting group, -X, that is bonded to a -OX
or -NHX group can
be removed to form -OH or -NHz, respectively, without affecting other covalent
bonds in the
molecule. At times, when desired, more than one protecting group can be
removed at a time, or
they can be removed sequentially. In compounds of the invention containing
more than one
protecting group, the protecting groups are the same or different.
Protecting groups are intended to be removed by known procedures, although it
will be
understood that the protected intermediates fall within the scope of this
invention. The removal of
the protecting group may be arduous or straightforward, depending upon the
economics and nature
of the conversions involved. In general, one will use a protecting group with
exocyclic amines or
with carboxyl groups during synthesis of a formula I compound. Por most
therapeutic applications
amine: groups should be deprotectcd. Protccling groups commonly are employed
to protect against
covalent modification of a sensitive group in reactions such as alkylation or
acylation. Ordinarily,
protecting groups are removed by, e.g. hyd: olysis, elimination or aminolysis.
Thus, simple
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WO 00/32177 PCT/US99/28082
functional considerations will suffice to guide the selection o: a reversible
or an irreversible
protecting group at a given locus on the invention compounds. Suitable
protecting groups and
criteria for their selection are described in T.W. Greene and P.G.M. Wuts,
Eds. "Protective Groups
in Organic Synthesis" 2nd edition, Wiley Press, at pps. 10-142, 143-174, 175-
223, 224-276, 277-
S 308, 309-405 and 406-454, which is incorporated herein by reference.
Determination of whether a group is a protecting group is made in the
conventional
manner, e.g., as illustrated by Kocienski, Philip J.; "Protecting Groups"
(Georg Thieme Verlag
Stuttgart, New York, 1994) (hereafter "Kocienski"), Section 1.1, page 2, and
Greene Chapter 1,
pages 1-9; and U.S. patent 5763483, all of which are incorporated herein by
reference. In
particular, a group is a protecting group if when, based on mole ratio, 90% of
that protecting group
has been removed by a deprotection reaction, no more than 50%, preferably 25%,
more preferably
10%, of the deprotected product molecules of the invention have undergone
changes to their
covalent bond structure or oxidation/reduction state other than those
occasioned by the removal of
the protecting group. When multiple protecting groups of the same type are
present in the molecule,
I S the mole ratios are determined when all of the groups of that type are
removed. When multiple
protecting groups of different types are present in the molecule, each type of
protecting group is
treated (and the mole ratios are determined) independently or together with
others depending on
whether the deprotection reaction conditions pertinent to one type are also
pertinent to the other
types present. In one embodiment of the invention, a group is a protecting
group if when, based on
mole ratio detenmined by conventional techniques, 90% of that protecting group
has been removed
by a conventional deprotection reaction, no more than 50%, preferably 25%,
more preferably 10%,
of the deprotected product molecules of the invention have undergone
irreversible changes to their
covalent bond structure or oxidation/reduction state other than those
occasioned by the removal of
the protecting group. Irreversible changes require chemical reactions (beyond
those resulting from
aqueous hydrolysis, acid/base neutralization or conventional separation,
isolation or purification) to
restore the covalent bond structure or oxidation/reduction state of the
deprotected molecule of the
invention.
Protecting groups are also described in detail together with general concepts
and specific
strategies for their use in Kocienski, Philip J.; "Protecting Groups" (Georg
Thieme Verlag Stuttgart,
New York, 1994), which is incorporated by reference in its entirety herein. In
particular Chapter 1,
Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting
Groups, pages 21-94,
Chapter 3, Diol Protecting Groups, pages 95-I 17, Chapter 4, Carboxyl
Protecting Groups, pages
118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184, Chapter 6,
Amino Protecting
Groups, pages 185-243, Chapter 7, Epilog, pages 244-252, and Index, pages 253-
260, are
incorporated with specificity in the context of their contents. More
particularly, Sections 2.3 Silyl
Ethers, 2.4 Alkyl Ethers, 2.5 Alkoxyalkyl Ethers (Acetals), 2.6 Reviews
(hydroxy and thiol
protecting groups), 3.2 Acetals, 3.3 Silylene Derivatives, 3.4 1,1,3,3-
Tetraisopropyldisiloxanylidene
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Derivatives, 3.5 Reviews (diol protecting groups), 4.2 Esters, 4.3 2,6,7-
Trioxabicyclo[2.2.2]octaves
[OBO] and Other Ortho Esters, 4.4 Oxazofines, 4.5 Reviews (carboxyl protecting
groups), 5.2 O,O-
Acetals, 5.3 S,S-Acetals, 5.4 O,S-Acetals, 5.5 Reviews (carbonyl protecting
groups); 6.2 N-Acyl
Derivatives, 6.3 N-Sulfonyl Derivatives, 6.4 N-Sulfenyl Derivatives, 6.5 N-
AIkyI Derivatives, 6.6
N-Silyl Derivatives, 6.7 Imine Derivatives, and 6.8 Reviews (amino protecting
groups), are each
incorporated with specificity where protection/deprotection of the requisite
funetionalities is
discussed. Further still, the tables "Index to the Principal Protecting
Groups" appearing on the
inside front cover and facing page, "Abbreviations" at page xiv, and "reagents
and Solvents" at page
xv are each incorporated herein at this location.
Typical hydroxy protecting groups are described in Greene at pages 14-118 and
include
Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-
Butylthiomethyl,
(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-Methoxybenzyloxymethyl,
(4-
Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl, 4-Pentenyloxymethyl,
Siloxymethyl,
2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl,
2-
(Trimethylsilyl}ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl,
Tetrahydropthiopyranyl, 1-Methoxycyclohexyf, 4-methoxytetrahydropyranyl, 4-
Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl S,S-Dioxido, 1-
[(2-Chloro-4-
methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-Dioxan-2-yl, Tetrahydrofuranyl,
Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-
methanobenzofuran-2-yl);
Substituted )ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl, 1-Methyl-1-
methoxyethyl, 1-
Methyl-I-benryloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-
Trichloroethyl, 2-
Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl, p-Chlorophenyl, p-
Methoxyphenyl, 2,4-
Dinitrophenyl, Benzyl); Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-
Dimethoxybenzyl, o-
Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl, p-
Phenylbenzyl, 2-
and 4-Picolyl, 3-Methyl-2-picoiyl N-Oxido, Diphenylmethyl, p, p'-
Dinitrobenzhydryl, 5-
Dibenzosuberyl, Triphenylmethyl, alpha-Naphthyldiphenylmethyl, p-
methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Trip-
methoxyphenyl)methyl,
4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4', 4"-Tris(4,5-
dichlorophthalimidophenyl)methyl, 4,4', 4"-Tris(Ievulinoyloxyphenyl)methyl,
4,4', 4"-
Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4', 4"-
dimethoxyphenyl)methyl, 1,1-
Bis(4-methoxyphenylrl'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9-
Phenyl-10-
oxo)anthryl, 1,3-Bcnzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl
Ethers (Trimethylsilyl,
Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl,
Diethylisopropylsily, Dimethylthexylsilyl,
t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl,
Triphenylsilyl,
Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl); Esters (Fonnate,
Benzoylformate, Acetate,
Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,
Methoxyacetate,
Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-
Phenylacetate, 3-
1G
CA 02352205 2001-05-23
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Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4-
(Ethylenedithio)pentanoate, Pivaloate,
Adainantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-
Trimethylbenzoate (Mesitoate); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,
2,2,2
Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl~thyl, 2-
(Triphenylphosphonio)ethyl,
Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-
Dimethoxybenzyl, o-
Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate, 4-Ethoxy~l-naphthyl,
Methyl
Dithiocarbonate); Groups With Assisted Cleavage (2-Iodobenzoate,;4-
Azidobutyrate, 4-Nitro-4-
methylpentanoate, o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate, 2-
(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate, 2-
(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters (2,6-Dichloro-4-
methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-Bis(I,1-
dimethylpropyl)phenoxyacetate, Chorodiphenylacetate, Isobutyrate,
Monosuccinoate, (E)-2-
Methyl-2-butenoate (Tigloate), o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, a-
Naphtheate,
Nitrate, Alkyl N,N,N', N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate,
Borate,
Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate,
Methanesulfonate
(Mesylate), Benzylsulfonate, Tosylate).
More typically hydroxy protecting groups include subtituted methyl ethers,
substituted
benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still
more typically, trialkylsilyl
ethers, tosylates and acetates.
Typ9oal 1,2- and 1,3-diol protecting groups are described in Greene at pages I
18-t42 and
include Cyclic Acetals and Ketals (Methylene, Ethylidene, I-t-Butylethylidene,
I-Phenylethylidene,
(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide
(Isopropylidene),
Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-
Methoxybenzylidene, 2,4-
Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic
Ortho Esters
(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-
Ethoxyethylidine, 1,2-Dimethoxyethylidene, alpha-Methoxybenzylidene, 1-(N,N-
Dimethylamino)ethylidene Derivative, alpha-(N,N-Dimethylamino)benzylidene
Derivative, 2-
Oxacyclopentylidene); and Silyl Derivatives (Di-t-butylsilylene Group, 1,3-
(1,1,3,3-
'fetraisopropyldisiloxanylidcne) Derivative, Tetra-t-butoxydisiloxane-1,3-
diylidene Derivative,
Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate, Phenyl Boronate).
More typically, 1,2- and 1,3-diol protecting groups include epoxides and
acetonides.
Typical amino protecting groups are described in Greene at pages 315-385 and
include
Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl, 9(2-Sulfo)fluoroenylmethyl, 9-
(2,7-
Dibromo)fluorenylmethyl, 2,7-Di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-
tetrahydrothioxanthyl)]methyl, 4-Methoxyphenacyl); Substituted Ethyl (2,2,2-
Trichoroethyl, 2-
Trimethylsilylethyl, 2-Phenylethyl, t-(1-Adamantyl)-1-methylethyl, 1,1-
Dimethyl-2-haloethyl, 1,1-
Dimethyl-2,2-dibromoethyl, I,I-Dimethyl-2,2,2-trichloroethyl, I-Methyl-1-(4-
biphenylyl;ethyl, 1-
17
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WO 00/32177 PCT/US99/28082
(3,5-Di-t-butylphenyl~ 1-methylethyl, 2-(2'- and 4'-Pyridyl)ethyl, 2-(N,N-
Dicyclohexylcarboxamido)ethyl, t-Butyl, 1-Adamantyl, Vinyl, Allyl, 1-
Isopropylallyl, Cinnamyl, 4-
Nitrocinnamyl, 8-Quinolyl, N-Hydroxypiperidinyl, Alkyldithio, Benryl, p-
Methoxybenzyl, p-
Nitrobenzyl, p-Bromobenzyl, p-Chorobenryl, 2,4-Dichlorobenzyl, 4-
Methylsulfinylbenzyl, 9-
Anthrylmethyl, Diphenylmethyl); Groups With Assisted Cleavage (2-
Methylthioethyl, 2-
Methylsulfonylethyl, 2-(p-Toluenesulfonyl)ethyl, [2-(1,3-Dithianyl)]methyl, 4-
Methylthiophenyl,
2,4-Dimethylthiophenyl, 2-Phosphonioethyl, 2-Triphenylphosphonioisopropyl, I,1-
Dimethyl-2-
cyanoethyl, m-Choro-p-acyioxybenzyl, p-(Dihydroxyboryl)benzyl, 5-
Benzisoxazolylmethyl, 2-
(Trifluoromethyl)-6-chromonylmethyl); Groups Capable of Photolytic Cleavage (m-
Nitrophenyl,
3,5-Dimethoxybenzyl, o-Nitrobenzyl, 3,4-Dimethoxy-6-nitrobenryl, Phenyl(o-
nitrophenyl)methyl);
Urea-Type Derivatives (Phenothiazinyl-(l0~carbonyl Derivative, N'-p-
Toluenesulfonylaminocarbonyl, N'-Phenylaminothiocarbonyl); Miscellaneous
Carbamates (t-Amyl,
S-Benzyl Thiocarbamate, p-Cyanobenzyl, Cyclobutyl, Cyclohexyl, Cyclopentyl,
Cyclopropylmethyl, p-Decyloxybenzyl, Diisopropylmethyl, 2,2-
Dimethoxycarbonylvinyl, o-(N,N-
Dimethylcarboxamido)benzyl, 1,1-Dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-
Dimethylptopynyl, Di(2-pyridyl)methyl, 2-Furanylmethyl, 2-Iodoethyl,
Isobornyl, Isobutyl,
Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-Methylcyclobutyl, 1-
Methylcyclohexyl, 1-Methyl-
I-cyclopropylmethyl, 1-Methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-Methyl-I-(p-
phenylazophenyl)ethyl, I-Methyl-1-phenylethyl, I-Methyl-1-(4-pyridyl)ethyl,
Phenyl, p-
(Phenylazo)benzyl, 2,4,6-Tri-t-butylphenyl, 4-(Trimethylammonium)benzyl, 2,4,6-
Trimethylbenzyl); Amides (N-Fonnyl, N-Acetyl, N-Choroacetyl, N-Trichoroacetyl,
N-
Trifluoroacetyl, N-Phenylacetyl, N-3-Phenylpropionyl, N-Picolinoyl, N-3-
Pyridylcarboxamide, N-
Benzoylphenylaianyl Derivative, N-Benzoyl, N-p-Phenylbenzoyl); Amides With
Assisted Cleavage
(N-o-Nitrophenylacetyl, N-o-Nitrophenoxyacetyl, N-Acetoacetyl, (N'-
Dithiobenzyloxycarbonylamino)acetyl, N-3-(p-Hydroxyphenyl)propionyl, N-3-(o-
Nitrophenyl)propionyl, N-2-Methyl-2-(o-nitrophenoxy)propionyl, N-2-Methyl-2-(0-
phenylazophenoxy)propionyl, N-4-Chlorobutyryl, N-3-Methyl-3-nitrobutyryl, N-o-
Nitrocinnamoyl,
N-Acetylmethionine Derivative, N-o-Nitrobenzoyl, N-o-
(Benzoyloxymethyl)benzoyl, 4,5-
Diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-Phthalimide, N-
Dithiasuccinoyl, N-2,3-
Diphenylmaleoyl, N-2,5-Dimethylpyrrolyl, N-1,1,4,4-
Tetramethyldisilylazacyclopentane Adduct,
5-Substituted 1,3-Dimethyl-1,3,5-triazacyclohexan-2-one, 5-Substituted 1,3-
Dibenzyl-1,3,5-
triazacyclohexan-2-one, 1-Substituted 3,5-Dinitro-4-pyridonyl); N-Alkyl and N-
Aryl Amines (N-
Methyl, N-Allyl, N-[2-(Trimethylsilyl)ethoxy]methyl, N-3-Acetoxypropyl, N-(1-
Isopropyl-4-nitro-
2-oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-Benzyl, N-Di(4-
methoxyphenyl)methyl,
N-5-Dibenzosuberyl, N-Triphenylmethyl, N-(4-Methoxyphenyl)diphenylmethyl, N-9-
Phenylfluorenyl, N-2,7-Dichloro-9-fluorenylmethylene, N-Ferrocenylmethyl, N-2-
Picolylamine N'-
Oxide); Irvine Derivatives (N-1,1-Dimethylthiomethylene, N-Benzylidene, N-p-
18
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methoxybenylidene, N-Diphenylmethylene, N-[(2-Pyridyl)mesityl]methylene,
N,(N',N'-
Dimethylaminomethylene, N,N'-Isopropylidene, N-p-Nitrobenzylidene, N-
Salicylidene, N-5-
Chlorosalicylidene, N-(5-Chloro-2-hydroxyphenyl)phenylmethylene, N-
Cyclohexylidene);
Enamine Derivative (N-(5,5-Dimethyl-3-oxo-1-cyclohexenyl)); N-Metal
Derivatives (N-Borane
Derivatives, N-Diphenylborinic Acid Derivative, N-
[Phenyl(pentacarbonylchromium- or -
tungsten)Jcarbenyl, N-Copper or N-Zinc Chelate); N-N Derivatives (N-Nitro, N-
Nitroso, N-Oxide);
' _ N-P,Derivatives (N-Diphenylphosphinyl, N-Dimethylthiophosphinyl, N-
Diphenylthiophosphinyl,
N-Dialkyl Phosphoryl, N-Dibenzyl Phosphoryl, N-biphenyl Phosphoryl); N-Si
Derivatives; N-S
Derivatives; N-Sulfenyl Derivatives (N-Benzenesulfenyl, N-o-
Nitrobenzenesulfenyl, N-2,4-
Dinitrobenzenesulfenyl, N-Pentachlorobenzenesulfenyl, N-2-nitro-4-
methoxybenzenesulfenyl, N-
Triphenyimethylsulfenyl, N-3-Nitropyridinesulfenyl); andN-Sulfonyl Derivatives
(N-p-
Toluenesulfonyl, N-Benzenesulfonyl, N-2,3,6-Trimethyl-4-
methoxybenzenesulfonyl, N-2,4,6-
Trimethoxybenzenesulfonyl, N-2,6-Dimethyl-4-methoxybenzenesulfonyl, N-
Pentamethylbenzenesulfonyl, N-2,3,5,6; 'fetramethyl-4-methoxybenzenesulfonyl,
N-4-
methoxybenzenesulfonyl, N-2,4,6- Trimethylbenzenesulfonyl, N-2,6-Dimethoxy-4-
methylbenzenesulfonyl, N-2,2,5,7,8-Pentamethylchroman-6-sulfonyl, N-
Methanesulfonyl, N-.beta.-
Trimethylsilyethanesulfonyl, N-9-Anthracenesulfonyl, N-4-(4', 8'-
Dimethoxynaphthylmethyl)benzenesulfonyl, N-BenzylsulfonyI, N-
Trifluoromethylsulfonyl, N-
Phenacylsulfonyl).
Mode typically, amino protecting groups include carbamates and amides, still
more
typically, N-acetyl groups.
Stereoisomers. The formula 1 and formula 2A or 2B compounds include enriched
or
resolved optical isomers at any or all asymmetric atoms as are apparent from
the depictions. Both
racemic and diasteromeric mixtures, as well as the individual optical isomers
can be isolated or
synthesized so as to be substantially free of their enantiomeric or
diastereomeric partners, and these
are all within the scope of the invention. Chiral centers may be found in
invention compounds at,
for example, Rl, R2 or R4.
One or more of the following methods are used to prepare the enantiomerically
enriched or
pure isomers herein. The methods are listed in approximately their order of
preference, i.e.; one
ordinarily should employ stereospecific synthesis from chiral precursors
before chromatographic
resolution before spontaneous crystallization.
Stereospecific synthesis is described in the examples. Methods of this type
conveniently
are used when the appropriate chiral starting material is available and
reaction steps are chosen that
do not result in undesired racemization at chiral sites. One advantage of
stereospecific synthesis is
that it does not produce undesired enantiomers that must be removed from the
final product, thereby
lowering overall synthetic yield. In general, those skilled.in the art would
understand what starting
19
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materials and reaction conditions should be used to obtain the desired
enantiomerically enriched or
pure isomers by stereospecific synthesis.
If a suitable stereospecific synthesis cannot be empirically designed or
determined with
routine experimenr<ltion then those skilled in the art would turn to other
methods. One method of
general utility is chromatographic resolution of enantiomers on chiral
chromatography resins.
These resins are packed in columns, commonly called Pickle columns, and are
commercially
available. The columns contain a chiral stationary phase. The racemate is
placed in solution and
loaded onto the column, and thereafter separated by HPLC. See for example,
Proceedings
Chromatographic Society - International Symposium on Chiral Separations, Sept.
3-4, 1987, which
is incorporated herein by reference. Examples of chiral columns that could be
used to screen for the
optimal separation technique would include Diacel Chriacel OD, Regis Pickle
Covalent D-
phenylglycine, Regis Pickle Type lA, Aster Cyclobond II, Aster Cyclobond III,
Serva Chiral D-
DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate
column,
Aster Cyclobond 1-Beta, or Regis Pickle Covalent D-Naphthylalanine. Not all of
these columns are
likely to be effective with every racemic mixture. However, those skilled in
the art understand that
a certain amount of routine screening may be required to identify the most
effective stationary
phase. When using such columns it is desirable to employ embodiments of the
compounds of this
invention in which the charges are not neutralized, e.g., where acidic
functionalities such as
carboxyl are not esterified or amidated.
An4ther method entails converting the enantiomers in the mixture to
diasteriomers with
chiral auxiliaries and then separating the conjugates by ordinary column
chromatography. This is a
very suitable method, particularly when the embodiment contains a free
hydroxyl that will form a
salt or covalent bond to a chiral auxiliary. Chirally pure amino acids,
organic acids or
organosulfonic acids are all worthwhile exploring as chiral auxiliaries, all
of which are well known
in the art. Salts with such auxiliaries can be formed, or they can be
covalently (but reversibly)
bonded to the functional group.
Enzymatic resolution is another method of potential value. In such methods one
prepares
covalent derivatives of the enantiomers in the racemic mixture, generally
lower alkyl esters, and
then exposes the derivative to enzymatic cleavage, generally hydrolysis. For
this method to be
successful an enzyme must be chosen that is capable of stereospecific
cleavage, so it is frequently
necessary to routinely screen several enzymes. If esters are to be cleaved,
then one selects a group
of esterases, phosphatases, and lipases and determines their activity on the
derivative. Typical
esterases are from liver, pancreas or other animal organs, and include porcine
liver esterase.
If the enantiomeric mixture separates from solution.or a melt as a
conglomerate, i.e., a _
mixture of enantiomerically pure crystals, then the crystals can be
mechanically separated, thereby
producing the enantiomerically enriched preparation. This method, however, is
not practical for
large-scale preparations and is of limited value for true racemic compounds.
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Asymmetric synthesis is another technique for achieving enantiomeric
enrichment. For
example, a chiral protecting group is reacted with the group to be protected
and the reaction mixture
allowed to equilibrate. If the reaction is enantiomerically specific then the
product will be enriched
in that enantiomer.
Further guidance in the separation of enantiomeric mixtures can be found, by
way of
example and not limitation, in "Enantiomers, Racemates, and resolutions", Jean
Jacques, Andre
' _ Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL,
1991, ISBN 0-89464-
618-4): Part 2, Resolution of Enantiomer Mixture, pages 217-435; more
particularly, section 4,
Resolution by Direct Crystallization, pages 217-251, section 5, Formation and
Separation of
Diastereomers, pages 251-369, section 6, Crystallization-Induced Asymmetric
Transformations,
pages 369-378, and section 7, Experimental Aspects and Art of Resolutions,
pages 378-435; still
more particularly, section 5.1.4, Resolution of Alcohols, Transformation of
Alcohols into Salt-
Forming Derivatives, pages 263-266, section 5.2.3, Covalent Derivatives of
Alcohols, Thiols, and
Phenols, pages 332-335, section 5.1.1, Resolution of Acids, pages 257-259,
section 5.1.2,
Resolution of Bases, pages 259-260, section 5.1.3, Resolution of Amino Acids,
page 261-263,
section 5.2.1, Covalent Derivatives of Acids, page 329, section 5.2.2,
Covalent derivatives of
Amines, pages 330-331, section 5.2.4, Covalent Derivatives of Aldehydes,
Ketones, and
Sulfoxides, pages 335-339, and section 5.2.7, Chromatographic Behavior of
Covalent
Diastereomers, pages 348-354, all of which are incorporated herein by
reference.
Emjiodiments include compositions that transiently occur when a method step or
operation
is performed. For example, when a formula 1 compound is contacted with an
excipient, e.g., water,
a cyclodextrin, a PEG, an alcohol, propylene glycol, benzyl alcohol or benzyl
benzoate, the
composition before addition of one ingredient with another is a non-homogenous
mixture. As the
ingredients are contacted, the mixture's homogeneity increases and the
proportion of ingredients
relative to each other approaches a desired value. Thus, some compositions as
disclosed herein,
optionally contain less than about 3% w/w water, e.g., less than 0.5% w/w
water, can comprise
about 0.0001-99% w/w of a formula 1 compound SIICh aS 16a-hromoepiandrosterone
and one or
more excipients. These transient compositions are intermediates that
necessarily arise when one
makes an invention composition or formulation and they are included in
invention embodiments to
the extent that they are patentable.
Formula 1 compounds. The formula 1 comQounds, or the "compounds of the
invention",
are useful to treat a subject having, or prevent infection of a subject with,
one or more togaviruses.
Togaviruses, as used herein includes the Togaviridae family, including the
Alphavirus and
Rubivirus genera, as welt as the flavivirus family (Flaviviridae) and the
Flavivirus and Pestivirus
genera. A review of virus taxonomy and the biology of these viruses may be
found at, e.g., B.N.
Fields, et al., editors, Fundamental Virology, 3'd edition, 1996, Lippencott-
Raven Publishers,
chapter 1 (pages 15-58) and chapter 17 (pages 523-54J), which is incorporated
herein by reference.
21
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_ For preferred formula t compounds, the Ri moiety bonded to the steroid ring
is generally in _
the ~i configuration, two Rl are bonded to QI and X is a double bonded oxygen
moiety (-0).
Typically, one of the R, bonded to QZ is hydrogen in the (3 configuration, the
other Ri bonded to QZ
is hydrogen or a halogen, usually bromine, in the a configuration and a double
bond is present at
the 5-6 positions. Such prefen;ed compounds include dehydroepiandrosterone
("DHEA") and 16a-
bromodehydroepiandrosterone ("Br-DHEA").
Other preferred formula 1 compounds include 17-ketosteriods of formula 1 where
a double
bond is present at the 5-6 positions, X is =O, Qi is -CHZ- or -CHBr-, RZ is -
H, -S(O)(O~OH, -
S(O)(O)-ONa, -S(O)(O~O-CHZ-CH(O-C(O)-R6)-CHZ-O-C(O~R6 (where R6 independently
is C,_"
straight or branched alkyl), -P(O)(O~O-CHz-CH(O-C(O)RD)-CHI-O-C(O~R~ (where R~
independently is a glucuronide group or C,.~4 straight or branched alkyl) or
R2 is a glucuronide
group. Other preferred compounds include compound having the structures 20-43
RI R~ X R~ R~ X
Rt Ds Ri R~ Qs
R~ R~ R' R
R~ R~ R~ R, R~ R'
R~ Q3 R~ R~ D3 R~
R~ R~ ~R~ R~ Rr ~R
Rz R~ R~ Rz .R~ R> >
Ri x I ~ \ _Rt R~ ~ I ~ ~ wRt
R~ R~ / 'R R~ Rt R~
t~R~ R~ ~ R~ R~ R~ R~
21
R~ R' X R~ R~ X
R~ Ds Ri R~ Ds
R~ Y R~
R' R~ R1 R, R~ R, Y
R~ D3 R~ R~ G13 R~
R~ R~ ~ Rr R'
~R R~ ~ R~
Rz ~ R~ Rz R' R~
R~ ~ I ~ \ ,R~ R~ ~ I ~ ~~R~
R~ R~ R~ R~
R~ R~ R~ Rt R~ R~ R~ R~
22 23
22
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2001-05-23
WO 00/321 77 PCT/US99l18082
R
R~ ~ X R~ X
R~
R~ Ds R~ Rt Qe
R~ R~
Rt R~ Rt R~
R~ R~
R~ Y R Y
A3
R~ R~ ~R R~ R~ ~
R ~ R~
RZ ~ R' R2 ~ R' R1
w
R~ ~ ~ R~ R~ ~ ~ ~
_ ! R~
. R R~ R~ R~
R R R
R
~ ~ ~ R~ R~
~ R~
~
24 25
R~ R~ X
R~ QeR~ R~ X
R~
R~ R~
R Rt R~
~
R~ R~ R R~
R~ Q R ~
R
3 R~ R, ~
~ ~
R~ R ~ Q3 Rt
\ ''
R2 R~ R~ R~ R ~ ~R
1R - ~
~
~ RZ R~ R,
R1 R1 \
R R~ R~ ~ R~
~ ~ R
R' , '
R~ Rt R~
R~
26 2~
R~ Rt X
R~ Q eR~
R~
Y
Rt R't r
Rt
R~ Q3 R~
R~ R ~ R~
R
RZ R' R~
~
R~ ~ ~
,
R~
~ R~
R~ R'
R
28 29
23
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WO 00/3217 7 PCT/US99/28082
R '
Rt ~ X R~R~
R~ Qs R~ R~ Q s X
R, R
R~ R~.
R~ ~ R' ~
R~ QR Y R~ QR Y
R1 R~~ Rt R '
v R~ \ R~
R2 R~ R Rz R~ R
~ ~ ~ ~
R~ ~ ~ R~ ~ ~
R~ ~R~
_ ~ R~ ~ R~
R~ R~ R~ R~
R, R
30 31
R~ R~ X R~R~ X
Rt Q s R~ R~ Qs
R~ R~
R~ R~ R R~
R~ R~ R~ ~
R~
R~ Q R R~ 'R
~
3 Qs ~
R~ R t ~ R~ R~~
R~ R~
Rz R' R~ R2 R' R~
R I ~O
R~ ~ ~ \O ~ ~
R~ R~
R~ R~ R~ R~ R~
Rt R~
R~
32 33
_ o R'R~ X
R~ Q s
R~
Y
R'
R~ R~
R~ R ~ R~
t
Qs
R~ R ~ _
1 R
'
RZ R~ Rt
R
O
R
rctR~ R~ R~ R~
R~ R~
rc~
34 35
24
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WO 00/32177 PCT/US99/28082
_ Kt X
Rt "t Rt -
C18 Kt
X
Rt
Rt
08
Rt Rt
Rt Rt Rt Y Y
Rt Rt
Rt
Rt
~
Rt
~3 C ~3
~\ i
R2 Rt Rt h
RZ R
\
_Rt
R R R
Rt I ~~O Rt ~O
I
_ Rt Rt
Rt Rt Rt Rt
Rt Rt
Rt
Rt
36 37
Rt X
Rt Rt Rt
Ds Rt
X
Rt
Rt
Qs
Rt Rt
Rt Rt Rt Rt
Rt Rt
Rt
Rt
Rt Rt \
\ Rt
Rt
Gds
Rt Rt ~ ~
Rt Rt
Rt ,
_Rt
Rz ~ Rt Rt ~ Rt
R2 Rt
Rt ~ ~
~ w
w0 Rt
\O
~
~
Rt Rt Rt R
t
t
38 39
_
n
Y
tt
Ht Rt Rt
40 41
Rt R~ R~ 08 X R R Rt R~ ~ X
- t s
Rt Rt
Rt Rt Rt Rt Y R Rt Rt Rt
Q3 t Q3
Rt Rt ~ Rt Rt
w Rt \ Rt
R2 ~ Rt Rt R2 ~ Rt Rt
Rt ~ ~ ~~O Rt -~ ~ ~O
Rt Rt Rt Rt Rt Rt
CA 02352205 2001-05-23
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. 42 43
wherein for each of structures 20-43
Q3 and Q6 are each -C(Ri)3 wherein each R, is independently selected;
X and Y independently are -OH, -H, lower alkyl (e.g., C,.~ alkyl), -C(Or0-Rs, -
O-C(O~Rs,
halogen or, X and Y together with the R, at the same position independently
are a ketone (=O);
each R, is independently selected and has the definition given above; and
Ri has the definition given above.
In some embodiments, the formula 1 compound has the structure 20-43 and 2, 3,
4, 5 or 6
R, groups independently are -OH, halogen or alkoxy, and the remaining R, are
a1I hydrogen; RZ is -
OH, an ester a thioester or a carbamate, or Rz, together with the R, at the 3-
position comprises =O;
Y is -H, -OH, a halogen or -O-C(O)-Rs, or Y, together with the R, at the 16-
position comprises =O;
X is -OH or -O-C(O)-Rs, or X, together with the R, at the 17-position
comprises =O; and Q~ and Q~
independently are -CHI or -CHzOH. Such embodiments include structure 20-43
compounds where
two -OH are present at the 3-position, the 16-position or at the 17-position.
Preferred invention embodiments include compounds having the formula 44
n
Y
44
wherein Y is hydrogen or bromine, RA, is -H, -S(O)(O)-OH, -S(O)(O)-ONa, -
S(O)(O)-O-CHz-
CH(O-C(O)-R6)-CHZ-O-C(O)-R6, -P(O)(O)-O-CHZ-CH(O-C(O)-R~)-CHZ-O-C(O)-R~ or a
glucuronide group of structure (A). In other preferred embodiments, Y and R44
in formula 44 are
both hydrogen. An especially preferred compound is dehydroepiandrosterone (Y
and R" in
formula 44 are both hydrogen and the double bond at the 5-6 position is
present). In other
embodiments, the compound is epiandrosterone (Y and R44 in formula 44 are both
hydrogen and the
double bond at the 5-6 position is absent). A 16-haloepiandrosterone with a F,
Cl, Br or I at the 16
position can also be used as an antiviral agent, e.g., 16a-
bromoepiandrosterone. Other preferred
compounds are (i) 16a-bromodehydroepiandrosterone, (ii) dehydroepiandrosterone-
3-sulfate (Y is -
H and R~ is -S(O)(O~OM in formula 44 are both fiydrogen and the double bond at
the 5-6 position
is present) and (iii) S~i-androstan-3(3-0l-17-one. Related embodiments
comprise compounds related
to formula 44 compounds comprise the formula 44 compounds wherein 1, 2, 3, 4,
5 or 6 hydrogen
atoms that are bonded to the steroid nucleus are substituted with
independently selected -OH, -Br, -
Cl, -F, -I, -OCH3 or -OCzHs atoms or groups.
In other embodiments, the 17-kctosteroids of formula I arc dchydro-
epiandrosterone where
R" in formula 44 is a -S(O)(O)-O-CI-1Z-CH(O-C(O)-Itb)-CHi-O-C(O)-Rs, -P(O)(O)-
0-CHz-CH(O-
26
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WO 00/32177 PCT/US99/28082
C(O)-R~)-CHZ-O-C(OrR? or a glucuronide group of structwe (A), Y is hydrogen
and the 5-6 -
double bond is present. Other formula 44 compounds include conjugates of
dehydrocpiandrostcrone wherein Y is hydrogen, a double bond is present at the
5-G position and Iia,
is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoyl sulfate, O-
dihexadecylglycerol
sulfate, hexadecane sulfonate, dioctadecanoylglycerol phosphate or O-
hexadecylglycerol
phosphate.
In another preferred aspect of the invention, the steroid of formula 1 is a
compound of
formula 45
A__
-- 45
wherein Rso is -H, -OH or =O; R5, is -Br, -CI, -F or -I; R52 is -OH or =O;
R.d9 is -H, -OH, or -OR33;
and R53 is C,_,8 alkyl, CZ.,e alkenyl, C2_~s alkynyl, a C,_,8 ester, a C,_,a
thioester, wherein any of the
foregoing Ci_is or CZ_,8 groups is substituted at one or more hydrogen atoms
with one or more
independently selected -O-, -S-, -OH, -NHz, -SH or =O groups or R53 is
thioacetal, a sulfate ester, a
sulfonate ester, a carbamate or a thioester. In one preferred aspect, R,~ is -
O-C(O)-CHz-CHZ-
CH(R5~)-Cl~'(Rss)-CHzRs,~ wherein Rs4 is -NHz, -OH, -SH, -O-P03, -SO~ or -
OSO,; Rss is -H, -NHZ,
-OH, -SH, -O-P03, -S03 or -OS03; and R56 is C,_,a alkyl, CZ.~$ alkenyl, CZ_,g
alkynyl, a C,.,g ester, a
C,.iB thioester, wherein any of the foregoing C,_,8 or CZ_lg groups is
substituted at one or more
hydrogen atoms with one or more independently selected -OH, -NH2, -SH or =O
groups, and the
precursors, metabolites and analogs thereof. Related embodiments comprise
compounds related to
formula 45 compounds wherein 1, 2, 3, 4, S or 6 hydrogen atoms that are bonded
to the steroid
nucleus are substituted with independently selected -OH, -Br, -Cl, -F, -I, -
OCH3 or -OC2H5 atoms or
groups.
In other preferred embodiments, the formula 1 compounds have the formula 1 B
or 1 C
x
t~
or
1B 1C
wherein each R, independently is -H, -OH, a halogen, -CHCH2, -CHCHCH3, -CCH, -
CCCH3, or,
or, the other moiety that is bonded to the same carbon atom is absent and R,
is =O; RZ is -H, -OH, a
27
S
CA 02352205 2001-05-23
WO 00/321?? PCT/US99/28082
halogen, C,_a alkoxy, -S-C(O)-(CH2)m R,, -C(O~S-(CHi)m-R,, -O-S(Ox0)-(CHz)m
R,, -O-S(O)(O~
O-(CHz)m It4, -O-C(O)-NH-(CHi)m-It4, -NH-C(0~0-(CHi)m-R,, -O-C(S~(CHi)m R,, -
C(S}-O- ,
(CHi)m R,, -O-C(O)-(CH2)m R, or -C(O~O-(CHz)m Re; R, is -H, -CH3, -C2H5, -
C3H~, -CzH,OH, -
C3H60H, -CH2-CH=-O-CH3, -CH2-CHZ-O-CHZ-CH3, -CHI-CHi-O-CHZ-CHzOH, a C3.~
alkenyl
group, a C3~ alkynyl group, benzyl.or phenyl, wherein the phenyl or benzyl
groups are optionally
substituted with I, 2, or 3 independently selected halogen, C~~, alkoxy, -OH, -
SH, -O- or-NH-
moieties; and Q3 and Q6 independently are -H, -CH; or -CH~OH; QZ is -C(R,)2-
or -CHZ-CHi-; and
m is 0, I, 2 or 3. In these embodiments, Q3 and Q6 are usually both in the (3-
configuration, typicaily
they are -CH3, Qi usually comprises -CHZ-, -C(O)-, -CH(Br)-, -CH(1~, or -
CH(OH)- with the Br, I
or OH moieties in the a-configuration, or QZ comprises =O, and R, at the 7-
position is -H, -OH or
=O. Related embodiments comprise compounds related to formula 1B and 1G
compounds wherein
I, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucleus are
substituted with
independently selected -OH, -Br, -Cl, -F, -I, -OCH3 or -OCZHs atoms or groups.
The formula 1 compounds can exist in a crystalline or polymorphic form.
Metabolites. Aiso falling within the scope of this invention are the in vivo
metabolites of
the compounds of the invention, to the extent such products are novel and
unobvious over the prior
art. Such products may result for example from the oxidation, reduction,
hydrolysis, amidation,
esterification and the like of the administered formula 1 compound, due to
enzymatic or chemical
processes. Accordingly, the invention includes novel and unobvious compounds
produced by a
process comprising contacting a compound of this invention with a subject,
e.g., a human, rodent or
a primate, for a period of time sufficient to yield a metabolic product
thereof. Such products
typically are identified by preparing a radiolabelled (e.g. C~4 or H3)
compound of the invention,
administering it parenterally or orally in a detectable dose (e.g. greater
than about 0.5 mg/kg) to an
animal such as rat, mouse, guinea pig, primate, or to a human, allowing
su~cient time for
metabolism to occur (typically about 30 seconds to about 30 hours) and
isolating its conversion
products from the urine, blood or other biological samples. These products are
easily isolated since
they are labeled (others are isolated by the use of antibodies capable of
binding epitopes surviving
in the metabolite). The metabolite structures are determined in conventional
fashion, e.g. by HPLC,
MS or NMR analysis. In general, analysis of metabolites is done in the same
way as conventional
drug metabolism studies well-known to those skilled in the art. The conversion
products, so long as
they are not otherwise found in vivo, are useful in diagnostic assays for
therapeutic dosing of the
compounds of the invention even if they possess no therapeutic activity of
their own.
The following description exemplifies embodiments of the formula 1 compounds.
Group 1. Exemplary embodiments include the formula 1 compounds named in table
B
. 35 based on the compound structure designations defined in table A. Each
compound named in Table
B is depicted as a compound of formula 4
28
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PCT/US99/28082
H
_ Rz
4
where Q3 and Q6 are both -CH3, Q, is -CHZ-.and Rz, R,A, and Y and X have the
structures
designated in Table A. The compounds named according to Tables A and B are
referred to as
S "group 1" compounds.
Compounds named in Table B are designated by numbers assigned to R2, R,A, Y
and X
according to the following compound naming convention, RZ.R,A.Y.X, using the
numbered
chemical structures depicted in Table A. As shown in formula 4, Rz is in the
3~i-position and
hydrogen fills the remaining valence or RZ is double bonded to the 3 carbon,
R,A is an R, group at
the 7~3-position or R,A is an R, group double bonded to the 7 carbon, Y is in
the 16a-position and
hydrogen fills the remaining valence or RZ is double bonded to the 16 carbon
and X is in the 17(3-
position and,hydrogen fills the remaining valence or X is double bonded to the
17 carbon. When
R2, R,A, Y or X is a divalent moiety, e.g., =O, the hydrogen at the
corresponding position is absent.
Thus, the group 1 compound named 1.2.1.1 specifies a formula 4 structure with
a ~3-hydroxyl
bonded to carbons at the 3- and 7-positions (the variable groups R2 and R,A
respectively), an a-
brominc bondcd to carbon 16 (thc variablc group Y) and doublc bondcd oxygcn
(=0) at carbon 17
(the variable group X), i.e., having the structure shown below.
1.2.1.1
29
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WO 00/32177 PCT/US99/28082
TABLE A
R1A
I -OH I -1~1
2 =O 2 -OH
3 -O-P(O)(O~OH 3 =O
' _ 4 -O-P(O)(O)-O-CHZ-CH(O-C(O)-CH3)-CHZ-O-C(O)CH34 -CH3
5 -O-S(OXO~OH 5 -OCH3
6 -O-S(O)(O)-O'Na+ 6 -OCZHs
7 -O-S(O)(O)-OCZHs 7 -OCHZCHZCH3
8 -O-S(O)(O)-O-CHz-CH(O-C(O)-CH,)-CHz-O-C(O)CH,-OCH(CH~)CH,
8
9 -O-S(O)(O)-OCHICH2CH~CHa 9 -OCHzCHZCH~CH3
10 -O-S(O)(OrOC(CH3)3 10 -OC(CH3)3
Y
1 -Br 1
2 -CI 2 -OH
3 -I 3 -H
4 -F 4 -F
5 -H 5 -CI
6 -Oli 6 -I3r
7 =O 7 _I
8 -O-C(O)-CH3 8 -O-C(O)-CH3
9 -O-C(O)-CH2CH3 9 -O-C(O)-CH2CH3
10 -O-CIO~CH,CH~CH, 10 -O-C(O) CH,CH,CH,
TAB B
1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6, 1.1.1.7, 1.1.1.8,
1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2,
1.1.2.3, 1.1.2.4, 1.1.2.5, 1.1.2.6, 1.I.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10,
1.1.3.1, 1.1.3.2, 1.1.3.3, 1.1.3.4,
3 0 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10, 1.1.4.1, 1.1.4.2,
1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6,
1.1.4.7, 1.1.4.8, 1.1.4.9, 1.1.4.1 0, 1.1.5.1, 1.1.5.2, 1.1.x.3, 1.1.5.4,
1.1.5.5, 1.1.5.6, 1.1.5.7, 1.1.5.8,
1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5, 1.1.6.6,
1.1.5.7, 1.1.6.8, 1.1.6.9, 1.1.6.10,
1.1.7.1, 1.1.7.2, 1.1.7.3, 1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.?.8,
1.1.7.9, 1.1.7.10, 1.1.8.1, 1.1.8.2,
1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9, I.I.8.10,
1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4,
:'15 1.1.9.5. 1.1.9.6, 1.1.9.7, 1.1.9.8. 1.1.9.9, 1.1.9.10. 1.1.10.1.
1.1.10.2, 1.1.10.3, 1.1.10.4, 1.1.10.5,
1.1.10.6,1.1.10.7,1.1.10.8,1.1.10.9,1.1.10.10,1.2.1.1,1.2:1.2,1.2.1.3,1.2.1.4,1
.2.1.5,1.2.1.6,
1.2.1.7, 1.2.1.8, 1.2.1.9, 1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4,
1.2.2.5, 1.2.2.6, 1.2.2.7, 1.2.2.8,
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WO 00/32177 PCT/US99/28082
1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4, 1.2.3.5, 1.2.3.6,
1.2.3.?, 1.2.3.8, 1.2.3.9, 1.2.3.10,
1.2.4.1, 1.2.4.2, 1.2.4.3, 1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8,
1.2.4.9, 1.2.4.10, 1.2.5.1, 1.2.5.2, ,
1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8, 1.2.5.9, 1.2.5.10,
1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4,
1.2.6.5, 1.2.6.6, 1.2.6.7, 1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2,
1.2.7.3, 1.2.7.4, I.2.7.5, 1.2.7.6,
1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3, 1.2.8.4,
1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8,
1.2.8.9, 1.2.8.10, 1.2.9.1, 1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6,
1.2.9.7, 1.2.9.8, 1.2.9.9, 1.2.9.10,
' _
1.2.10.1,1.2.10.2,1.2.10.3,1.2.10.4,1.2.10.5,1.2.10.6,1.2.10.7,1.2.10.8,1.2.10.
9,1.2.10.10,
1.3.1.1, 1.3.1.2, 1.3.1.3, 1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8,
1.3.1.9, 1.3.1.10, 1.3.2.1, 1.3.2.2,
1.3.2.3,1.3.2.4,I.3.2.5,1.3.2.6,1.3.2.7,I.3.2.8,1.3.2.9,1.3.2.10,1.3.3.1,1.3.3.
2,1.3.3.3,1.3.3.4,
1.3.3.5, 1.3.3.6, 1.3.3.7, 1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2,
1.3.4.3, 1.3.4.4, 1.3.4.5, 1.3.4.6,
1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2, 1.3.5.3, 1.3.5.4,
1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8,
1.3.5.9, 1.3.5.10, 1.3.6.1, 1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6,
1.3.6.7, 1.3.6.8, 1.3.6.9, 1.3.6.10,
1.3.7.1,1.3.7.2,1.3.7.3,1.3.7.4,1.3.7.5,1.3.7.6,1.3.7.7,1.3.7.8,1.3.7.9,1.3.7.1
0,1.3.8.1,1'.3.8.2,
1.3.8.3, 1.3.8.4, 1.3.8.5, 1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10,
1.3.9.1, 1.3.9.2, 1.3.9.3, 1.3.9.4,
1.3.9.5,1.3.9.6,1.3.9.7,1.3.9.8,1.3.9.9,1.3.9.10,1.3.10.1,1.3.10.2,1.3.10.3,1.3
.10.4,1.3.10.5,
1.3.10.6,1.3.10.7,1.3.10.8,1.3.10.9,I.3.10.10,1.4.1.1,1.4.1.2,1.4.1.3,1.4.1.4,1
.4.1.5,1.4.1.6,
1.4.1.7, 1.4.1.8, 1.4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2, 1.4.2.3, 1.4.2.4,
1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8,
1.4.2.9, 1.4.2.10, 1.4.3.1, 1.4.3.2, 1.4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6,
1.4.3.7, 1.4.3.8, 1.4.3.9, 1.4.3.10,
1.4.4.1, 1.4.4.2, 1.4.4.3, 1.4.4.4, 1.4.4.5, 1.4.4.6, 1.4.4.7, 1.4.4.8,
1.4.4.9, 1.4.4.10, 1.4.5.1, 1.4.5.2,
1.4.5.3, 1.4;5.4, 1.4.5.5, 1.4.5.6, 1.4.5.7, 1.4.5.8, 1.4.5.9, 1.4.5.10,
1.4.6.1, 1.4.6.2, 1.4.6.3, 1.4.6.4,
1.4.6.5, 1.4.6.6, 1.4.6.7, 1.4.6.8, 1.4.6.9, 1.4.6.10, 1.4.7.1, 1.4.7.2,
1.4.7.3, 1.4.7.4, 1.4.7.5, 1.4.7.6,
1.4.7.7, 1.4.7.8, 1.4.7.9, 1.4.7.10, 1.4.8.1, 1.4.8.2, 1.4.8.3, 1.4.8.4,
1.4.8.5, 1.4.8.6, 1.4.8.7, 1.4.8.8,
1.4.8.9, 1.4.8.10, 1.4.9.1, 1.4.9.2, 1.4.9.3, 1.4.9.4, 1.4.9.5, 1.4.9.6,
1.4.9.7, 1.4.9.8, 1.4.9.9, 1.4.9.10,
1.4.10.1,1.4.10.2,1.4.10.3,1.4.t0.4,1.4.10.5,1.4.10.6,1.4.10.7,1.4.10.8,1.4.10.
9,1.4.10.10,
1.5.1.1, 1.5.1.2, 1.5.1.3. 1.5.1.4, 1.5.1.5, 1.5.1.6, 1.5.1.7, 1.5.1.8,
1.5.1.9, 1.5.1.10, 1.5.2.1, 1.5.2.2,
1.5.2.3, 1.5.2.4, 1.5.2.5, 1.5.2.6, 1.5.2.7, 1.5.2.8, 1.5.2.9, 1.5.2.10,
1.5.3.1, 1.5.3.2, 1.5.3.3, 1.5.3.4,
1.5.3.5, 1.5.3.6, 1.5.3.7, 1.5.3.8, 1.5.3.9, 1.5.3.10, 1.5.4.1, 1.5.4.2,
1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6,
1.5.4.7, 1.5.4.8, 1.5.4.9, 1.5.4.10, 1.5.5.1, 1.5.5.2, 1.5.5.3, 1.5.5.4,
1.5.5.5, 1.5.5.6, 1.5.5.7, 1.5.5.8,
1.5.5.9, 1.5.5.10, 1.5.6.1, 1.5.6.2, 1.5.6.3, 1.5.6.4, 1.5.6.5, 1.5.6.6,
1.5.6.7, 1.5.6.8, 1.5.6.9, 1.5.6.10,
3 0 1.5.7.1, 1.5.7.2, 1.5.7.3, 1.5.7.4, 1.5.7.5, 1.5.7.6, 1.5.7.7, 1.5.7.8,
1.5.7.9, 1.5.7.10, 1.5.8.1, 1.5.8.2,
1.5.8.3, 1.5.8.4, 1.5.8.5, 1.5.8.6, 1.5.8.7, 1.5.8.8, 1.5.8,9, 1.5.8.10,
1.5.9.1, 1.5.9.2, 1.5.9.3, 1.5.9.4,
1.5.9.5,1.5.9.6,1.5.9.7,1.5.9.8,1.5.9.9,1.5.9.10,1.5.10.1,1.5.10.2,1.5.10.3,1.5
.10.4,1.5.10.5,
1.5.10.6,1.5.10.7,1.5.10.8,1.5.10.9,1.5.10.10,1.6.1.1,1.6.1.2,i.6.1.3,1.6.1.4,1
.6.1.5,1.6.1.6,
1.6.1.7, 1.6.1.8, 1.6.1.9, 1.6.1.10, 1.6.2.1, 1.6.2.2, 1.6.2.3, 1.6.2.4,
1.6.2.5, 1.6.2.6, 1.6.2.7, 1.6.2,8,
I.G.2.9, 1.G.2.lU, 1.6.3.1, I.G.3.2, 1.6.3.3, 1.6.3.4, I.G.3.5, I.G.3.G,
I.G.3.7, 1.6.3.8, 1.6.3.9, 1.6.3.10,
1.6.4.1, 1.6.4.2, 1.6.4.3, 1.6.4.4, 1.6.4.5, 1.6.4.6, 1.6.4.7, 1.6.4.8,
1.6.4.9, 1.6.4.10, 1.6.5.1, 1.6.5.2,
1.6.5.3, 1.6.5.4, 1.6.5.5, 1.6.5.6, 1.6.5.7, 1.6.5.8, 1.6.5.9, 1.6.5.10,
1.6.6.1, 1:6.6.2, 1.6.6.3, 1.6.6.4,
31
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1.6:6.5,1.6.6.6,1.6.6.7,1.6.6.8,I.6.6.9,1.6.6.10,1.6.7.I,1.6.7.2,1.6.7.3,1.6.7.
4,1.6.7.5,1.6.7.6,
1.6.7.7, 1.6.7.8, 1.6.7.9, 1.6.7.10, 1.6.8.1, 1.6.8.2, 1.6.8.3, 1.6.8.4,
1.6.8.5, 1.6.8.6, 1.6.8.7, 1.6.8.8,
1.6.8.9, 1.6.8.10, 1.6.9.1, 1.6.9.2, 1.6.9.3, 1.6.9.4, 1.6.9.5, 1.6.9.6,
1.6.9.7, 1.6.9.8, 1.6:9.9, 1.6.9.10,
1.6.10.1,1.6.10.2,1.6.10.3,1.6.10.4,1.6.10.5,1.6.10.6,1.6.10.7,1.6.I0.8,1.6.10.
9,1.6.10.10,
1.7.1.1,1.7.1.2, 1.7.1.3, 1.7.1.4, 1.7.1.5, 1.7.1.6, 1.7.1.7, 1.7.1.8,
1.7.1.9, 1.7.1.10, 1.7.2.1, 1.7.2.2,
1.7.2.3,1.7.2.4, 1:7.2.5, 1.7.2.6, 1.7.2.7, 1.7.2.8, 1.7.2.9, 1.7.2.10,
1.7.3.1, 1.7.3.2, 1.7.3.3, 1.7.3.4,
1.7.3.5,1.7.3.6, 1:7.3.7, 1.7.3.8, 1.7.3.9, 1.7.3.10, 1.7.4.1, 1.7.4.2,
1.7.4.3, 1.7.4.4, 1.7.4.5, I.7.4.6,
1.7.4.7,1.7.4.8, 1.7.4.9, 1.7.4.10, 1.7.5.1, 1.7.5.2, 1.7.5.3, 1.7.5.4,
1.7.5.5, 1.7.5.6, 1.7.5.7, 1.7.5.8,
1.7.5.9,1.7.5.10, 1.7.6.1, 1.7.6.2, 1.7.6.3, 1.7.6.4, 1.7.6.5, 1.7.6.6,
1.7.6.7, 1.7.6.8, 1.7.6.9, 1.7.6.10,
1.7.7.1,1.7.7.2, 1.7.7.3, 1.7.7.4, 1.7.7.5, 1.7.7.6, 1.7.7.7, 1.7.7.8,
1.7.7.9, 1.7.7.10, 1.7.8.1, 1.7.8.2,
1.7.8.3,1.7.8.4, 1.7.8.5, 1.7.8.6, 1.7.8.7, 1.7.8.8, 1.7.8.9, 1.7.8.10,
1.7.9.1, 1.7.9.2, 1.7.9.3, 1.7.9.4,
1.7.9.5,1.7.9.6,I.7.9.7,1.7.9.8,1.7.9.9,1.7.9.10,1.7.10.1,1.7.10.2,1.7.10.3,1.7
.10.4,1.7.10.5,
1.7.10.6,1.7.10.7,1.7.10.8,1.7.10.9,1.7.10.10,1.8.1.1,1.8.1.2,1.8.1.3,1.8.1.4,1
.8.1.5,1.1.6,
1.8.1.7.1.8.1.8, 1.8.1.9, 1.8.1.10, 1.8.2.1, 1.8.2.2. 1.8.2.3. 1.8.2.4.
1.8.2.5, 1.8.2.1, 1.8.2.7, 1.8.2.8,
IS 1.8.2.9,1.8.2.10, 1.8.3.1, 1.8.3.2, 1.8.3.3. 1.8.3.4. I.R.3.5,
1.8.3.b,
1.8.3.7, 1.8.3.8, 1.8.3.9, 1.8.3.10,
1.8.4.1,1.8.4.2, 1.8.4.3, 1.8.4.4, 1.8.4.5, 1.8.4.6, 1.8.4.7, 1.8.4.8,
1.8.4.9, 1.8.4.10, 1.8.5.1, 1.8.5.2,
1.8.5.3,1.8.5.4, 1.8.5.5, 1.8.5.6, 1.8.5.7, 1.8.5.8, 1.8.5.9, 1.8.5.10,
1.8.6.1, 1.8.6.2, 1.8.6.3, 1.8.6.4,
1.8.6.5,1.8.6.6, 1.8.6.7, 1.8.6.8, 1.8.6.9, 1.8.6.10, 1.8.7.1, 1.8.7.2,
1.8.7.3, 1.8.7.4, 1.8.7.5, 1.8.7.6,
1.8.7.7,1.8.7.8, 1.8.7.9, 1.8.7.10, 1.8.8.1, 1.8.8.2, 1.8.8.3, 1.8.8.4,
1.8.8.5, 1.8.8.6, 1.8.8.7, 1.8.8.8,
1.8.8.9,I.8;8.10, 1.8.9.1, 1.8.9.2, I.8.9.3, 1.8.9.4, 1.8.9.5, 1.8.9.6,
1.8.9.7, 1.8.9.8, 1.8.9.9, 1.8.9.10,
1.8.10.1,
1.8.10.2,
1.8.10.3,
1.8.10.4,
1.8.10.5,
1.8.10.6,
1.8.10.7,
1.8.10.8,
1.8.10.9,
1.8.10.10,
1.9.1.1,1.9.1.2, 1.9.1.3, 1.9.1.4, 1.9.1.5, 1.9.1.6, 1.9.1.7, 1.9.1.8,
1.9.1.9, 1.9.1.10, 1.9.2.1, 1.9.2.2,
1.9.2.3,1.9.2.4, 1.9.2.5, 1.9.2.6, 1.9.2.7, 1.9.2.8, 1.9.2.9, 1.9.2.10,
1.9.3.1, 1.9.3.2, 1.9.3.3, 1.9.3.4,
1.9.3.5,1.9.3.6, 1.9.3.7, 1.9.3.8, 1.9.3.9, 1.9.3.10, 1.9.4.1, 1.9.4.2,
1.9.4.3, 1.9.4.4, 1.9.4.5, 1.9.4.6,
1.9.4.7,1.9.4.8, 1.9.4.9, 1.9.4.10, 1.9.5.1, 1.9.5.2, 1.9.5.3, 1.9.5.4,
1.9.5.5, 1.9.5.6, 1.9.5.7, 1.9.5.8,
1.9.5.9,1.9.5.10, 1.9.6.1, 1.9.6.2, 1.9.6.3, 1.9.6.4, 1.9.6.5, 1.9.6.6,
1.9.6.7, 1.9.6.8, 1.9.6.9, 1.9.6.10,
r
1.9.7.1,1.9.7.2, 1.9.7.3, 1.9.7.4, 1.9.7.5, 1.9.7.6, 1.9.7.7, 1.9.7.8,
1.9.7.9, 1.9.7.10, 1.9.8.1, 1.9.8.2,
1.9.8.3,1.9.8.4, 1.9.8.5, 1.9.8.6, 1.9.8.7, 1.9.8.8, 1.9.8.9, 1.9.8.10,
1.9.9.1, 1.9.9.2, 1.9.9.3, 1.9.9.4,
1.9.9.S,I.9.9.6,1.9.9.7,1.9.9.8,1.9.9.9,1.9.9.10,1.9.10.1,1.9.10.2,1.9.10.3,1.9
.10.4,1.9.10.5,
1.9.10.6.1.9.10.7. 1.9.10.8. 1.9.10.9. 1.9.10.10. 1.10.1.1. 1.10.1.2,
1.10.1.3, 1.10.1.4, 1.10.1.5,
1.10.1.6,1.10.1.7, 1.10.1.8, 1.10.1.9, 1.10.1.10, 1.10_2.1, 1.10.2.2,
1.10.2.3, 1.10.2.4, 1.10.2.5,
1.10.2.6,1.10.2.7, 1.10.2.8, 1.10.2.9, 1.10.2.10, 1.10.3.1, 1.10.3.2,
1.10.3.3, I.10.3.4, 1.10.3.5,
1.10.3.6,1.10.3.7,1.10.3.8,1.10.3.9,1.10.3.10,1.10.4.1,1.10.4.2,I.10.4.3,1.10.4
.4,I.10.4.5,
1.10.4.6,1.10.4.7,1.10.4.8,1.10.4.9,1.10.4.10,1.10.5.1,1.10.5.2,1.10.5.3,1.10.5
.4,1.10.5.5,
1.10.5.6,1.10.5.7,1.10.5.8,1.10.5.9,1.10.5.10,1.10.6.1,1.10.6.2,1.10.6.3,1.10.6
.4,1.10.6.5,
1.10.6.6,1.10.6.7,1.10.6.8,1.10.6.9,1.10.6.10,1.10.7.1,1.10.7.2,1.10.7.3,1.10.7
.4,1.I0.7.5,
1.10.7.6, 1.10.7.7, 1.10.7.8, 1.1(1.7.9, 1.10.7.10, 1.10.8.1, 1.10.8.2,
1.10.8.3, 1.10.8.4, 1.10.8.5,
32
S
CA 02352205 2001-05-23
WO 00132177 PCTJUS99/28082
1.10.8.6, 1.10.8.7, 1.10.8.8, 1.10.8.9, 1.10.8.10, 1.10.9.1, 1.10.9.2,
1.10.9.3, 1.10.9.4, 1.10.9.5, _
1.10.9.6,1.10.9.7,1.J0.9.8,1.10.9.9,1.10.9.10,1.10.10.1,1.10.10.2,1.10.10.3,1.1
0.10.4,
1.10.10.5, 1.10.10.6, 1.10.10.7, 1.10.10.8, 1.10.10.9, 1.10.10.10, 2.1.1.1,
2.1.1.2, 2. L 1.3, 2.1.1.4,
2.1.1.5, 2.1.1.6, 2.1.1.7, 2.1.1.8, 2.1.1.9, 2.1.1.10, 2.1.2.1, 2.1.2.2,
2.1.2.3, 2.1.2.4, 2.1.2.5, 2.1.2.6,
2.1.2.7,2.1.2.8,2.1.2.9,2.1.2.10,2.1.3.1,2.1.3.2,2.1.3.3,2.1.3.4,2.1.3.5,2.1.3.
6,2.1.3.7,2.1.3.8,
2.1.3.9, 2.1.3.10, 2.1.4.1, 2.1.4.2, 2.1.4.3, 2.1.4.4, 2.1.4.5, 2.1.4.6,
2.1.4.7, 2.1.4.8, 2.1.4.9, 2.1.4.10,
2.1.5.1, 2.1.5.2, 2.1.5.3, 2.1.5.4, 2.1.5.5, 2.1.5.6, 2.1.5.7, 2.1.5.8,
2.1.5.9, 2.1.5.10, 2.1.6.1, 2.1.6.2,
2.1.6.3, 2.1.6.4, 2.1.6.5, 2.1.6.6, 2.1.6.7, 2.1.6.8, 2.1.6.9, 2.1.6.10,
2.1.7.1, 2.1.7.2, 2.1.7.3, 2.1.7.4,
2.1.7.5, 2.1.7.6, 2.1.7.7, 2.1.7.8, 2.1.7.9, 2.1.7.10, 2.1.8.1, 2.1.8.2,
2.1.8.3, 2.1.8.4, 2.1.8.5, 2.I.8.6,
2.1.8.7, 2.1.8.8, 2.1.8.9, 2.1.8.10, 2.1.9.1, 2.1.9.2, 2.1.9.3, 2.1.9.4,
2.1.9.5, 2.1.9.6, 2.1.9.7, 2.1.9.8,
2. i .9.9, 2.1.9.10, 2.1.10.1, 2.1.10.2, 2.1.10.3, 2.1.10.4, 2.1.10.5,
2.1.10.6, 2. I .10.7, 2.1.10.8,
2.1.10.9,2.1.10.10,2.2.1.1,2.2.1.2,2.2.1.3,2.2.1.4,2.2.1.5,2.2.1.6,2.2.1.7,2.2.
1.8,2.2.1.9,
2.2.1.10, 2.2.2.1, 2.2.2.2, 2.2.2.3, 2.2.2.4, 2.2.2.5, 2.2.2.6, 2.2.2.7,
2.2.2.8, 2.2.2.9, 2.2.2.1 9, 2.2.3.1,
2.2.3.2, 2.2.3.3, 2.2.3.4, 2.2.3.5, 2.2.3.6, 2.2.3.7, 2.2.3.8, 2.2.3.9,
2.2.3.10, 2.2.4.1, 2.2.4.2, 2.2.4.3,
2.2.4.4, 2.2.4.5, 2.2.4.6, 2.2.4.7, 2.2.4.8, 2.2.4.9, 2.2.4.10, 2.2.5.1,
2.2.5.2, 2.2.5.3, 2.2.5.4, 2.2.5.5,
2.2.5.6, 2.2.5.7, 2.2.5.8, 2.2.5.9, 2.2.5.10, 2.2.6.1, 2.2.6.2, 2.2.6.3,
2.2.6.4, 2.2.6.5, 2.2.6.6, 2.2.6.7,
2.2.6.8, 2.2.6.9, 2.2.6.10, 2.2.7.1, 2.2.7.2, 2.2.7.3, 2.2.7.4, 2.2.7.5,
2.2.7.6, 2.2.7.7, 2.2.7.8, 2.2.7.9,
2.2.7.10, 2.2.8.1, 2.2.8.2, 2.2.8.3, 2.2.8.4, 2.2.8.5, 2.2.8.6, 2.2.8.7,
2.2.8.8, 2.2.8.9, 2.2.8.10, 2.2.9.1,
2.2.9.2,2.2.9.3,2.2.9.4,2.2.9.5,2.2.9.6,2.2.9.7,2.2.9.8,2.2.9.9,2.2.9.10,2.2.10
.1,2.2.10.2,
2.2.10.3,2.2:10.4,2.2.10.5,2.2.10.6,2.2.10.7,2.2.10.8,2.2.10.9,2.2.10.10,2.3.1.
1,2.3.1.2,2.3.1.3,
2.3.1.4, 2.3.1.5, 2.3.1.6, 2.3.1.7, 2.3.1.8, 2.3.1.9, 2.3.1.10, 2.3.2.1,
2.3.2.2, 2.3.2.3, 2.3.2.4, 2.3.2.5,
2.3.2.6, 2.3.2.7, 2.3.2.8, 2.3.2.9, 2.3.2.10, 2.3.3.1, 2.3.3.2, 2.3.3.3,
2.3.3.4, 2.3.3.5, 2.3.3.6, 2.3.3.7,
2.3.3.8, 2.3.3.9, 2.3.3.10, 2.3.4.1, 2.3.4.2, 2.3.4.3, 2.3.4.4, 2.3.4.5,
2.3.4.6, 2.3.4.7, 2.3.4.8, 2.3.4.9,
2.3.4.10,2.3.5.1,2.3.5.2,2.3.5.3,2.3.5.4,2.3.5.5,2.3.5.6,2.3.5.7,2.3.5.8,2.3.5.
9,2.3.5.10,2.3.6.1,
2.3.6.2, 2.3.6.3, 2.3.6.4, 2.3.6.5, 2.3.6.6, 2.3.6.7, 2.3.6.8, 2.3.6.9,
2.3.6.10, 2.3.7.1, 2.3.7.2, 2.3.7.3,
2.3.7.4, 2.3.7.5, 2.3.7.6, 2.3.7.7, 2.3.7.8, 2.3.7.9, 2.3.7.10, 2.3.8.I,
2.3.8.2, 2.3.8.3, 2.3.8.4, 2.3.8.5,
2.3.8.6, 2.3.8.7, 2.3.8.8, 2.3.8.9, 2.3.8.10, 2.3.9.1, 2.3.9.2, 2.3.9.3,
2.3.9.4, 2.3.9.5, 2.3.9.6, 2.3.9.7,
2.3.9.8,2.3.9.9,2.3.9.10,2.3.10.1,2.3.10.2,2.3.10.3,2.3.10.4,2.3.l0.5,2.3.10.6,
2.3.10.7,2.3.10.8,
2.3.IU.9,2.3.10.10,2.4.1.1,2.4.1.2,2.4.1.3,2.4.1.4,2.4.1.5,2.4.1.6,2.4.1.7,2.4.
1.8,2.4.1.9,
2.4.1.10,2.4.2.1,2.4.2.2,2.4.2.3,2.4.2.4,2.4.2.5,2.4.2.6,2.4.2.7,2.4.2.8,2.4.2.
9,2.4.2.10,2.4.3.1,
2.4.3.2, 2.4.3.3, 2.4.3.4, 2.4.3.5, 2.4.3.6, 2.4.3.7, 2.4,3.8, 2.4.3.9,
2.4.3.10, 2.4.4.1, 2.4.4.2, 2.4.4.3,
2.4.4.4, 2.4.4.5, 2.4.4.6, 2.4.4.7, 2.4.4.8, 2.4.4.9, 2.4.4.10, 2.4.5.1,
2.4.5.2, 2.4.5.3, 2.4.5.4, 2.4.5.5,
2.4.5.6, 2.4.5.7, 2.4.5.8, 2.4.5.9, 2.4.5.10, 2.4.6.1, 2.4.6.2, 2.4.6.3,
2.4.6.4, 2.4.6.5, 2.4.6.6, 2.4.6.7,
2.4.6.8, 2.4.6.9, 2.4.6.10, 2.4.7.1, 2.4.7.2, 2.4.7.3, 2.4.7.4, 2.4.7.5,
2.4.7.6, 2.4.7.7, 2.4.7.8, 2.4.7 9,
2.4.7.10,2.4.R.1,2.4.8.2,2.4.8.3,2.4.R.4,2.4.8.5,2.4.8.6,2.4.8.7,2.4.8.8,2.4.8.
9,2.4.8.10,2.4.9.1,
2.4.9.2,2.4.9.3,2.4.9.4,2.4.9.5,2.4.9.6,2.4.9.7,2.4.9.8,~.4.9.9,2.4.9.10,2.4.10
.1,2.4.10.2,
2.4.10.3,2.4.10.4,2.4.10.5,2.4.10.6,2.4.10.7,2.4.10.8,2.4.10.9,2.4.10.10,2.5.1.
1,2.5.1.2,2.5.1.3,
33
CA 02352205 2001-05-23
WO 00/32177 PC'f/US99/28082
2.5.1.4, 2.5.1.5, 2.5.1.6, 2.5.1.7, 2.5.1.8, 2.5.1.9, 2.5.1.10, 2.5.2.1,
2.5.2.2, 2.5.2.3, 2.5.2.4, 2.5.2.5, .
2.5.2.6, 2.5.2.7, 2.5.2.8, 2.5.2.9, 2.5.2.10, 2.5.3.1, 2.5.3.2, 2.5.3.3,
2.5.3.4, 2.5.3.5, 2.5.3.6, 2.5.3.7,
2.5.3.8, 2.5.3.9, 2.5.3.10, 2.5.4.1, 2.5.4.2, 2.5.4.3, 2.5.4.4, 2.5.4.5,
2.5.4.6, 2.5.4.7, 2.5.4.8, 2.5.4.9,
2.5.4.10, 2.5.5.1, 2.5.5.2, 2.5.5.3, 2.5.5.4, 2.5.5.5, 2.5.5.6, 2.5.5.7,
2.5.5.8, 2.5.5.9, 2.5.5.10, 2.5.6.1,
S 2.5.6.2, 2.5.6.3, 2.5.6.4, 2.5.6.5, 2.5.6.6, 2.5.6.7, 2.5.6.8, 2.5.6.9,
2.5.6.10, 2.5.7.1, 2.5.7.2, 2.5.7.3,
2.5.7.4, 2.5.7.5, 2.5.7.6, 2.5.7.7, 2.5.7.8, 2.5.7.9, 2.5.7.10, 2.5.8.1,
2.5.8.2, 2.5.8.3, 2.5.8.4, 2.5.8.5,
2.5.8.6, 2.5.8.7, 2.5.8.8, 2.5.8.9, 2.5.8.10, 2.5.9.1, 2.5.9.2, 2.5.9.3,
2.5.9.4, 2.5.9.5, 2.5.9.6, 2.5.9.7,
2.5.9.8,2.5.9.9,2.5.9.10,2.5.10.I,2.5.10.2,2.5.10.3,2.5.10.4,2.5.10.5,2.5.10.6,
2.5.10.7,2.5.10.8,
2.5.10.9,2.5.10.10,2.6.1.1,2.6.1.2,2.6.1.3,2.6.1.4,2.6.1.5,2.6.1.6,2.6.1.7,2.6.
1.8,2.6.1.9,
2.6.1.10,2.6.2.1,2.6.2.2,2.6.2.3,2.6.2.4,2.6.2.5,2.6.2.6,2.6.2.7,2.6.2.8,2.6.2.
9,2.6.2.10,2.6.3.1,
2.6.3.2, 2.6.3.3, 2.6.3.4, 2.6.3.5, 2.6.3.6, 2.6.3.7, 2.6.3.8, 2.6.3.9,
2.6.3.10, 2.6.4.1, 2.6.4.2, 2.6.4.3,
2.6.4.4, 2.6.4.5, 2.6.4.6, 2.6.4.7, 2.6.4.8, 2.6.4.9, 2.6.4.10, 2.6.5.1,
2.6.5.2, 2.6.5.3, 2.6.5.4, 2.6.5.5,
2.6.5.6, 2.6.5.7, 2.6.5.8, 2.6.5.9, 2.6.5.10, 2.6.6.1, 2.6.6.2, 2.6.6.3,
2.6.6.4, 2.6.6.5, 2.6.6.6, 2.6.6.7,
2.6.6.8, 2.6.6.9, 2.6.6.10, 2.6.7.1, 2.6.7.2, 2.6.7.3, 2.6.7.4, 2.6.7.5,
2.6.7.6, 2.6.7.7, 2.6.7.8, 2.6.7.9,
IS
2.6.7.10,2.6.8.1,2.6.8.2,2.6.8.3,2.6.8.4,2.6.8.5,2.6.8.6,2.6.8.7,2.6.8.8,2.6.8.
9,2.6.8.10,2.6.9.1,
2.6.9.2,2.6.9.3,2.6.9.4,2.6.9.5,2.6.9.6,2.6.9.7,2.6.9.8,2.6.9.9,2.6.9.10,2.6.10
.1,2.6.10.2,
2.6.10.3,2.6.10.4,2.6.10.5,2.6.10.6,2.6.10.7,2.6.10.8,2.6.10.9,2.6.10.10,2.7.1.
1,2.7.I.2,2.7.1.3,
2.7.1.4, 2.7.1.5, 2.7.1.6, 2.7.1.7, 2.7.1.8, 2.7.1.9, 2.7.1.10, 2.7.2.1,
2.7.2.2, 2.7.2.3, 2.7.2.4, 2.7.2.5,
2.7.2.6, 2.7.2.7, 2.7.2.8, 2.7.2.9, 2.7.2.(0, 2.7.3.1, 2.7.3.2, 2.7.3.3,
2.7.3.4, 2.7.3.5, 2.7.3.6, 2.7.3.7,
2.7.3.8, 2.7.x.9, 2.7.3.10, 2.7.4.1, 2.7.4.2, 2.7.4.3, 2.7.4.4, 2.7.4.5,
2.7.4.6, 2.7.4.7, 2.7.4.8, 2.7.4.9,
2.7.4.10, 2.7.5.1, 2.7.5.2, 2.7.5.3, 2.7.5.4, 2.7.5.5, 2.7.5.6, 2.7.5.7,
2.7.5.8, 2.7.5.9, 2.7.5.10, 2.7.6.1,
2.7.6.2, 2.7.6.3, 2.7.6.4, 2.7.6.5, 2.7.6.6, 2.7.6.7, 2.7.6.8, 2.7.6.9,
2.7.6.10, 2.7.7.1, 2.7.7.2, 2.7.7.3,
2.7.7.4, 2.7.7.5, 2.7.7.6, 2.7.7.7, 2.7.7.8, 2.7.7.9, 2.7.7.10, 2.7.8.1,
2.7.8.2, 2.7.8.3, 2.7.8.4, 2.7.8.5,
2.7.8.6, 2.7.8.7, 2.7.8.8, 2.7.8.9, 2.7.8.10, 2.7.9.1, 2.7.9.2, 2.7.9.3,
2.7.9.4, 2.7.9.5, 2.7.9.6, 2.7.9.7,
2.7.9.8,2.7.9.9,2.7.9.10,2.7.10.1,2.7.10.2,2.7.10.3,2.7.10.4,2.7.10.5,2.7.10.6,
2.7.10.7,2.7.10.8,
2.7.10.9,2.7.10.10,2.8.1.1,2.8.1.2,2.8.1.3,2.8.1.4,2.8.1.5,2.8.1.6,2.8.1.7,2.8.
1.8,2.8.1.9,
2.8.1.10, 2.8.2.1, 2.8.2.2, 2.8.2.3, 2.8.2.4, 2.8.2.5, 2.8.2.6, 2.8.2.7,
2.8.2.8, 2.8.2.9, 2.8.2.10, 2.8.3.1,
2.8.3.2, 2.8.3.3, 2.8.3.4, 2.8.3.5, 2.8.3.6, 2.8.3.7, 2.8.3.8, 2.8.3.9,
2.8.3.10, 2.8.4.1, 2.8.4.2, 2.8.4.3,
2.8.4.4, 2.8.4.5, 2.8.4.6, 2.8.4.7, 2.8.4.8, 2.8.4.9, 2.8.4.10, 2.8.5.1,
2.8.5.2, 2.8.5.3, 2.8.5.4, 2.8.5.5,
3 0 2.8.5.6, 2.8.5.7, 2.8.5.8, 2.8.5.9, 2.8.5.10, 2.8.6.1, 2.8.6.2, 2.8.6.3,
2.8.6.4, 2.8.6.5, 2.8.6.6, 2.8.6.7,
2.8.6.8, 2.8.6.9, 2.8.6.10, 2.8.7.1, 2.8.7.2, 2.8.7.3, 2.8_7.4, 2.8.7.5,
2.8.7.6, 2.8.7.7, 2.8.7.8, 2.8.7.9,
2.8.7.10, 2.8.8.1, 2.8.8.2, 2.8.8.3, 2.8.8.4, 2.8.8.5, 2.8.8.6, 2.8.8.7,
2.8.8.8. 2.8.8.9. 2.8.8.10. 2.8.9.1,
2.8.9.2,2.8.9.3,2.8.9.4,2.8.9.5,2.8.9.6,2.8.9.7,2.8.9.8,2.8.9.9,2.8.9.10,2.8.10
.1,2.8.10.2,
2.8.10.3,2.8.10.4,2.8.10.5,2.8.10.6,2.8.10.7,2.8.10.8,2.8.10.9,2.8.10.10,2.9.1.
1,2.9.1.2,2.91.3,
3 5 2.9.1.4, 2.9.1.5, 2.9.1.6, 2.9.1.7, 2.9.1.8, 2.9.1.9, 2.9.1.10, 2.9.2.1,
2.9.2.2, 2.9.2.3, 2.9.2.4, 2.9.2.5,
2.9.2.6, 2.9.2.7, 2.9.2.8, 2.9.2.9, 2.9.2.10, 2.9.3.1, 2.9.3.2, 2.9.3.3,
2.9.3.4, 2.9.3.5, 2.9.3.6, 2.9.3.7,
2.9.3.8, 2.9.3.9, 2.9.3.10, 2.9.4.1, 2.9.4.2, 2.9.4.3, 2.9.4.4, 2.9.4.5,
2.9.4.6, 2.9.4.7, 2.9.4.8, 2.9.4.9,
34
CA 02352205 2001-05-23
wo oor~am~ Pcrius99n8oa2
2.9.4.10, 2.9.5.1, 2.9.5.2, 2.9.5.3, 2.9.5.4, 2.9.5.5, 2.9.5.6, 2.9.5.7,
2.9.5.8, 2.9.5.9, 2.9.5.10, 2.9.6.1,
2.9.6.2, 2.9.6.3, 2.9.6.4, 2.9.6.5, 2.9.6.6, 2.9.6.7, 2.9.6.8, 2.9.6.9,
2.9.6.10, 2.9.7.1, 2.9.7.2, 2.9.7.3,
2.9.7.4,2.9.7.5,2.9.7.6,2.9.7.7,2.9.7.8,2.9.7.9,2.9.7.10,2.9.8.1,2.9.8.2,2.9.83
,2.9.8.4,2.9.8.5,
2.9.8.6, 2.9.8.7, 2.9.8.8, 2.9.8.9, 2.9.8.10, 2.9.9.1, 2.9.9.2, 2.9.9.3,
2.9.9.4, 2.9.9.5, 2.9.9.6, 2.9.9.7,
2.9.9.8,2.9.9.9,2.9.9.10,2.9.10.1,2.9.10.2,2.9.10.3,2.9.10.4,2.9.10.5,2.9.10.6,
2.9.10.7,2.9.10.8,
2.9.10.9,2.9.10.10,
2.10.1.1,2.10.1.2,2.10.1.3,2.10.1.4,2.10:1.5,2.10.1.6,2.10.1.7,2.10.1.8,
- _
2.10.1.9,2.10.1.10,2.10.2.1,2.10.2.2,2.10.2.3,2.10.2.4,2.10.2.5,2.10.2.6,2.10.2
.7,2.10.2.8,
2.10.2.9,2.10.2.10,2.10.3.1,2.10.3.2,2.10.3.3,2.10.3.4,2.10.3.5,2.10.3.6,2.10.3
.7,2.10.3.8,
2.10.3.9,2.10.3.10,2.10.4.1,2.10.4.2,2.10.4.3,2.10.4.4,2.10.4.5,2.10.4.6,2.10.4
.7,2.10.4.8,
2.10.4.9,2.I0.4.10,2.10.5.1,2.10.5.2,2.10.5.3,2.10.5.4,2.10.5.5,2.10.5.6,2.10.5
.7,2.10.5.8,
2.10.5.9,2.10.5.10,2.10.6.1,2.10.6.2,2.10.6.3,2.10.6.4,2.10.6.5,2.10.6.6,2.10.6
.7,2.10.6.8,
2.10.6.9,2.10.6.10,2.10.7.1,2.10.7.2,2.10.7.3,2.10.7.4,2.10.7.5,2.10.7.6,2.10.7
.7,2.10.7.8,
2.10.7.9,2.10.7.10,2.10.8.1,2.10.8.2,2.10.8.3,2.10.8.4,2.10.8.5,2.10.8.6,2.10.8
.7,2.10.x.8,
2.10.8.9,2.10.8.10,2.10.9.1,2.10.9.2,2.10.9.3,2.10.9.4,2.10.9.5,2.10.9.6,2.10.9
.?,2.10.9.8,
IS
2.10.9.9,2.10.9.10,2.10.10.1,2.10.10.2,2.10.10.3,2.10.10.4,2.10.10.5,2.10.10.6,
2.10.10.7,
2.10.10.8,2.10.10.9,2.10.10.10,3.1.1.1,3.1.1.2,3.1.1.3,3.1.1.4,3.1.1.5,3.1.1.6,
3.1.1.7,3.1.1.8,
3.1.1.9, 3.1.1.10, 3.1.2.1, 3.1.2.2, 3.1.2.3, 3.1.2.4, 3.1.2.5, 3.1.2.6,
3.1.2.7, 3.1.2.8, 3.1.2.9, 3.I.2.10,
3.1.3.1, 3.1.3.2, 3.1.3.3, 3.1.3.4, 3.1.3.5, 3.1.3.6, 3.1.3.7, 3.1.3.8,
3.1.3.9, 3.1.3.10, 3.1.4.1, 3.1.4.2,
3.1.4.3, 3.1.4.4, 3.1.4.5, 3.1.4.6, 3.1.4.7, 3.1.4.8, 3.1.4.9, 3.1.4.10,
3.1.5.1, 3.1.5.2, 3.1.5.3, 3.1.5.4,
3.1.5.5, 3.1.x.6, 3.1.5.7, 3.1.5.8, 3.1.5.9, 3.1.5.10, 3.1.6.1, 3.1.6.2,
3.1.6.3, 3.1.6.4, 3.1.6.5, 3.1.6.6,
3.1.6.7, 3.1.6.8, 3.1.6.9, 3.1.6.10, 3.1.7.1, 3.1.7.2, 3.1.7.3, 3.1.7.4,
3.1.7.5, 3.1.7.6, 3.1.7.7, 3.1.7.8,
3.1.7.9, 3.1.7.1 0, 3.1.8.1, 3.1.8.2, 3.1.8.3, 3.1.8.4, 3.1.8.5, 3.1.8.6,
3.1.8.7, 3.1.8.8, 3.1.8.9, 3.1.8.10,
3.1.9.1, 3.1.9.2, 3.1.9.3, 3.1.9.4, 3.1.9.5, 3.1.9.6, 3.1.9.7, 3.1.9.8,
3.1.9.9, 3.1.9.10, 3.1.10.1,
3.1.10.2, 3.1.10.3, 3.1.10.4, 3.1.10.5, 3.1.10.6, 3.1.10.7, 3.1.10.8,
3.1.10.9, 3.1.10.10, 3.2.1.1,
3.2.1.2, 3.2.1.3, 3.2.1.4, 3.2.1.5, 3.2.1.6, 3.2.1.7, 3.2.1.8, 3.2.1.9,
3.2.1.10, 3.2.2.1, 3.2.2.2, 3.2.2.3,
3.2.2.4, 3.2.2.5, 3.2.2.6, 3.2.2.7, 3.2.2.8, 3.2.2.9, 3.2.2.10, 3.2.3.1,
3.2.3.2, 3.2.3.3, 3.2.3.4, 3.2.3.5,
3.2.3.6, 3.2.3.7, 3.2.3.8, 3.2.3.9, 3.2.3.10, 3.2.4.1, 3.2.4.2, 3.2.4.3,
3.2.4.4, 3.2.4.5, 3.2.4.6, 3.2.4.7,
3.2.4.8, 3.2.4.9, 3.2.4.10, 3.2.5.1, 3.2.5.2, 3.2.5.3, 3.2.5.4, 3.2.5.5,
3.2.5.6, 3.2.5.7, 3.2.5.8, 3.2.5.9,
3.2.5.10, 3.2.6.1, 3.2.6.2, 3.2.6.3, 3.2.6.4, 3.2.6.5, 3.2.6.6, 3.2.6.7,
3.2.6.8, 3.2.6.9, 3.2.6.10, 3.2.7.1,
3 0 3.2.7.2, 3.2.7.3, 3.2.7.4, 3.2.7.5, 3.2.7.6, 3.2.7.7, 3.2.7.8, 3.2.7.9,
3.2.7.10, 3.2.8.1, 3.2.8.2, 3.2.8.3,
3.2.8.4, 3.2.8.5, 3.2.8.6, 3.2.8.7, 3.2.8.8, 3.2.8.9, 3.2.$.10, 3.2.9.1,
3.2.9.2, 3.2.9.3, 3.2.9.4, 3.2.9.5,
3.2.9.6,3.2.9.7,3.2.9.8,3.2.9.9,3.2.9.10,3.2.10.1,3.2.10.2,3.2.10.3,3.2.I0.4,3.
2.10.5,3.2.10.6,
3 .2.10.7, 3 .2.10.8, 3.2.10.9, 3 .2.10.10, 3.3 .1.1, 3.3.1.2, 3.3.1.3,
3.3.1.4, 3.3.1.5., 3.3.1.6, 3 .3 . I .7,
3.3.1.8, 3.3.1.9, 3.3.1.10, 3.3.2.1, 3.3.2.2, 3.3.2.3, 3.3.2.4, 3.3.2.5,
3.3.2.6, 3.3.2.7, 3.3.2.8, 3.3.29,
3.3.2.10,3.3.3.1,3.3.3.2,3.3.3.3,3.3.3.4,3.3.3.5,3.3.3.6,3.3.3.7,3.3.3.8,3.3.3.
9,3.3.3.10,3.3.4.1,
3.3.4.2, 3.3.4.3, 3.3.4.4, 3.3.4.5, 3.3.4.6, 3.3.4.7, 3.3.4.8, 3.3.4.9,
3.3.4.10, 3.3.5.1, 3.3.5.2, 3.3.5.3,
3.3.5.4, 3.3.5.5, 3.3.5.6, 3.3.5.7, 3.3.5.8, 3.3.5.9, 3.3.5.10, 3.3.6.1,
3.3.6.2, 3.x.6.3, 3.3.6.4, 3.3.6.5,
CA 02352205 2001-05-23
wo oor~zm Pcrius99nsos2
3.3.6.6, 3.3.6.7, 3.3.6.8, 3.3.6.9, 3.3.6.10, 3.3.7.1, 3.3.7.2, 3.3.7.3,
3.3.7.4, 3.3.7.5, 3.3.7.6, 3.3.7.7, _
3.3.7.8, 3.3.7.9, 3.3.7.10, 3.3.8.1, 3.3.8.2, 3.3.8.3, 3.3.8.4, 3.3.8.5,
3.3.8.6, 3.3.8.7, 3.3.8.8, 3.3.8.9,
3.3.8.10, 3.3.9.1, 3.3.9.2, 3.3.9.3, 3.3.9.4, 3.3.9.5, 3.3.9.6, 3.3.9.7,
3.3.9.8, 3.3.9.9, 3.3.9.10,
3.3.10.1,3.3.10.2,3.3.10.3,3.3.10.4,3.3.10.5,3.3.10.6,3.3.10.7,3.3.10.8,3.3.10.
9,3.3.10.10,
3.4.1.1, 3.4.1.2, 3.4.1.3, 3.4.1.4, 3.4.1.5, 3.4.1.6, 3.4.1.7, 3.4.1.8,
3.4.1.9, 3.4.1.10, 3.4.2.1, 3.4.2.2,
3.4.2.3, 3.4.2.4, 3.4.2.5, 3.4.2.6, 3.4.2.7, 3.4.2.8, 3.4.2.9, 3.4.2.10,
3.4.3.1, 3.4.3.2, 3.4.3.3, 3.4.3.4,
3.4.3.,5, 3.4.3.6, 3.4.3.7, 3.4.3.8, 3.4.3.9, 3.4.3.10, 3.4.4.1, 3.4.4.2,
3.4.4.3, 3.4.4.4, 3.4.4.5, 3.4.4.6,
3.4.4.7, 3.4.4.8, 3.4.4.9, 3.4.4.10, 3.4.5.1, 3.4.5.2, 3.4.5.3, 3.4.5.4,
3.4.5.5, 3.4.5.6, 3.4.5.7, 3.4.5.8,
3.4.5.9, 3.4.5.10, 3.4.6.1, 3.4.6.2, 3.4.6.3, 3.4.6.4, 3.4.6.5, 3.4.6.6,
3.4.6.7, 3.4.6.8, 3.4.6.9, 3.4.6.10,
3.4.7.1, 3.4.7.2, 3.4.7.3, 3.4.7.4, 3.4.7.5, 3.4.7.6, 3.4.7.7, 3.4.7.8,
3.4.7.9, 3.4.7.10, 3.4.8.1, 3.4.8.2,
3.4.8.3, 3.4.8.4, 3.4.8.5, 3.4.8.6, 3.4.8.7, 3.4.8.8, 3.4.8.9, 3.4.8.10,
3.4.9.1, 3.4.9.2, 3.4.9.3, 3.4.9.4,
3.4.9.5,3.4.9.6,3.4.9.7,3.4.9.8,3.4.9.9,3.4.9.10,3.4.10.1,3.4.10.2,3.4.10.3,3.4
.10.4,3.4.10.5,
3.4.10.6,3.4.10.7,3.4.10.8,3.4.10.9,3.4.10.10,3.5.1.1,3.5.1.2,3.5.1.3,3.5.1.4,3
.5.1.5,3.51.6,
3.5.1.7, 3.5.1.8, 3.5.1.9, 3.5.1.10, 3.5.2.1, 3.5.2.2, 3.5.2.3, 3.5.2.4,
3.5.2.5, 3.5.2.6, 3.5.2.7, 3.5.2.8,
3.5.2.9, 3.5.2.10, 3.5.3.1, 3.5.3.2, 3.5.3.3, 3.5.3.4, 3.5.3.5, 3.5.3.6,
3.5.3.7, 3.5.3.8, 3.5.3.9, 3.5.3.10,
3.5.4.1, 3.5.4.2, 3.5.4.3, 3.5.4.4, 3.5.4.5, 3.5.4.6, 3.5.4.7, 3.5.4.8,
3.5.4.9, 3.5.4.10, 3.5.5.1, 3.5.5.2,
3.5.5.3, 3.5.5.4, 3.5.5.5, 3.5.5.6, 3.5.5.7, 3.5.5.8, 3.5.5.9, 3.5.5.10,
3.5.6.1, 3.5.6.2, 3.5.6.3, 3.5.6.4,
3.5.6.5, 3.5.6.6, 3.5.6.7, 3.5.6.8, 3.5.6.9, 3.5.6.10, 3.5.7.1, 3.5.7.2,
3.5.7.3, 3.5.7.4, 3.5.7.5, 3.5.7.6,
3.5.7.7, 3.5.7.8, 3.5.7.9, 3.5.7.10, 3.5.8.1, 3.5.8.2, 3.5.8.3, 3.5.8.4,
3.5.8.5, 3.5.8.6, 3.5.8.7, 3.5.8.8,
3.5.8.9, 3.5.x.10, 3.5.9.1, 3.5.9.2, 3.5.9.3, 3.5.9.4, 3.5.9.5, 3.5.9.6,
3.5.9.7, 3.5.9.8, 3.5.9.9, 3.5.9.10,
3.5.10.1,3.5.10.2,3.5.10.3,3.5.10.4,3.5.10.5,3.5.10.6,3.5.10.7,3.5.10.8,3.5.10.
9,3.5.10.10,
3.6.1.1, 3.6.1.2, 3.6.I.3, 3.6.1.4, 3.6.1.5, 3.6.1.6, 3.6.1.7, 3.6.1.8,
3.6.1.9, 3.6.1.10, 3.6.2.1, 3.6.2.2,
3.6.2.3, 3.6.2.4, 3.6.2.5, 3.6.2.6, 3.6.2.7, 3.6.2.8, 3.6.2.9, 3.6.2.I0,
3.6.3.1, 3.6.3.2, 3.6.3.3, 3.6.3.4,
3.6.3.5, 3.6.3.6, 3.6.3.7, 3.6.3.8, 3.6.3.9, 3.6.3.10,3.6.4.1, 3.6.4.2,
3.6.4.3, 3.6.4.4, 3.6.4.5, 3.6.4.6,
3.6.4.7, 3.6.4.8, 3.6.4.9, 3.6.4.10, 3.6.5.1, 3.6.5.2, 3.6.5.3, 3.6.5.4,
3.6.5.5, 3.6.5.6, 3.6.5.7, 3.6.5.8,
3.6.5.9, 3.6.5.10, 3.6.6.1, 3.6.6.2, 3.6.6.3, 3.6.6.4, 3.6.6.5'3:fs,6.6,
3.6.6.7, 3.6.6.8, 3.6.6.9, 3.6.6.10,
3.6.7.1, 3.6.7.2, 3.6.7.3, 3.6.7.4, 3.6.7.5, 3.6.7.6, 3.6.7.7, 3.6.7.8,
3.6.7.9, 3.6.7.I0, 3.6.8.1, 3.6.8.2,
3.6.8.3, 3.6.8.4, 3.6.8.5, 3.6.8.6, 3.6.8.7, 3.6.8.8, 3.6.8.9, 3.6.8.10,
3.6.9.1, 3.6.9.2, 3.6.9.3, 3.6.9.4,
3.6.9.5,3.6.9.6,3.6.9.7,3.6.9.8,3.6.9.9,3.6.9.10,3.6.10.1,3.6.10.2,3.6.10.3,3.6
.10.4,3.6.10.5,
3.6.10.6, 3.6.10.7, 3.6.10.8, 3.6.10.9, 3.6.10.10, 3.7.1.1, 3.7.1.2, 3.7.1.3,
3.7.1.4, 3.7.1.5, 3.7.1.6,
3.7.1.7, 3.7.1.8, 3.7.1.9, 3.7.1.10, 3.7.2.1, 3.7.2.2, 3.7.2.3, 3.7.2.4,
3.7.2.5, 3.7.2.6, 3.7.2.7, 3.7.2.8,
3.7.2.9, 3.7.2.10, 3.7.3.1, 3.7.3.2, 3.7.3.3, 3.7.3.4, 3.7.3.5, 3.7.3.6,
3.7.3.7, 3.7.3.8, 3.7.3.9, 3.7.3.10,
3.7.4.1, 3.7.4.2, 3.7.4.3, 3.7.4.4, 3.7.4.5, 3.7.4.6, 3.7.4.7, 3.7.4.8,
3.7.4.9, 3.7.4.10, 3.7.5.1, 3.7.5.2,
3.7.5.3,3.7.5.4,3.7.5.5,3.7.5.6,3.7.5.7,3.7.5.8,3.7.5.9,3.7.5.10,3.7.6.1,3.7.6.
2,3.7.6.3,3.7.6:4,
3 5 3.7.6.5, 3.7.6.6, 3.7.6.7, 3.7.6.8, 3.7.6.9, 3.7.6.10, 3.7.7.1, 3.7.7.2,
3.7.7.3, 3.7.7.4, 3.7.7.5, 3.7.7.6,
3.7.7.7, 3.7.7.8, 3.7.7.9, 3.7.7.10, 3.7.8.1, 3.7.8.2, 3.7.8.3, 3.7.8.4,
3.7.8.5, 3.7.8.6, 3.7.8.7, 3.7.8.8,
3:7.8.9, 3.7.8.10, 3.7.9.1, 3.7.9.2, 3.7.9.3, 3.7.9.4, 3.7.9.5, 3.7.9.6,
3.7.9.7, 3.7.9.8, 3.7.9.9, 3.7.9.10,
36
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/Z8082 .
3.7.10.1,3.7.10.2,3.7.10.3,3.7.10.4,3.7.10.5,3.7.10.6,3.7.10.7,3.7.10.8,3.7.10.
9,3.7.10.10, _
3.8.1.1, 3.8.1.2, 3.8.1.3, 3.8.1.4, 3.8.1.5, 3.8.1.6, 3.8.1.7, 3.8.1.8,
3.8.I.9, 3.8.1.10, 3.8.2.1, 3.8.2.2,
3.8.2.3, 3.8.2.4, 3.8.2.5, 3.8.2.6, 3.8.2.7, 3.8.2.8, 3.8.2.9, 3.8.2.10,
3.8.3.1, 3.8.3.2, 3.8:3.3, 3.8.3.4,
3.8.3.5, 3.8.3.6, 3.8.3.7, 3.8.3.8, 3.8.3.9, 3.8.3.10, 3.8.4.1, 3.8.4.2,
3.8.4.3, 3.8.4.4, 3.8.4.5, 3.8.4.6,
3.8.4.7, 3.8.4.8, 3.8.4.9, 3.8.4.10, 3.8.5.1, 3.8.5.2, 3.8.5.3, 3.8.5.4,
3.8.5.5, 3.8.5.6, 3.8.5.7, 3.8.5.8,
3.8.5.9, 3.8.5.10, 3.8.6.1, 3.8.6.2, 3.8.6.3, 3.8.6.4, 3.8.6.5, 3.8.6,6,
3.8.6.7, 3.8.6.8, 3.8.6.9, 3.8.6.10,
- _ 3.8.7.1, 3.8.7.2, 3.8.7.3, 3.8.7.4, 3.8.7.5, 3.8.7.6, 3.8.7.7, 3.8.7.8,
3.8.7.9, 3.8.7.10, 3.8.8.1, 3.8.8.2,
3.8.8.3, 3.8.8.4, 3.8.8.5, 3.8.8.6, 3.8.8.7, 3.8.8.8, 3.8.8.9, 3.8.8.10,
3.8.9.1, 3.8.9.2, 3.8.9.3, 3.8.9.4,
3.8.9.5,3.8.9.6,3.8.9.7,3.8.9.8,3.8.9.9,3.8.9.10,3.8.10.1,3.8.10.2,3.8.10.3,3.8
.10.4,3.8.10.5,
3.8.10.6,3.8.10.7,3.8.10.8,3.8.10.9,3.8.10.10,3.9.1.1,3.9.1.2,3.9.1.3,3.9.1.4,3
.9.1.5,3.9.1.6,
3.9.1.7, 3.9.1.8, 3.9.1.9, 3.9.1.10, 3.9.2.1, 3.9.2.2, 3.9.2.3, 3.9.2.4,
3.9.2.5, 3.9.2.6, 3.9.2.7, 3.9.2.8,
3.9.2.9, 3.9.2.10, 3.9.3.1, 3.9.3.2, 3.9.3.3, 3.9.3.4, 3.9.3.5, 3.9.3.6,
3.9.3.7, 3.9.3.8, 3.9.3.9, 3.9.3.10,
3.9.4.1, 3.9.4.2, 3.9.4.3, 3.9.4.4, 3.9.4.5, 3.9.4.6, 3.9.4.7, 3.9.4.8,
3.9.4.9, 3.9.4.10, 3.9.5.1,x.9.5.2,
3.9.5.3, 3.9.5.4, 3.9.5.5, 3.9.5.6, 3.9.5.7, 3.9.5.8, 3.9.5.9, 3.9.5.10,
3.9.6.1, 3.9.6.2, 3.9.6.3, 3.9.6.4,
3.9.6.5, 3.9.6.6, 3.9.6.7, 3.9.6.8, 3.9.6.9, 3.9.6.10, 3.9.7.1, 3.9.7.2,
3.9.7.3, 3.9.7.4, 3.9.7.5, 3.9.7.6,
3.9.7.7, 3.9.7.8, 3.9.7.9, 3.9.7.10, 3.9.8.1, 3.9.8.2, 3.9.8.3, 3.9.8.4,
3.9.8.5, 3.9.8.6, 3.9.8.7, 3.9.8.8,
3.9.8.9, 3.9.8.10, 3.9.9.1, 3.9.9.2, 3.9.9.3, 3.9.9.4, 3.9.9.5, 3.9.9.6,
3.9.9.7, 3.9.9.8, 3.9.9.9, 3.9.9.10,
3.9.10.1,3.9.10.2,3.9.10.3,3.9.10.4,3.9.10.5,3.9.10.6,3.9.10.7,3.9.10.8,3.9.10.
9,3.9.10.10,
3.10.1.1,3.10.1.2,3.10.1.3,3.10.1.4,3.10.1.5,3.10.1.6,3.10.1.7,3.10.1.8,3.10.1.
9,3.10.1.10,
3.10.2.1,3.)0.2.2,3.10.2.3,3.10.2.4,3.10.2.5,3.10.2.6,3.10.2.7,3.10.2.8,3.10.2.
9,3.10.2.10,
3.10.3.1,3.10.3.2,3.10.3.3,3.10.3.4,3.10.3.5,3.10.3.6,3.10.3.7,3.10.3.8,3.10.3.
9,3.10.3.10,
3.10.4.1,3.10.4.2,3.10.4.3,3.10.4.4,3.10.4.5,3.10.4.6,3.10.4.7,3.10.4.8,3.10.4.
9,3.10.4.10,
3.10.5.1,3.10.5.2,3.10.5.3,3.10.5.4,3.10.5.5,3.10.5.6,3.10.5.7,3.10.5.8,3.10.5.
9,3.10.5.10,
3.10.1.1, 3.10.6.2, 3.10.6.3, 3.10.6.4, 3.10.6.5, 3.10.6.6, 3.10.6.7,
3.10.6.8, 3.10.6.9, 3.10.6.10,
3.10.7.1,3.10.7.2,3.10.7.3,3.10.7.4,3.10.7.5,3.10.7.6,3.10.7.7,3.10.7.8,3.10.7.
9,3.10.7.10,
3.10.8.1,3.10.8.2,3.10.8.3,3.10.8.4,3.10.8.5,3.10.8.6,3.10.8.7,3.10.8.8,3.10.8.
9,3.10.8.10,
3.10.9.1,3.10.9.2,3.10.9.3,3.10.9.4,3.10.9.5,3.10.9.6,3.10.9.7,3.10.9.8,3.10.9.
9,3.10.9.10,
3.10.10.1,3.10.I0.2,3.10.10.3,3.10.10.4,3.10.10.5,3.10.10.6,3.10.10.7,3.10.10.8
,3.10.10.9,
3.10.10.10,4.1.1.1,4.1.1.2,4.1.1.3,4.1.1.4,4.1.1.5,4.1.1.6,4.1.1.7,4.1.1.8,4.1.
1.9,4.1.1.10,
3 0 4.1.2.1, 4.1.2.2, 4.1.2.3, 4.1.2.4, 4.1.2.5, 4.1.2.6, 4.1.2.7, 4.1.2.8,
4.1.2.9, 4.1.2.10, 4.1.3.1, 4.1.3.2,
4.1.3.3, 4.1.3.4, 4.1.3.5, 4.1.3.6, 4.1.3.7, 4.1.3.8, 4.1.3.9, 4.1.3.10,
4.1.4.1, 4.1.4.2, 4.1.4.3, 4.1.4.4,
4.1.4.5, 4.1.4.6, 4.1.4.7, 4.1.4.8, 4.1.4.9, 4.1.4.10, 4.1.5.1, 4.1.5.2,
4.1.5.3, 4.1.5.4, 4.1.5.5, 4.1.5.6,
4.1.5.7, 4.1.5.8, 4.1.5.9, 4.1.5.10, 4.1.6.1, 4.1.6.2, 4.1.6.3, 4.1.6.4,
4.1.6.5, 4.1.6.6, 4.1.6.7, 4.1.6.8,
4.1.6.9, 4.1.6.10, 4.1.7.1, 4.1.7.2, 4.1.7.3, 4.1.7.4, 4.1.7.5, 4.1.7.6,
4.1.7.7, 4.1.7.8, 4.1.7.9, 4.1.7.10,
4.1.8.1, 4.1.8.2, 4.1.8.3, 4.1.8.4, 4.1.8.5, 4.1.8.6, 4.1.8.7, 4.1.8.8,
4.1.8.9, 4.1.8.10, 4.1.9.1, 4.1.9.2,
4.1.9.3,4.1.9.4,4.1.9.5,4.1.9.6,4.1.9.7,4.1.9.8,4.1.9.9,4.1.9.10,4.1.10.1,4.1.1
0.2,4.1.10.3,
4.1.10.4,4.1.10.5,4.1.10.6,4.1.I0.7,4.1.10.8,4.1.10.9,4.1.t0.10,4.2.1.1,4.2.1.2
,4.2.1.3,4.2.1.4,
37
s
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/Z8082
4.2:1.5, 4.2.1.6, 4.2.1.7, 4.2.1.8, 4.2.1.9, 4.2.1.10, 4.2.2.1, 4.2.2.2,
4.2.2.3, 4.2.2.4, 4.2.2.5, 4.2.2.6,
4.2.2.7, 4.2.2.8, 4.2.2.9, 4.2.2.10, 4.2.3.1, 4.2.3.2, 4.2.3.3, 4.2.3.4,
4.2.3.5, 4.2.3.6, 4.2.3.7, 4.2.3.8, ,
4.2.3.9, 4.2.3.10, 4.2.4.1, 4.2.4.2, 4.2.4.3, 4.2.4.4, 4.2.4.5, 4.2.4.6,
4.2.4.7, 4.2.4.8, 4.2.4.9, 4.2.4.10,
4.2.5.1, 4.2.5.2, 4.2.5.3, 4.2.5.4, 4.2.5.5, 4.2.5.6, 4.2.5.7, 4.2.5.8,
4.2.5.9, 4.2.5.10, 4.2.6.1, 4.2.6.2,
4.2.6.3, 4.2.6.4, 4.2.6.5, 4.2.6.6, 4.2.6.7, 4.2.6.8, 4.2.6.9, 4.2.6.10,
4.2.7.1, 4.2.7.2, 4.2.7.3, 4.2.7.4,
4.2.7.5, 4.2.7.6, 4.2.7.7, 4.2.7.8, 4.2.7.9, 4.2.7.10, 4.2.8.1, 4.2.8:2,
4.2.8.3, 4.2.8.4, 4.2.8.5, 4.2.8.6,
. 4.2.$.7, 4.2.8.8, 4.2.8.9, 4.2.8.10, 4.2.9.1, 4.2.9.2, 4.2.9.3, 4.2.9.4,
4.2.9.5, 4.2.9.6, 4.2.9.7, 4.2.9.8,
4.2.9.9,4.2.9.10,4.2.10.1,4.2.10.2,4.2.10.3,4.2.10.4,4.2.10.5,4.2.10.6,4.2.10.7
,4.2.10.8,
4.2.10.9,4.2.10.10,4.3.1.1,4.3.1.2,4.3.1.3,4.3.1.4,4.3.1.5,4.3.1.6,4.3.1.7,4.3.
1.8,4.3.1.9,
4.3.1.10,4.3.2.1,4.3.2.2,4.3.2.3,4.3.2.4,4.3.2.5,4.3.2.6,4.3.2.7,4.3.2.8,4.3.2.
9,4.3.2.10,4.3.3.1,
4.3.3.2, 4.3.3.3, 4.3.3.4, 4.3.3.5, 4.3.3.6, 4.3.3.7, 4.3.3.8, 4.3.3.9,
4.3.3.10, 4.3.4.1, 4.3.4.2, 4.3.4.3,
4.3.4.4, 4.3.4.5, 4.3.4.6, 4.3.4.7, 4.3.4.8, 4.3.4.9, 4.3.4.10, 4.3.5.1,
4.3.5.2, 4.3.5.3, 4.3.5.4, 4.3.5.5,
4.3.5.6, 4.3.5.7, 4.3.5.8, 4.3.5.9, 4.3.5.10, 4.3.6.1, 4.3.6.2, 4.3.6.3,
4.3.6.4, 4.3.6.5, 4.3.6.6,'x.3.6.7,
4.3.6.8, 4.3.6.9, 4.3.6.10, 4.3.7.1, 4.3.7.2, 4.3.7.3, 4.3.7.4, 4.3.7.5,
4.3.7.6, 4.3.7.7, 4.3.7.8, 4.3.7.9,
IS
4.3.7.10,4.3.8.1,4.3.8.2,4.3.8.3,4.3.8.4,4.3.8.5,4.3.8.6,4.3.8.7,4.3.8.8,4.3.8.
9,4.3.8.10,4.3.9.1,
4.3.9.2,4.3.9.3,4.3.9.4,4.3.9.5,4.3.9.6,4.3.9.7,4.3.9.8,4.3.9.9,4.3.9.10,4.3.10
.1,4.3.10.2,
4.3.10.3,4.3.10.4,4.3.10.5,4.3.10.6,4.3.10.7,4.3.10.8,4.3.10.9,4.3.10.10,4.4.1.
1,4.4.1.2,4.4.1.3,
4.4.1.4, 4.4.1.5, 4.4.1.6, 4.4.1.7, 4.4.1.8, 4.4.1.9, 4.4.1.10, 4.4.2.1,
4.4.2.2, 4.4.2.3, 4.4.2.4, 4.4.2.5,
4.4.2.6, 4.4.2.7, 4.4.2.8, 4.4.2.9, 4.4.2.10, 4.4.3.1, 4.4.3.2, 4.4.3.3,
4.4.3.4, 4.4.3.5, 4.4.3.6, 4.4.3.7,
4.4.3.8, 4.4.3.9, 4.4.3.10, 4.4.4.1, 4.4.4.2, 4.4.4.3, 4.4.4.4, 4.4.4.5,
4.4.4.6, 4.4.4.7, 4.4.4.8, 4.4.4.9,
4.4.4.10, 4.4.5.1, 4.4.5.2, 4.4.5.3, 4.4.5.4, 4.4.5.5, 4.4.5.6, 4.4.5.7,
4.4.5.8, 4.4.5.9, 4.4.5.10, 4.4.6.1,
4.4.6.2, 4.4.6.3, 4.4.6.4, 4.4.6.5, 4.4.6.6, 4.4.6.7, 4.4.6.8, 4.4.6.9,
4.4.6.10, 4.4.7.1, 4.4.7.2, 4.4.7.3,
4.4.7.4, 4.4.7.5, 4.4.7.6, 4.4.7.7, 4.4.7.8, 4.4.7.9, 4.4.7.10, 4.4.8.1,
4.4.8.2, 4.4.8.3, 4.4.8.4, 4.4.8.5,
4.4.8.6, 4.4.8.7, 4.4.8.8, 4.4.8.9, 4.4.8.10, 4.4.9.1, 4.4.9.2, 4.4.9.3,
4.4.9.4, 4.4.9.5, 4.4.9.6, 4.4.9.7,
4.4.9.8,4.4.9.9,4.4.9.10,4.4.10.1,4.4.10.2,4.4.10.3,4.4.10.4,4.4.10.5,4.4.10.6,
4.4.10.7,4.4.10.8,
4.4.10.9,4.4.10.10,4.5.1.1,4.5.1.2,4.5.1.3,4.5.1.4,4.5.1.5,4.5.1.6,4.5.1.7,4.5.
1.8,4.5.1.9,
4.5.1.10, 4.5.2.1, 4.5.2.2, 4.5.2.3, 4.5.2.4, 4.5.2.5, 4.5.2.6, 4.5.2.7,
4.5.2.8, 4.5.2.9, 4.5.2.10, 4.5.3.1,
4.5.3.2, 4.5.3.3, 4.5.3.4, 4.5.3.5, 4.5.3.6, 4.5.3.7, 4.5.3.8, 4.5.3.9,
4.5.3.I0, 4.5.4.1, 4.5.4.2, 4.5.4.3,
4.5.4.4, 4.5.4.5, 4.5.4.6, 4.5.4.7, 4.5.4.8, 4.5.4.9, 4.5.4.10, 4.5.5.1,
4.5.5.2, 4.5.5.3, 4.5.5.4, 4.5.5.5,
4.5.5.6, 4.5.5.7, 4.5.5.8, 4.5.5.9, 4.5.5.10, 4.5.6.1, 4.5.6.2, 4.5.6.3,
4.5.6.4, 4.5.6.5, 4.5.6.6, 4.5.6.7,
4.5.6.8, 4.5.6.9, 4.5.6.10, 4.5.7.1, 4.5.7.2, 4.5.7.3, 4.5.7.4, 4.5.7.5,
4.5.7.6, 4.5.7.7, 4.5.7.8, 4.5.7.9,
4.5.7.10, 4.5.8.1, 4.5.8.2, 4.5.8.3, 4.5.8.4, 4.5.8.5, 4.5.8.6, 4.5.8.7,
4.5.8.8, 4.5.8.9, 4.5.8.10, 4.5.9.1,
4.5.9.2,4.5.9.3,4.5.9.4,4.5.9.5,4.5.9.6,4.5.9.7,4.5.9.8,4.5.9.9,4.5.9.10,4.5.10
.1,4.5.10.2,
4.5.10.3,4.5.10.4,4.5.10.5,4.5.10.6,4.5.10.7,4.5.10.8,4.5.10.9,4.5.10.10,4.6.1.
1,4.6.1.2,4.6.1.3,
4.6.1.4, 4.6.1.5, 4.6.1.6, 4.6.1.7, 4.6.1.8, 4.6.1.9, 4.6.1.10, 4.6.2.1,
4.6.2.2, 4.6.2.3, 4.6.2.4, 4.6.2.5,
4.6.2.6, 4.6.2.7, 4.6.2.8, 4.6.2.9, 4.6.2.10, 4.6.3.1, 4.6.3.2,.4.6.3.3,
4.6.3.4, 4.6.3.5, 4.6.3.6, 4.6.3.7,
4.6.3.8, 4.6.3.9, 4.6.3.10, 4.6.4.1, 4.6.4.2, 4.6.4.3, 4.6.4.4, 4.6.4.5,
4.6.4.6, 4.6.4.7, 4.6.4.8, 4.6.4.9,
38
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WO 00132177 PCTNS99/28082
4.6.4.10, 4.6.5.1, 4.6.5.2, 4.6.5.3, 4.6.5.4, 4.6.5.5, 4.6.5.6, 4.6.5.7,
4.6.5.8, 4.6.5.9, 4.6.5.10, 4.6.6.1,
4.6.6.2, 4.6.6.3, 4.6.6.4, 4.6.6.5, 4.6.6.6, 4.6.6.7, 4.6.6.8, 4.6.6.9,
4.6.6.10, 4.6.7.1, 4.6.7.2, 4.6.7.3,
4.6.7.4, 4.6.7.5, 4.6.7.6, 4.6.7.7, 4.6.7.8, 4.6.7.9, 4.6.7.10, 4.6.8.1,
4.6.8.2, 4.6.8.3, 4.6:8.4, 4.6.8.5,
4.6.8.6, 4.6.8.7, 4.6.8.8, 4.6.8.9, 4.6.8.10, 4.6.9.1, 4.6.9.2, 4.6.9.3,
4.6.9.4, 4.6.9.5, 4.6.9.6, 4.6.9.7,
4.6.9.8,4.6.9.9,4.6.9.10,4.6.10.1,4.6.10.2,4.6.10.3,4.6.10.4,4.6.10.5,4.6.10.6,
4.6.10.7,4.6.10.8,
4.6.10.9,4.6.10.10,4.7.1.1,4.7.1.2,4.7.1.3,4.7.1.4,4.7.1.5,4.7.1.6,4.7.1.7,4.7.
1.8,4.7.1.9,
4.7.1.10, 4.7.2.1, 4.7.2.2, 4.7.2.3, 4.7.2.4, 4.7.2.5, 4.7.2.6, 4.7.2.7,
4.7.2.8, 4.7.2.9, 4.7.2.10, 4.7.3.1,
4.7.3.2, 4.7.3.3, 4.7.3.4, 4.7.3.5, 4.7.3.6, 4.7.3.7, 4.7.3.8, 4.7.3.9,
4.7.3.10, 4.7.4.1, 4.7.4.2, 4.7.4.3,
4.7.4.4, 4.7.4.5, 4.7.4.6, 4.7.4.7, 4.7.4.8, 4.7.4.9, 4.7.4.10, 4.7.5.1,
4.7.5.2, 4.7.5.3, 4.7.5.4, 4.7.5.5,
4.7.5.6, 4.7.5.7, 4.7.5.8, 4.7.5.9, 4.7.5.10, 4.7.6.1, 4.7.6.2, 4.7.6.3,
4.7.6.4, 4.7.6.5, 4.7.6.6, 4.7.6.7,
4.7.6.8, 4.7.6.9, 4.7.6.10, 4.7.7.1, 4.7.7.2, 4.7.7.3, 4.7.7.4, 4.7.7.5,
4.7.7.6, 4.7.7.7, 4.7.7.8, 4.7.7.9,
4.7.7.10, 4.7.8.1, 4.7.8.2, 4.7.8.3, 4.7.8.4, 4.7.8.5, 4.7.8.6, 4.7.8.7,
4.7.8.8, 4.7.8.9, 4.7.8.10, 4.7.9.1,
4.7.9.2,4.7.9.3,4.7.9.4,4.7.9.5,4.7.9.6,4.7.9.7,4.7.9.8,4.7.9.9,4.7.9.10,4.7.10
.1,4.7.10.2,
4.7.10.3,4.7.10.4,4.7.10.5,4.7.10.6,4.7.10.7,4.7.10.8,4.7.10.9,4.7.10.10,4.8.1.
1,4.8.1.2,4.8.1.3,
4.8.1.4, 4.8.1.5, 4.8.1.6, 4.8.1.7, 4.8.1.8, 4.8.1.9, 4.8.1.10, 4.8.2.1,
4.8.2.2, 4.8.2.3, 4.8.2.4, 4.8.2.5,
4.8.2.6, 4.8.2.7, 4.8.2.8, 4.8.2.9, 4.8.2.10, 4.8.3.1, 4.8.3.2, 4.8.3.3,
4.8.3.4, 4.8.3.5, 4.8.3.6, 4.8.3.7,
4.8.3.8, 4.8.3.9, 4.8.3.10, 4.8.4.I, 4.8.4.2, 4.8.4.3, 4.8.4.4, 4.8.4.5,
4.8.4.6, 4.8.4.7, 4.8.4.8, 4.8.4.9,
4.8.4.10, 4.8.5.1, 4.8.5.2, 4.8.5.3, 4.8.5.4, 4.8.5.5, 4.8.5.6, 4.8.5.7,
4.8.5.8, 4.8.5.9, 4.8.5.10, 4.8.6.1,
4.8.6.2, 4.8.6.3, 4.8.6.4, 4.8.6.5, 4.8.6.6, 4.8.6.7, 4.8.6.8, 4.8.6.9,
4.8.6.10, 4.8.7.1, 4.8.7.2, 4.8.7.3,
4.8.7.4, 4.8.;7.5, 4.8.7.6, 4.8.7.7, 4.8.7.8, 4.8.7.9, 4.8.7.10, 4.8.8.1,
4.8.8.2, 4.8.8.3, 4.8.8.4, 4.8.8.5,
4.8.8.6, 4.8.8.7, 4.8.8.8, 4.8.8.9, 4.8.8.10, 4.8.9.1, 4.8.9.2, 4.8.9.3,
4.8.9.4, 4.8.9.5, 4.8.9.6, 4.8.9.7,
4.8.9.8,4.8.9.9,4.8.9.10,4.8.10.1,4.8.10.2,4.8.10.3,4.8.10.4,4.8.10.5,4.8.10.6,
4.8.10.7,4.8.10.8,
4.8.10.9,4.8.10.10,4.9.1.1,4.9.1.2,4.9.1.3,4.9.1.4,4.9.1.5,4.9.1.6,4.9.1.7,4.9.
1.8,4.9.1.9,
4.9.1.10, 4.9.2.1, 4.9.2.2, 4.9.2.3, 4.9.2.4, 4.9.2.5, 4.9.2.6, 4.9.2.7,
4.9.2.8, 4.9.2.9, 4.9.2.10, 4.9.3.1,
4.9.3.2, 4.9.3.3, 4.9.3.4, 4.9.3.5, 4.9.3.6, 4.9.3.7, 4.9.3.8, 4.9.3.9,
4.9.3.1 0, 4.9.4.1, 4.9.4.2, 4.9.4.3,
4.9.4.4, 4.9.4.5, 4.9.4.6, 4.9.4.7, 4.9.4.8, 4.9.4.9, 4.9.4.10, 4.9.5.1,
4.9.5.2, 4.9.5.3, 4.9.5.4, 4.9.5.5,
4.9.5.6, 4.9.5.7, 4.9.5.8, 4.9.5.9, 4.9.5.10, 4.9.6.1, 4.9.6.2, 4.9.6.3,
4.9.6.4, 4.9.6.5, 4.9.6.6, 4.9.6.7,
4.9.6.8, 4.9.6.9, 4.9.6.10, 4.9.7.1, 4.9.7.2, 4.9.7.3, 4.9.7.4, 4.9.7.5,
4.9.7.6, 4.9.7.7, 4.9.7.8, 4.9.7.9,
4.9.7.10, 4.9.8.1, 4.9.8.2, 4.9.8.3, 4.9.8.4, 4.9.8.5, 4.9.8.6, 4.9.8.7,
4.9.8.8, 4.9.8.9, 4.9.8.10, 4.9.9.1,
4.9.9.2, 4.9.9.3, 4.9.9.4, 4.9.9.5, 4.9.9.6, 4.9.9.7, 4.9.9.8, 4.9.9.9,
4.9.9.10, 4.9.10.1, 4.9.10.2,
4.9.10.3, 4.9.10.4, 4.9.10.5, 4.9.10.6, 4.9.10.7, 4.9.1Q.8, 4.9.10.9,
4.9.10.10, 4.10.1.1, 4.10.1.2,
4.10.1.3,4.10.1.4,4.10.1.5,4.10.1.6,4.10.1.7,4.10.1.8,4.10.1.9,4.10.1.10,4.10.2
.1,4.10.2.2,
4.10.2.3,4.10.2.4,4.10.2.5,4.10.2.6,4.10.2.7,4.10.2.8,4.10.2.9,4.10.2.10,4.10.3
.1,4.10.3.2,
4.10.3.3, 4.10.3.4, 4.10.3.5, 4.10.3.6, 4.10.3.7, 4.10.3.8, 4.10.3.9,
4.10.3.10, 4.10.4.1, 4.10.4.2,
3 5 4.1 U.4.3, 4. I U.4.4, 4. I U.4.5, 4. I U.4.6, 4. i U.4.7, 4. I 0.4.8, 4.
I 0.4.9, 4.1 U.4.1 U, 4. I U.S.1, 4. ! U.5.2,
4.10.5.3,4.10.5.4,4.10.5.5,4.10.5.6,4.10.5.7,4.10.5.8,4.J0.5.9,4.10.5.10,4.10.6
.1,4.10.6.2,
4.10.6.3,4.10.6.4,4.10.6.5,4.I0.6.6,4.10.E.7,4.10.6.8,4.10.6.9,4.10.6.10,4.10.7
.1,4.10.7.2,
39
CA 02352205 2001-05-23
WO 00/32177 PCTNS99/28082
4.10.7.3,4.10.7.4,4.10.7.5,4.10.7.6,4.10.7.7,4.10.7.8,4.10.7.9,4.10.7.10,4.10.8
.1,4.10.8.2,
4.10.8.3,4.10.8.4,4.10.8.5,4.10.8.6,4.10.8.7,4.10.8.8,4.10.8.9,4.10.8.10,4.10.9
.1,4.10.9.2,
4.10.9.3,4.10.9.4,4.10.9.5,4.10.9.6,4.10.9.7,4.10.9.8,4.10.9.9,4.10.9.10,4.10.1
0.1,4.IO.I0.2,
4.10.10.3,4.10.10.4,4.10.10.5,4.10.10.6,4.10.10.7,4.10.10.8,4.10.10.9,4.10.10.1
0,5.1.1.1,
5.1.1.2, 5.1.1.3, 5.1.1.4, 5.1.1.5, 5.1.1.6, 5.1.1.7, 5.1.1.8, 5.1.1.9,
5.1.1.10, 5.1.2.1, 5.1.2.2, 5.1.2.3,
5.1.2.4, 5.1.2.5, S.I.2.6, 5.1.2.7, 5.1.2.8, 5.1.2.9, S.I.2.10, 5.1.3:1,
5.1.3.2, 5.1.3.3, 5.1.3.4, 5.1.3.5,
5.1.3.6, 5.1.3.7, 5.1.3.8, 5.1.3.9, 5.1.3.10, 5.1.4.1, 5.1.4.2, 5.1.4.3,
5.1.4.4, 5.1.4.5, 5.1.4.6, 5.1.4.7,
5.1.4.8, 5.1.4.9, 5.1.4.10, 5.1.5.1, 5.1.5.2, 5.1.5.3, 5.1.5.4, 5.1.5.5,
5.1.5.6, 5.1.5.7, 5.1.5.8, 5.1.5.9,
5.1.5.10, 5.1.6.1, 5.1.6.2, 5.1.6.3, 5.1.6.4, 5.1.6.5, 5.1.6.6, 5.1.6.7,
5.1.6.8, 5.1.6.9, 5.1.6.10, 5.1.7.1,
5.1.7.2, 5.1.7.3, 5.1.7.4, 5.1.7.5, 5.1.7.6, 5.1.7.7, 5.1.7.8, 5.1.7.9,
5.1.7.10, 5.1.8.1, 5.1.8.2, 5.1.8.3,
5.1.8.4, 5.1.8.5, 5.1.8.6, 5.1.8.7, 5.1.8.8, 5.1.8.9, 5.1.8.10, 5.1.9.1,
5.1.9.2, 5.1.9.3, 5.1.9.4, 5.1.9.5,
5.1.9.6,5.1.9.7,5.1.9.8,5.1.9.9,5.1.9.10,5.1.10.1,5.1.10.2,5.1.10.3,5.1.10.4,5.
1.10.5,5.1.10.6,
5.1.10.7,5.1.10.8,5.1.10.9,5.1.10.10,5.2.1.1,5.2.1.2,5.2.1.3,5.2.1.4,5.2.1.5,5.
2.1.6,5.2.1.7,
5.2.1.8, 5.2.1.9, 5.2.1.10, 5.2.2.1, 5.2.2.2, 5.2.2.3, 5.2.2.4, 5.2.2.5,
5.2.2.6, 5.2.2.7, 5.2.2.8, 5.2.2.9,
IS
5.2.2.10,5.2.3.1,5.2.3.2,5.2.3.3,5.2.3.4,5.2.3.5,5.2.3.6,5.2.3.7,5.2.3.8,5.2.3.
9,5.2.3.10,5.2.4.1,
5.2.4.2,5.2.4.3,5.2.4.4,5.2.4.5,5.2.4.6,5.2.4.7,5.2.4.8,5.2.4.9,5.2.4.10,5.2.5.
1,5.2.5.2,5.2.5.3,
5.2.5.4, 5.2.5.5, 5.2.5.6, 5.2.5.7, 5.2.5.8, 5.2.5.9, 5.2.5.10, 5.2.6.1,
5.2.6.2, 5.2.6.3, 5.2.6.4, 5.2.6.5,
5.2.6.6, 5.2.6.7, 5.2.6.8, 5.2.6.9, 5.2.6.10, 5.2.7.1, 5.2.7.2, 5.2.7.3,
5.2.7.4, 5.2.7.5, 5.2.7.6, 5.2.7.7,
5.2.7.8, 5.2.7.9, 5.2.7.10, 5.2.8.1, 5.2.8.2, 5.2.8.3, 5.2.8.4, 5.2.8.5,
5.2.8.6, 5.2.8.7, 5.2.8.8, 5.2.8.9,
5.2.8.10, S.Z:9.1, 5.2.9.2, 5.2.9.3, 5.2.9.4, 5.2.9.5, 5.2.9.6, 5.2.9.7,
5.2.9.8, 5.2.9.9, 5.2.9.10,
5.2.10.1, 5.2.10.2, 5.2.10.3, 5.2.10.4, 5.2.10.5, 5.2.10.6, 5.2.10.7,
5.2.10.8, 5.2.10.9, 5.2.10.10,
5.3.1.1, 5.3.1.2, 5.3.1.3, 5.3.1.4, 5.3.1.5, 5.3.1.6, 5.3.1.7, 5.3.1.8,
5.3.1.9, 5.3.1.10, 5.3.2.1, 5.3.2.2,
5.3.2.3, 5.3.2.4, 5.3.2.5, 5.3.2.6, 5.3.2.7, 5.3.2.8, 5.3.2.9, 5.3.2.10,
5.3.3.1, 5.3.3.2, 5.3.3.3, 5.3.3.4,
5.3.3.5, 5.3.3.6, 5.3.3.7, 5.3.3.8, 5.3.3.9, 5.3.3.10, 5.3.4.1, 5.3.4.2,
5.3.4.3, 5.3.4.4, 5.3.4.5, 5.3.4.6,
5.3.4.7, 5.3.4.8, 5.3.4.9, 5.3.4.10, 5.3.5.1, 5.3.5.2, 5.3.5.3, 5.3.5.4,
5.3.5.5, 5.3.5.6, 5.3.5.7, 5.3.5.8,
5.3.5.9, 5.3.5.10, 5.3.6.1, 5.3.6.2, 5.3.6.3, 5.3.6.4, 5.3.6.5, 5.3.6.6,
5.3.6.7, 5.3.6.8, 5.3.6.9, 5.3.6.10,
5.3.7.1, 5.3.7.2, 5.3.7.3, 5.3.7.4, 5.3.7.5, 5.3.7.6, 5.3.7.7, 5.3.7.8,
5.3.7.9, 5.3.7.10, 5.3.8.1, 5.3.8.2,
5.3.8.3, 5.3.8.4, 5.3.8.5, 5.3.8.6, 5.3.8.7, 5.3.8.8, 5.3.8.9, 5.3.8.10,
5.3.9.1, 5.3.9.2, 5.3.9.3, 5.3.9.4,
5.3.9.5, 5.3.9.6, 5.3.9.7, 5.3.9.8, 5.3.9.9, 5.3.9.10, 5.3.10.1, 5.3.10.2,
5.3.10.3, 5.3.10.4, 5.3.10.5,
5.3.10.6,5.3.10.7,5.3.10.8,5.3.10.9,5.3.10.10,5.4.1.1,5.4.1.2,5.4.1.3,5.4.1.4,5
.4.1.5,5.4.1.6,
5.4.1.7, 5.4.1.8, 5.4.1.9, 5.4.1.10, 5.4.2.1, 5.4.2.2, 5 4.2.3, 5.4.2.4,
5.4.2.5, 5.4.2.6, 5.4.2.7, 5.4.2.8,
5.4.2.9, 5.4.2.10, 5.4.3.1, 5.4.3.2, 5.4.3.3, 5.4.3.4, 5.4.3.5, 5.4.3.6,
5.4.3.7, 5.4.3.8, 5.4.3.9, 5.4.3.10,
5.4.4.1, 5.4.4.2, 5.4.4.3, 5.4.4.4, 5.4.4.5, 5.4.4.6, 5.4.4.7, 5.4.4.8,
5.4.4.9, 5.4.4.10, 5.4.5.1, 5.4.5.2,
5.4.5.3, 5.4.5.4, 5.4.5.5, 5.4.5.6, 5.4.5.7, 5.4.5.8, 5.4.5.9, 5.4.5.10,
5.4.6.1, 5.4.6.2, 5.4.6.3, 5.4.6.4,
5.4.6.5, 5.4.6.6, 5.4.6.7, 5.4.6.8, 5.4.6.9, 5.4.6.10, 5.4.7.1, 5.4.7.2,
5.4.7.3, 5.4.7.4, 5.4.7.5, 5.4.7.6,
5.4.7.7, 5.4.7.8, 5.4.7.9, 5.4.7.10, 5.4.8.1, 5.4.8.2, 5.4.8.3,.5.4.8.4,
5.4.8.5, 5.4.8.6, 5.4.8.7, 5.4.8.8,
5.4.8.9, 5.4.8.10, 5.4.9.1, 5.4.9.2, 5.4.9.3, 5.4.9.4, 5.4.9.5, 5.4.9.6,
5.4.9.7, 5.4.9.8, 5.4.9.9, 5.4.9.10,
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
5.4.10.1,5.4.10.2,5.4.10.3,5.4.10.4,5.4.10.5,5.4.10.6,5.4.10.7,5.4.10.8,5.4.10.
9,5.4.10.10,
5.5.1.1, S.S.1.2, S.S.1.3, 5.5.1.4, S.S.1.5, 5.5.1.6, 5.5.1.7, S.S.1.8,
S.S.1.9, S.S.1.10, 5.5.2.1, S.S.2.2,
S.S.2.3, 5.5.2.4, 5.5.2.5, S.S.2.6, 5.5.2.7, 5.5.2.8, S.S.2.9, S.S.2.10,
5.5.3.1, S.S.3.2, 5.5.3.3, S.S.3.4,
5.5.3.5, S.S.3.6, S.S.3.7, 5.5.3.8, S.S.3.9, S.S.3.10, S.S.4.1, 5.5.4.2,
S.S.4.3, S.S.4.4, 5.5.4.5, S.S.4.6,
S.S.4.7, 5.5.4.8, 5.5.4.9, 5.5.4.10, S.S.S.I, S.S.S.2, S.S.5.3, S.S.S.4,
S.S.S.S, S.S.S.6, S.S.5.7, S.S.5.8,
5.5.5.9, S.S.S.10, 5.5.6.1, S.S.6.2, 5.5.6.3,5.5.6.4, 5.5.6.5, 5.5.6:6,
5.5.6.7, 5.5.6.8, 5.5.6.9, S.S.6.10,
5.5.7.1, S.S.7.2, S.S.7.3, S.S.7.4, S.S.7.5, 5.5.7.6, 5.5.7.7, 5.5.7.8,
5.5.7.9, S.S.7.10, 5.5.8.1, S.S.8.2,
5.5.8.3, S.S.8.4, S.S.8.S, 5.5.8.6, 5.5.8.7, 5.5.8.8, S.S.8.9, S.S.8.10,
S.S.9.1, S.S.9.2, 5.5.9.3, S.S.9.4,
S.S.9.S, 5.5.9.6, S.S.9.7, S.S.9.8, S.S.9.9, 5.5.9.10, S.S.10.1, S.S.10.2,
S.S.10.3, 5.5.10.4, S.S.lO.S,
S.S.10.6, S.S.10.7, 5.5.10.8, S.S.10.9, S.S.l0.I0, 5.6.1.1, 5.6.1.2, 5.6.1.3,
5.6.1.4, 5.6.1.5, 5.6.1.6,
5.6.1.7, 5.6.1.8, 5.6.1.9, 5.6.1.10, 5.6.2.1, 5.6.2.2, 5.6.2.3, 5.6.2.4,
5.6.2.5, 5.6.2.6, 5.6.2.7, 5.6.2.8,
5.6.2.9, 5.6.2.10, 5.6.3.1, 5.6.3.2, 5.6.3.3, 5.6.3.4, 5.6.3.5, 5.6.3.6,
5.6.3.7, 5.6.3.8, 5.6.3.9, 5.6.3.10,
5.6.4.1, 5.6.4.2, 5.6.4.3, 5.6.4.4, 5.6.4.5, 5.6.4.6, 5.6.4.7, 5.6.4.8,
5.6.4.9, 5.6.4.10, 5.6.5.1, 5.6.5.2,
5.6.5.3, 5.6.5.4, S.6.S.S, 5.6.5.6, 5.6.5.7, S.6.S.8, 5.6.5.9, 5.6.5.10,
5.6.6.1, 5.6.6.2, 5.6.6.3, 5.6.6.4,
IS 5.6.6.5, 5.6.6.6, 5.6.6.7, 5.6.6.8, 5.6.6.9, 5.6.6.10, 5.6.7.1, 5.6.7.2,
5.6.7.3, 5.6.7.4, 5.6.7.5, 5.6.7.6,
5.6.7.7, 5.6.7.8, 5.6.7.9, 5.6.7.10, 5.6.8.1, 5.6.8.2, 5.6.8.3, 5.6.8.4,
5.6.8.5, 5.6.8.6, 5.6.8.7, 5.6.8.8,
5.6.8.9, 5.6.8.10, 5.6.9.1, 5.6.9.2, 5.6.9.3, 5.6.9.4, 5.6.9.5, 5.6.9.6,
5.6.9.7, 5.6.9.8, 5.6.9.9, 5.6.9.10,
5.6.10.1,5.6.10.2,5.6.10.3,S.6.I0.4,5.6.10.5,5.6.10.6,5.6.10.7,5.6.10.8,5.6.10.
9,5.6.10.10,
5.7.1.1, 5.7.1.2, 5.7.1.3, 5.7.1.4, 5.7.1.5, 5.7.1.6, 5.7.1.7, 5.7.1.8,
5.7.1.9, 5.7.1.10, 5.7.2.1, 5.7.2.2,
5.7.2.3, 5.7.2.4, 5.7.2.5, 5.7.2.6, 5.7.2.7, 5.7.2.8, 5.7.2.9, 5.7.2.10,
5.7.3.1, 5.7.3.2, 5.7.3.3, 5.7.3.4,
5.7.3.5, 5.7.3.6, 5.7.3.7, 5.7.3.8, 5.7.3.9, 5.7.3.10, 5.7.4.1, 5.7.4.2,
5.7.4.3, 5.7.4.4, 5.7.4.5, 5.7.4.6,
5.7.4.7, 5.7.4.8, 5.7.4.9, 5.7.4.10, 5.7.5.1, 5.7.5.2, 5.7.5.3, 5.7.5.4,
S.7.S.S, 5.7.5.6, S.7.S.7, 5.7.5.8,
S.7.S.9, 5.7.5.10, 5.7.6.1, 5.7.6.2, 5.7.6.3, 5.7.6.4, 5.7.6.5, 5.7.6.6,
5.7.6.7, 5.7.6.8, 5.7.6.9, 5.7.6.10,
5.7.7.1, 5.7.7.2, 5.7.7.3, 5.7.7.4, 5.7.7.5, 5.7.7.6, 5.7.7.7, 5.7.7.8,
5.7.7.9, 5.7.7.10, 5.7.8.1, 5.7.8.2,
5.7.8.3, 5.7.8.4, 5.7.8.5, 5.7.8.6, 5.7.8.7, 5.7.8.8, 5.7.8.9, 5.7.8.10,
5.7.9.1, 5.7.9.2, 5.7.9.3, 5.7.9.4,
5.7.9.5,5.7.9.6,5.7.9.7,5.7.9.8,5.7.9.9,5.7.9.10,5.7.10.1,5.7.10.2,5.7.10.3,5.7
.10.4,5.7.10.5,
5.7.10.6,5.7.10.7,5.7.10.8,5.7.10.9,5.7.10.10,5.8.1.1,5.8.1.2,5.8.1.3,5.8.1.4,5
.8.1.5,5.8.1.6,
5.8.1.7, 5.8.1.8, 5.8.1.9, 5.8.1.10, 5.8.2.1, 5.8.2.2, 5.8.2.3, 5.8.2.4,
5.8.2.5, 5.8.2.6, 5.8.2.7, 5.8.2.8,
5.8.2.9, 5.8.2.10, 5.8.3.1, 5.8.3.2, 5.8.3.3, 5.8.3.4, 5.8.3.5, 5.8.3.6,
5.8.3.7, 5.8.3.8, 5.8.3.9, 5.8.3.10,
3 0 5.8.4.1, 5.8.4.2, 5.8.4.3, 5.8.4.4, 5.8.4.5, 5.8.4.6, 5.8.4.7, 5.8.4.8,
5.8.4.9, 5.8.4.10, 5.8.5.1, 5.8.5.2,
5.8.5.3, 5.8.5.4, 5.8.5.5, 5.8.5.6, 5.8.5.7, 5.8.5.8, 5.8.5.9, 5.8.5.10,
5.8.6.1, 5.8.6.2, 5.8.6.3, 5.8.6.4,
5.8.6.5, 5.8.6.6, 5.8.6.7, 5.8.6.8, 5.8.6.9, 5.8.6.10, 5.8.7.1, 5.8.7.2,
5.8.7.3, 5.8.7.4, 5.8.7.5, 5.8.7.6,
5.8.7.7, 5.8.7.8, 5.8.7.9, 5.8.7.10, 5.8.8.1, 5.8.8.2, 5.8.8.3, 5.8.8.4,
5.8.8.5, 5.8.8.6, 5.8.8.7, 5.8.8.8,
5.8.8.9, 5.8.8.10, 5.8.9.1, 5.8.9.2, 5.8.9.3, 5.8.9.4, 5.8.9.5, 5.8.9.6,
5.8.9.7, 5.8.9.8, 5.8.9.9, 5.8.9_10,
5.8.10.1,5.8.10.2,5.8.10.3,5.8.10.4,5.8.10.5,5.8.10.6,5.8.10.7,5.8.10.8,5.8.10.
9,5.8.10.10,
5.9.1.1, 5.9.1.2, 5.9.1.3, 5.9.1.4, 5.9.1.5, 5.9.1.6, 5.9.1.7, 5.9.1.8,
5.9.1.9, 5.9.1.10, 5.9.2.1, 5.9.2.2,
5.9.2.3, 5.9.2.4, 5.9.2.5, 5.9.2.6, 5.9.2.7, 5.9.2.8, 5.9.2.9, 5.9.2.10,
5.9.3.1, 5.9.3.2, 5.9.3.3, 5.9.3.4,
41
CA 02352205 2001-05-23
WO 00/32177 PGT/US99/28082
5.9.3.5, 5.9.3.6, 5.9.3.7, 5.9.3.8, 5.9.3.9, 5.9.3.IU, 5.9.4.1, 5.9.4.2,
5.9.4.3, 5.9.4.4, 5.9.4.5, 5.9.4.6, _
5.9.4.7,5.9.4.8,5.9.4.9,5.9.4.10,5.9.S.I,5.9.5.2,5.9.5.3,5.9.5.4,5.9.5.5,5.9.5.
6,5.9.5.7,5.9.5.8,
5.9.5.9, 5.9.5.10, 5.9.6.1, 5.9.6.2, 5.9.6.3, 5.9.6.4, 5.9.6.5, 5.9.6.6,
5.9.6.7, 5.9.6.8, 5.9:6.9, 5.9.6.10,
5.9.7.1, 5.9.7.2, 5.9.7.3, 5.9.7.4, 5.9.7.5, 5.9.7.6, 5.9.7.7, 5.9.7.8,
5.9.7.9, 5.9.7.10, 5.9.8.1, 5.9.8.2,
5.9.8.3, 5.9.8.4, 5.9.8.5, 5.9.8.6, 5.9.8.7, 5.9.8.8, 5.9.8.9, 5.9.8.10,
5.9.9.1, 5.9.9.2, 5.9.9.3, 5.9.9.4,
5.9.9.5,5.9.9.6,5.9.9.7,5.9.9.8,5.9.9.9,5.9.9.10,5.9.10.1,5.9.10.2,5.9.10.3,5.9
.10.4,5.9.10.5,
_
5.9.10.6,5.9.10.7,5.9.10.8,5.9.10.9,5.9.10.10,5.10.1.1,5.10.1.2,5.10.1.3,5.10.1
.4,5.10.1.5,
5.10.1.6, 5.10.1.7, 5.10.1.8, 5.10.1.9, 5.10.1.10, 5.10.2.1, 5.10.2.2,
5.10.2.3, S. i 0.2.4, 5.10.2.5,
5.10.2.6,5.10.2.7,5.10.2.8,5.10.2.9,5.10.2.10,5.10.3.1,5.10.3.2,5.10.3.3,5.10.3
.4,5.10.3.5,
5.10.3.6,5.10.3.7,S.I0.3.8,S.I0.3.9,5.10.3.10,5.10.4.1,5.10.4.2,5.10.4.3,5.10.4
.4,5.10.4.5,
5.10.4.6,5.10.4.7,5.10.4.8,5.10.4.9,5.10.4.10,5.10.5.1,5.10.5.2,5.10.5.3,5.10.5
.4,5.10.5.5,
5.10.5.6, 5.10.5.7, 5.10.5.8, 5.10.5.9, 5.10.5.10, 5.10.6.1, 5.10.6.2,
5.10.6.3, 5.10.6.4, 5.10.6.5,
5.10.6.6, 5.10.6.7, 5.10.6.8, 5.10.6.9, 5.10.6.10, 5.10.7.1, 5.10.7.2,
5.10.7.3, 5.10.7.4, 5.10.5,
5.10.7.6,5.10.7.7,5.10.7.8,5.10.7.9,5.10.7.10,5.10.8.1,5.10.8.2,5.10.8.3,5.10.8
.4,5.10.8.5,
5.10.8.6, 5.10.8.7, 5.10.8.8, 5.10.8.9, 5.10.8.10, 5.10.9.1, 5.10.9.2,
5.10.9.3, 5.10.9.4, S.I0.9.5,
5.10.9.6, 5.10.9.7, 5.10.9.8, 5.10.9.9, 5.10.9.10, 5.10.10.1, 5.10.10.2,
5.10.10.3, 5.10.10.4,
5. i 0. I 0. S, 5.10.10.6, 5.10.10.7, 5.10.10.8, 5.10.10.9, 5.10.10. t 0,
6.1.1.1, 6.1.1.2, 6.1.1.3, 6.1.1.4,
6.1.1.5, 6.1.1.6, 6.1.1.7, 6.1.1.8, 6.1.1.9, 6.1.1.10, 6.1.2.1, 6.1.2.2,
6.1.2.3, 6.1.2.4, 6.1.2.5, 6.1.2.6,
6.1.2.7, 6.1.2.8, 6.1.2.9, 6.1.2.10, 6.1.3.1, 6.1.3.2, 6.1.3.3, 6.1.3.4,
6.1.3.5, 6.1.3.6, 6.1.3.7, 6.1.3.8,
6.1.3.9, 6.1.$.10, 6.1.4.1, 6.1.4.2, 6.1.4.3, 6.1.4.4, 6.1.4.5, 6.1.4.6,
6.1.4.7, 6.1.4.8, 6.1.4.9, 6.1.4.10,
6.1.5.1, 6.1.5.2, 6.1.5.3, 6.1.5.4, 6.1.5.5, 6.1.5.6, 6.1.5.7, 6.1.5.8,
6.1.5.9, 6.1.5.10, 6.1.6.1, 6.1.6.2,
6.1.6.3, 6.1.6.4, 6.1.6.5, 6.1.6.6, 6.1.6.7, 6.1.6.8, 6.1.6.9, 6.1.6.10,
6.1.7.1, 6.1.7.2, 6.1.7.3, 6.1.7.4,
6.1.7.5, 6.1.7.6, 6.1.7.7, 6.1.7.8, 6.1.7.9, 6.1.7.10, 6.1.8.1, 6.1.8.2,
6.1.8.3, 6.1.8.4, 6.1.8.5, 6.1.8.6,
6.1.8.7, 6.1.8.8, 6.1.8.9, 6.1.8.10, 6.1.9.1, 6.1.9.2, 6.1.9.3, 6.1.9.4,
6.1.9.5, 6.1.9.6, 6.1.9.7, 6.1.9.8,
6.1.9.9, !.1.9.10, C. I .10.1, 6.1.10.2, 6.1.10.3, 6.1.10.4, 6.1.10.5,
(.1.10.6, 0.1.10.7, 6.1.10.8,
6.1.1 U.9, G. I . I U. I U, G.2. I . l , 6.2.1.2, G.Z. I .3, G.2. I .4, G.2. i
.S, G.2. I .G, 6.2.1.7, 6.2.1.8, 6.2.1.9,
6.2.1.10, 6.2.2.1, 6.2.2.2, 6.2.2.3, 6.2.2.4, 6.2.2.5, 6.2.2.6, 6.2.2.7,
6.2.2.8, 6.2.2.9, 6.2.2.10, 6.2.3.1,
6.2.3.2, 6.2.3.3, 6.2.3.4, 6.2.3.5, 6.2.3.6, 6.2.3.7, 6.2.3.8, 6.2.3.9,
6.2.3.10, 6.2.4.1, 6.2.4.2, 6.2.4.3,
6.2.4.4, 6.2.4.5, 6.2.4.6, 6.2.4.7, 6.2.4.8, 6.2.4.9, 6.2.4.10, 6.2.5.1,
6.2.5.2, 6.2.5.3, 6.2.5.4, 6.2.5.5,
3 0 6.2.5.6, 6.2.5.7, 6.2.5.8, 6.2.5.9, 6.2.5.10, 6.2.6.1, 6.2.6.2, 6.2.6.3,
6.2.6.4, 6.2.6.5, 6.2.6.6, 6.2.6.7,
6.2.6.8, 6.2.6.9, 6.2.6.10, 6.2.7.1, 6.2.7.2, 6.2.7.3, 6.2.7.4, 6.2.7.5,
6.2.7.6, 6.2.7.7, 6.2.7.8, 6.2.7.9,
6.2.7.10, 6.2.8.1, 6.2.8.2, 6.2.8.3, 6.2.8.4, 6.2.8.5, 6.2.8.6, 6.2.8.7,
6.2.8.8, 6.2.8.9, 6.2.8.10, 6.2.9.1,
6.2.9.2,6.2.9.3,6.2.9.4,6.2.9.5,6.2.9.6,6.2.9.7,6.2.9.8,6.2.9.9,6.2.9.10,6.2.10
.1,6.2.10.2,
6.2.10.3,6.2.10.4,6.2.10.5,6.2.10.6,6.2.10.7,6.2.10.8,6.2.10.9,6.2.10.10,6.3.1.
1,6.3.1.2,6.3:1.3,
6.3.1.4, 6.3.1.5, 6.3.1.6, 6.3.1.7, 6.3.1.8, 6.3.1.9, 6.3.1.10, 6.3.2.1,
6.3.2.2, 6.3.2.3, 6.3.2.4, 6.3.2.5,
6.3.2.6, 6.3.2.7, 6.3.2.8, 6.3 .2.9, 6.3.2.10, 6.3.3.1, 6.3.3 .2, .6.3.3.3,
6.3.3.4, 6.3 .3 .5, 6.3.3.6, 6.3.3.7,
6.3.3.8, 6.3.3.9, 6.3.3.10, 6.3.4.1, 6.3.4.2, 6.3.4.3, 6.3.4.4, 6.3.4.5,
6.3.4.6, 6.3.4.7, 6.3.4.8, 6.3.4.9,
42
s
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
6.3.4.10, 6.3.5.1, 6.3.5.2, 6.3.5.3, 6.3.5.4, 6.3.5.5, 6.3.5.6, 6.3.5.7,
6.3.5.8, 6.3.5.9, 6.3.5.10, 6.3.6.1,
6.3.6.2, 6.3.6.3, 6.3.6.4, 6.3.6.5, 6.3.6.6, 6.3.6.7, 6.3.6.8, 6.3.6.9,
6.3.6.10, 6.3.7.1, 6.3.7.2, 6.3.7.3,
6.3.7.4, 6.3.7.5, 6.3.7.6, 6.3.7.7, 6.3.7.8, 6.3.7.9, 6.3.7.10, 6.3.8.1,
6.3.8.2, 6.3.8.3, 6.3:8.4, 6.3.8.5,
6.3.8.6, 6.3.8.7, 6.3.8.8, 6.3.8.9, 6.3.8.10, 6.3.9.1, 6.3.9.2, 6.3.9.3,
6.3.9.4, 6.3.9.5, 6.3.9.6, 6.3.9.7,
6.3.9.8,6.3.9.9,6.3.9.10,6.3.10.1,6.3.10.2,6.3.10.3,6.3.10.4,6.3.10.5,6.3.10.6,
6.3.10.7,6.3.10.8,
6.3.10.9,6.3.10.10,6.4.1.1,6.4.1.2,6.4.1.3,6.4.1.4,6.4.1.5,6.4.1.6,6.4.1.7,6.4.
1.8,6.4.1.9,
6.4.1.1 0, 6.4.2.1, 6.4.2.2, 6.4.2.3, 6.4.2.4, 6.4.2.5, 6.4.2.6, 6.4.2.7,
6,4.2.8, 6.4.2.9, 6.4.2.1 0, 6.4.3.1,
6.4.3.2,6.4.3.3,6.4.3.4,6.4.3.5,6.4.3.6,6.4.3.7,6.4.3.8,6.4.3.9,6.4.3.10,6.4.4.
I,6.4.4.2,6.4.4.3,
6.4.4.4,6.4.4.5,6.4.4.6, 6.4.4.7, 6.4.4.8, 6.4.5.2,6.4.5.3,6.4.5.4,
6.4.4.9, 6.4.4.10, 6.4.5.1, 6.4.5.5,
106.4.5.6,6.4.5.7,6.4.5.8, 6.4.5.9, 6.4.5.10, 6.4.6.4,6.4.6.5,6.4.6.6,
6.4.6.1, 6.4.6.2, 6.4.6.3, 6.4.6.7,
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156.5.1.4,6.5.1.5,6.5.1.6, 6.5.1.7, 6.5.1.8, 6.5.2.2,6.5.2.3,6.5.2.4,
6.5.1.9, 6.5.1.10, 6.5.2.1, 6.5.2.5,
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6.5.3.1, 6.5.3.2, 6.5.3.3, 6.5.3.7,
6.5.3.8,6.5.3.9,6.5.3.10, 6.5.4.1, 6.5.4.2, 6.5.4.6,6.5.4.7,6.5.4.8,
6.5.4.3, 6.5.4.4, 6.5.4.5, 6.5.4.9,
6.5.4.10, 6.5.5.8,6.5.5.9,6.5.5.10,
6.5.5.1, 6.5.6.1,
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6.5.6.10,
206.5.7.4,6.S.y.S,6.5.7.6, 6.5.7.7, 6.5.7.8, 6.5.8.2,6.5.8.3,6.5.8.4,
6.5.7.9, 6.5.7.10, 6.5.8.1, 6.5.8.5,
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8,6.6.1.9,
6.6.1.10, , 6.6.2.2, 6.6.2.3, 6.6.2.4,6.6.2.8,6.6.2.9,6.6.2.10,
6.6.2.1 6.6.2.5, 6.6.2.6, 6.6.2.7, 6.6.3.1,
256.6.3.2,6.6.3.3,6.6.3.4, 6.6.3.5, 6.6.3.6, .6.3.10,6.6.4.1,6.6.4.2,
6.6.3.7, 6.6.3.8, 6.6.3.9, 6.6.4.3,
6
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6.6.6.8,6.6.6.9,6.6.6.10, 6.6.7.1, 6.6.7.2, 6.6.7.6,6.6.7.7,6.6.7.8,
6.6.7.3, 6.6.7.4, 6.6.7.5, 6.6.7.9,
6.6.7.10, , 6.6.8.2, 6.6.8.3, 6.6.8.4,6.6.8.8,6.6.8.9,6.6.8.10,
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6.7.1.4,6.7.1.5,6.7.1.6, 6.7.1.7, 6.7.1.8, 6.7.2.2,6.7.2.3,6.7.2.4,
6.7.1.9, 6.7.1.10, 6.7.2.1, 6.7.2.5,
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6.7.3.1, 6.7.3.2, 6.7.3.3, 6.7.3.7,
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6.7.4.3, 6.7.4.4, 6.7.4.5, 6.7.4.9,
356.7.4.10,6.7.5.1,6.7.5.2,6.7.5.3,6.7.5.4,6.7.5.5,6.7.5.6,6.7.5.7,
6.7.5.8,6.7.5.9,6.7.5.10,6.7.6.1,
6.7.6.2,6.7.6.3,6.7.6.4, 6.7.6.5, 6.7.6.6, .7.6.10,6.7.7.1,6.7.7.2,
6.7.6.7, 6.7.6.8, 6.7.6.9, 6.7.7.3,
6
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6.7.7.9, 6.7.7.10, 6.7.8.1, 6.7.8.5,
43
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
6.7.8.6, 6.7.8.7, 6.7.8.8, 6.7.8.9, 6.7.8.10, 6.7.9.1, 6.7.9.2, 6.7.9.3,
6.7.9.4, 6.7.9.5, 6.7.9.6, 6.7.9.7,
6.7.9.8,6.7.9.9,6.7.9.10,6.7.10.1,6.7.10.2,6.7.10.3,6.7.10.4,6.7.10.5,6.7.10.6,
6.7.10.7,6.7.10.8,
6.7.10.9,6.7.10.10,6.8.1.1,6.8.1.2,6.8.1.3,6.8.1.4,6.8.1.5,6.8.1.6,6.8.I.7,6.8.
1.8,6:8.1.9,
6.8.1.10, 6.8.2.1, 6.8.2.2, 6.8.2.3, 6.8.2.4, 6.8.2.5, 6.8.2.6, 6.8.2.7,
6.8.2.8, 6.8.2.9, 6.8.2.10, 6.8.3.1,
6.8.3.2, 6.8.3.3, 6.8.3.4, 6.8.3.5, 6.8:3.6, 6.8.3.7, 6.8.3.8, 6.8.3.9,
6.8.3.10, 6.8.4.1, 6.8.4.2, 6.8.4.3,
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6.8.5.2, 6.8.5.3, 6.8.5.4, 6.8.5.5,
6.8.5.6, 6.8.5.7, 6.8.5.8, 6.8.5.9, 6.8.5.10, 6.8.6.1, 6.8.6.2, 6.8.6.3,
6.8.6.4, 6.8.6.5, 6.8.6.6, 6.8.6.7,
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6.8.9.2,6.8.9.3,6.8.9.4,6.8.9.5,6.8.9.6,6.8.9.7,6.8.9.8,6.8.9.9,6.8.9.10,6.8.10
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6.9.2.2, 6.9.2.3, 6.9.2.4, 6.9.2.5,
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6.9.4.6, 6.9.4.7, 6.9.4.8, 6.9.4.9,
IS
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7.1.9.9, 7.1.9.10, 7.1.10.1,
44
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
7.1.10.2,7.t.10.3,7.1.10.4,7.1.10.5,7.1.10.6,7.1.10.7,7.1.10.8,7.1.10.9,7.1.10.
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7.2.1.10, 7.2.2.1, 7.2.2.2, 7.2.2.3,
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7.2.4.4, 7.2.4.5, 7.2.4.6, 7.2.4.7,
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7.2.6.8, 7.2.6.9, 7.2.6.1 0, 7.2.7.1,
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7.3.6.2, 7.3.6.3, 7.3.6.4, 7.3.6.5,
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s
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
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46
CA 02352205 2001-05-23
WO 00/32177 PCTNS99/28082
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47
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
8.4.8.6, 8.4.8.7, 8.4.8.8, 8.4.8.9, 8.4.8.10, 8.4.9.1, 8.4.9.2, 8.4.9.3,
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48
CA 02352205 2001-05-23
WO 00132177 PCTNS99/28082
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49
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
9.3.3.5, 9.3.3.6, 9.3.3.7, 9.3.3.8, 9.3.3.9, 9.3.3.10, 9.3.4.1, 9.3.4.2,
9.3.4.3, 9.3.4.4, 9.3.4.5, 9.3.4.6,
9.3.4.7, 9.3.4.8, 9.3.4.9, 9.3.4.10, 9.3.5.1, 9.3.5.2, 9.3.5.3, 9.3.5.4,
9.3.5.5, 9.3.5.6, 9.3.5.7, 9.3.5.8,
9.3.5.9, 9.3.5.10, 9.3.6.1, 9.3.6.2, 9.3.6.3, 9.3.6.4, 9.3.6.5, 9.3.6.6,
9.3.6.7, 9.3.6.8, 9.3.6.9, 9.3.6.10,
9.3.7.1, 9.3.7.2, 9.3.7.3, 9.3.7.4, 9.3.7.5, 9.3.7.6, 9.3.7.7, 9.3.7.8,
9.3.7.9, 9.3.7.10, 9.3.8.1, 9.3.8.2,
9.3.8.3, 9.3.8.4, 9.3.8.5, 9.3.8.6, 9.3.8.7, 9.3.8.8, 9.3.8.9, 9.3.8.10,
9.3.9.1, 9.3.9.2, 9.3.9.3. 9.3.9.4,
9.3.9.5, 9.3.9.6, 9.;1.9.7, 9.3.9.8, 9.3.9.9, 9.3.9.10, 9.3.10.1, 9.3.10.2,
9.3.10.3, 9.3.10.4, 9.3.10.5,
9.3.10.6,9.3.10.7,9.3.10.8,9.3.10.9,9.3.10.10,9.4.I.1,9.4.1.2,9.4.1.3,9.4.1.4,9
.4.1.5,9.4.1.6,
9.4.1.7, 9.4.1.8, 9.4.1.9, 9.4.1.10, 9.4.2.1, 9.4.2.2, 9.4.2.3, 9.4.2.4,
9.4.2.5, 9.4.2.6, 9.4.2.7, 9.4.2.8,
9.4.2.9, 9.4.2.10, 9.4.3.1, 9.4.3.2, 9.4.3.3, 9.4.3.4, 9.4.3.5, 9.4.3.6,
9.4.3.7, 9.4.3.8, 9.4.3.9, 9.4.3.10,
9.4.4.1, 9.4.4.2, 9.4.4.3, 9.4.4.4, 9.4.4.5, 9.4.4.6, 9.4.4.7, 9.4.4.8,
9.4.4.9, 9.4.4.10, 9.4.5.1, 9.4.5.2,
9.4.5.3, 9.4.5.4, 9.4.5.5, 9.4.5.6, 9.4.5.7, 9.4.5.8, 9.4.5.9, 9.4.5.10,
9.4.6.1, 9.4.6.2, 9.4.6.3, 9.4.6.4,
9.4.6.5, 9.4.6.6, 9.4.6.7, 9.4.6.8, 9.4.6.9, 9.4.6.10, 9.4.7.1, 9.4.7.2,
9.4.7.3, 9.4.7.4, 9.4.7.5, 9.4.7.6,
9.4.7.7, 9.4.7.8, 9.4.7.9, 9.4.7.10, 9.4.8.1, 9.4.8.2, 9.4.8.3, 9.4.8.4,
9.4.8.5, 9.4.8.6, 9.4.8.7, 94.8.8,
9.4.8.9, 9.4.8.10, 9.4.9.1, 9.4.9.2, 9.4.9.3, 9.4.9.4, 9.4.9.5, 9.4.9.6,
9.4.9.7, 9.4.9.8, 9.4.9.9, 9.4.9.10,
IS
9.4.10.1,9.4.10.2,9.4.10.3,9.4.10.4,9.4.10.5,9.4.10.6,9.4.10.7,9.4.10.8,9.4.10.
9,9.4.10.10,
9.5.1.1, 9.5.1.2, 9.5.1.3, 9.5.1.4, 9.5.1.5, 9.5.1.6, 9.5.1.7, 9.5.1.8,
9.5.1.9, 9.5.1.10, 9.5.2.1, 9.5.2.2,
9.5.2.3, 9.5.2.4, 9.5.2.5, 9.5.2.6, 9.5.2.7, 9.5.2.8, 9.5.2.9, 9.5.2.10,
9.5.3.1, 9.5.3.2, 9.5.3.3, 9.5.3.4,
9.5.3.5, 9.5.3.6, 9.5.3.7, 9.5.3.8, 9.5.3.9, 9.5.3.10, 9.5.4.1, 9.5.4.2,
9.5.4.3, 9.5.4.4, 9.5.4.5, 9.5.4.6,
9.5.4.7, 9.5.4.8, 9.5.4.9, 9.5.4.10, 9.5.5.1, 9.5.5.2, 9.5.5.3, 9.5.5.4,
9.5.5.5, 9.5.5.6, 9.5.5.7, 9.5.5.8,
9.5.5.9, 9.5.5.10, 9.5.6.1, 9.5.6.2, 9.5.6.3, 9.5.6.4, 9.5.6.5, 9.5.6.6,
9.5.6.7, 9.5.6.8, 9.5.6.9, 9.5.6.10,
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9.5.7.9, 9.5.7.10, 9.5.8.1, 9.5.8.2,
9.5.8.3, 9.5.8.4, 9.5.8.5, 9.5.8.6, 9.5.8.7, 9.5.8.8, 9.5.8.9, 9.5.8.10,
9.5.9.1, 9.5.9.2, 9.5.9.3, 9.5.9.4,
9.5.9.5, 9.5.9.6, 9.5.9.7, 9.5.9.8, 9.5.9.9, 9.5.9.10, 9.5.10.1, 9.5.10.2,
9.5.10.3, 9.5.10.4, 9.5.10.5,
9.5.10.6,9.5.10.7,9.5.10.8,9.5.10.9,9.5.10.10,9.6.1.1,9.6.1.2,9.6.1.3,9.6.1.4,9
.6.1.5,9.6.1.6,
9.6.1.7, 9.6.1.8, 9.6.1.9, 9.6.1.10, 9.6.2.1, 9.6.2.2, 9.6.2.3, 9.6.2.4,
9.6.2.5, 9.6.2.6, 9.6.2.7, 9.6.2.8,
9.6.2.9, 9.6.2.I0, 9.6.3.1, 9.6.3.2, 9.6.3.3, 9.6.3.4, 9.6.3.5, 9.6.3.6,
9.6.3.7, 9.6.3.8, 9.6.3.9, 9.6.3.10,
9.6.4.1, 9.6.4.2, 9.6.4.3, 9.6.4.4, 9.6.4.5, 9.6.4.6, 9.6.4.7, 9.6.4.8,
9.6.4.9, 9.6.4.10, 9.6.5.1, 9.6.5.2,
9.6.5.3, 9.6.5.4, 9.6.5.5, 9.6.5.6, 9.6.5.7, 9.6.5.8, 9.6.5.9, 9.6.5.10,
9.6.6.1, 9.6.6.2, 9.6.6.3, 9.6.6.4,
9.6.6.5, 9.6.6.6, 9.6.6.7, 9.6.6.8, 9.6.6.9, 9.6.6.10, 9.6.7.1, 9.6.7.2,
9.6.7.3, 9.6.7.4, 9.6.7.5, 9.6.7.6,
3 0 9.6.7.7, 9.6.7.8, 9.6.7.9, 9.6.7.10, 9.6.8.1, 9.6.8.2, 9.6.8.3, 9.6.8.4,
9.6.8.5, 9.6.8.6, 9.6.8.7, 9.6.8.8,
9.6.8.9,9.6.8.10,9.6.9.1,9.6.9.2,9.6.9.3,9.6.9.4,9.6_9.5,9.6.9.6,9.6.9.7,9.6.9.
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9,9.6.10.10,
9.7.1.1, 9.7.1.2, 9.7.1.3, 9.7.1.4, 9.7.1.5, 9.7.I.6, 9.7.1.7, 9.7.1.8,
9.7.1.9, 9.7.I.10, 9.7.2.1, 9.7.2.2,
9.7.2.3, 9.7.2.4, 9.7.2.5, 9.7.2.6, 9.7.2.7, 9.7.2.8, 9.7.2.9, 9.7.2.10,
9.7.3.1, 9.7.3.2, 9.7.3.3, 9.7.3.4,
9.7.3.5, 9.7.3.6, 9.7.3.7, 9.7.3.8, 9.7.3.9, 9.7.3.10, 9.7.4.1, 9.7.4.2,
9.7.4.3, 9.7.4.4, 9.7.4.5, 9.7.4.6,
9.7.4.7, 9.7.4.8, 9.7.4.9, 9.7.4.10, 9.7.5.1, 9.7.5.2, 9.7.5.3, 9.7.5.4,
9.7.5.5, 9.7.S.G, 9.7.5.7, 9.7.5.8,
9.7.5.9, 9.7.5.10, 9.7.6.1, 9.7.6.2, 9.7.6.3, 9.7.6.4, 9.7.6.5, 9.7.6.6,
9.7.6.7, 9.7.6.8, 9.7.6.9, 9.7.6.10,
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/Z8082
9.7.7.1, 9.7.7.2, 9.7.7.3, 9.7.7.4, 9.7.7.5, 9.7.7.6, 9.7.7.7, 9.7.7.8,
9.7.7.9, 9.7.7.10, 9.7.8.1, 9.7.8.2, .
9.7.8.3, 9.7.8.4, 9.7.8.5, 9.7.8.6, 9.7.8.7, 9.7.8.8, 9.7.8.9, 9.7.8.10,
9.7.9.1, 9.7.9.2, 9.7.9.3, 9.7.9.4,
9.7.9.5,9.7.9.6,9.7.9.7,9.7.9.8,9.7.9.9,9.7.9.10,9.7.10.1,9.7.10.2,9.7.10.3,9.7
.10:4,9.7.10.5,
9.7.10.6,9.7.10.7,9.7.10.8,9.7.10.9,9.7.10.10,9.8.1.1,9.8.1.2,9.8.1.3,9.8.1.4,9
.8.1.5,9.8.1.6,
9.8.1.7, 9.8.1.8, 9.8.1.9, 9.8.1.10, 9.8.2.1, 9.8.2.2, 9.8.2.3, 9.8.2.4,
9.8.2.5, 9.8.2.6, 9.8.2.7, 9.8.2.8,
9.8.2.9, 9.8.2.10, 9.8.3.1, 9.8.3.2, 9.8.3.3, 9.8.3.4, 9.8.3.5, 9.8.3:6,
9.8.3.7, 9.8.3.8, 9.8.3.9, 9.8.3.10,
9.8.4.1, 9.8.4.2, 9.8.4.3, 9.8.4.4,
9.8.4.5, 9.8.4.6, 9.8.4.7, 9.8.4.8,
9.8.4.9, 9.8.4.10, 9.8.5.1, 9.8.5.2,
9.8.5.3, 9.8.5.4, 9.8.5.5, 9.8.5.6, 9.8.6.1, 9.8.6.2,
9.8.5.7, 9.8.5.8, 9.8.5.9, 9.8.5.10, 9.8.6.3, 9.8.6.4,
9.8.6.5, 9.8.6.6, 9.8.6.7, 9.8.6.8, 9.8.7.3, 9.8.7.4,
9.8.6.9, 9.8.6.10, 9.8.7.1, 9.8.7.2, 9.8.7.5, 9.8.7.6,
9.8.7.7, 9.8.7.8, 9.8.7.9, 9.8.7.10, 9.8.8.5, 9.8.8.6,
9.8.8.1, 9.8.8.2, 9.8.8.3, 9.8.8.4, 9.8.8.7, 9.8.8.8,
9.8.8.9, 9.8.8.10, 9.8.9.1, 9.8.9.2, 9.8.9.7, 9.8.9.8,
9.8.9.3, 9.8.9.4, 9.8.9.5, 9.8.9.6, 9.8.9.9, 9.8.9.10,
9.8.10.1, 9.8.10.2, 9.8. I 0.3, 9.8.10.4,9. 8.10.8, 9. 8.10.9,
9.8.10.5, 9.8.10.6, 9.8.10.7, 9.8.10. I 0,
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9.9.1.5, 9.9.1.6, 9.9.1.7, 9.9.1.8,
9.9.1.9, 9.9.1.10, 9.9.2.1,x.9.2.2,
9.9.2.3, 9.9.2.4, 9.9.2.5, 9.9.2.6, 9.9.3.1, 9.9.3.2,
9.9.2.7, 9.9.2.8, 9.9.2.9, 9.9.2.10, 9.9.3.3, 9.9.3.4,
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9.9.4.7, 9.9.4.8, 9.9.4.9, 9.9.4.10, 9.9.5.5, 9.9.5.6,
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2,10.1.7.3,
51
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
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10.1.9.1, 10.1.9.2, 10.1.9.3,
10.1.9.4,10.1.9.5,10.1.9.6,10.1.9.7,10.1.9.8,10.1.9.9,10.1.9.10,10.1.10.1,10.1.
10.2,10.1.10.3,
10.1.10.4,10.1.10.5,10.1.10.6,10.1.10.7,10.1.10.8,I0.1.10.9,10.1.10.10,10.2.1.1
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10.2.1.3,10.2.1.4,10.2.1.5,10.2.1.6,10.2.1.7,10.2.I.8,10.2.1.9,10.2.1.I0,10.2.2
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10.2.4.3, 10.2.4.4, 10.2.4.5, 10.2.4.6, 10.2.4.7, 10.2.4.8, 10.2.4.9,
10.2.4.10, 10.2.5.1, 10.2.5.2,
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.1,10.2.9.2,
10.2.9.3, 10.2.9.4, 10.2.9.5, 10.2.9.6, 10.2.9.7, 10.2.9.8, 10.2.9.9,
10.2.9.10, 10.2.10.1, 10.x.10.2,
10.2.10.3,10.2.10.4,10.2.10.5,10.2.10.6,10.2.10.7,10.2.10.8,10.2.10.9,10.2.10.1
0,10.3.1.1,
10.3.1.2,10.3.1.3,10.3.1.4,10.3.1.5,10.3.1.6,10.3.1.7,10.3.1.8,10.3.1.9,10.3.1.
10,10.3.2.1,
10.3.2.2, 10.3.2.3, 10.3.2.4, 10.3.2.5, 10.3.2.6, 10.3.2.7, 10.3.2.8,
10.3.2.9, 10.3.2.10, 10.3.3.1,
10.3.3.2,10.3.3.3,10.3.3.4,10.3.3.5,10.3.3.6,10.3.3.7,10.3.3.8,10.3.3.9,10.3.3.
10,10.3.4.1,
10.3.4.2,10.3.4.3,10.3.4.4,10.3.4.5,10.3.4.6,10.3.4.7,10.3.4.8,10.3.4.9,10.3.4.
10,10.3.5.1,
10.3.5.2,10.3.5.3,10.3.5.4,I0.3.5.5,10.3.5.6,10.3.5.7,10.3.5.8,10.3.5.9,10.3.5.
10,10.3.6.1,
10.3.6.2,10;3.6.3,10.3.6.4,10.3.6.5,10.3.6.6,10.3.6.7,10.3.6.8,10.3.6.9,10.3.6.
10,10.3.7.1,
10.3.7.2,10.3.7.3,10.3.7.4,10.3.7.5,10.3.7.6,10.3.7.7,10.3.7.8,10.3.7.9,10.3.7.
10,10.3.8.1,
10.3.8.2,10.3.8.3,10.3.8.4,10.3.8.5,10.3.8.6,10.3.8.7,10.3.8.8,10.3.8.9,10.3.8.
10,10.3.9.1,
10.3.9.2,10.3.9.3,10.3.9.4,10.3.9.5,10.3.9.6,10.3.9.7,10.3.9.8,10.3.9.9,10.3.9.
10,I0.3.10.i,
10.3.10.2,10.3.10.3,10.3.10.4,10.3.10.5,10.3.10.6,10.3.10.7,10.3.10.8,10.3.10.9
,10.3.10.10,
10.4.1.1,10.4.1.2,10.4.1.3,I0.4.1.4,10.4.1.5,10.4.1.6,10.4.1.7,10.4.1.8,10.4.1.
9,10.4.1.10,
10.4.2.1,10.4.2.2,10.4.2.3,10.4.2.4,10.4.2.5,10.4.2.6,10.4.2.7,10.4.2.8,10.4.2.
9,10.4.2.10,
10.4.3.1, 10.4.3.2, 10.4.3.3, 10.4.3.4, 10.4.3.5, 10.4.3.6, 10.4.3.7,
10.4.3.8, 10.4.3.9, 10.4.3.10,
10.4.4.1,10.4.4.2,10.4.4.3,10.4.4.4,10.4.4.5,10.4.4.6,10.4.4.7,10.4.4.8,10.4.4.
9,10.4.4.10,
10.4.5.1,10.4.5.2,10.4.5.3,10.4.5.4,10.4.5.5,10.4.5.6,10.4.5.7,10.4.5.8,10.4.5.
9,10.4.5.10,
10.4.6.1, 10.4.6.2, 10.4.6.3, 10.4.6.4, 10.4.6.5, 10.4.6.6, 10.4.6.7,
10.4.6.8, 10.4.6.9, 10.4.6.10,
10.4.7.1, 10.4.7.2, 10.4.7.3, 10.4.7.4, 10.4.7.5, 10.4.7.6, 10.4.7.7,
10.4.7.8, 10.4.7.9, 10.4.7.10,
I U.4.8. I , I 0.4.8.2, I 0.4.8.3, I 0.4.8.4, I 0.4.8.5, I 0.4.8.6, i U.4.8.7,
I 0.4.8.8, I 0.4.8.9, t U.4.8. t U,
I0.4.9.l,10.4.9.2,I0.4.9.3,I0.4.9.4,10.4.9.5,10.4.9.6,10.4.9.7,10.4.9.8,10.4.9.
9,10.4.9.10,
10.4.10.1,10.4.10.2,10.4.10.3,10.4.10.4,10.4.10.5,10.4.10.6,10.4.10.7,10.4.10.8
,10.4.10.9,
10.4.10.10,10.5.1.1,10.5.1.2,10.5.1.3,10.5.1.4,10.5.I.5,10.5.1.6,10.5.1.7,10.5.
1.8,10.5.1.9,
10.5.I.10,10.5.2.1,10.5.2.2,10.5.2.3,10.5.2.4,10.5.2.5,10.5.2.6,10.5.2.7,10.5.2
.8,10.5.2.9,
10.5.2.10,10.5.3.1,10.5.3.2,10.5.3.3,10.5.3.4,10.5.3.5,10.5.3.6,10.5.3.7,10.5.3
.8,10.5.3.9,
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10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3, 10.5.4.4, 10.5.4.5, 10.5.4.6,
10.5.4.7, 10.5.4.8, 10.5.4.9,
10.5.4.10,10.5.5.1,10.5.5.2,10.5.5.3,10.5.5.4,10.5.5.5,10.5.5.6,10.5.5.7,10.5.5
.8,10.5.5.9,
10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4, 10.5.6.5, 10.5.6.6,
10.5.6.7, 10.5.6.8,-10.5.6.9,
10.5.6.10,10.5.7.1,10.5.7.2,10.5.7.3,10.5.7.4,10.5.7.5,10.5.7.6,10.5.7.7,10.5.7
.8,10.5.7.9,
10.5.7.10,10.5.8.1,10.5.8.2,10.5.8.3,10.5.8.4,10.5.8.5,10.5.8.6,10.5.8.7,10.5.8
.8,10.5.8.9,
I 0.5.8.10. 10.5.9.1, 10.5.9.2. 10.5.9.3. 10.5.9.4, 10.5.9.5. 10.5.9.6,
10.5.9.7, 10.5.9.8, 10.5.9.9,
'
10.5.9.10,10.5.10.1,10.5.10.2,10.5.10.3,10.5.10.4,10.5.10.5,10.5.10.6,10.5.10.7
,10.5.10.8,
10.5.10.9,
10.5.10.10,
10.6.1.1,
10.6.1.2,
10.6.1.3,
10.6.1.4,
10.6.1.5,
10.6.1.6,
10.6.1.7,
10.6.1.8,
10.6.1.9,10.6.1.10,10.6.2.1,10.6.2.2,10.6.2.3,10.6.2.4,10.6.2.5,10.6.2.6,10.6.2
.7,10.6.2.8,
1010.6.2.9,10.6.2.10,10.6.3.1,10.6.3.2,10.6.3.3,10.6.3.4,10.6.3.5,10.6.3.6,10.6
.3.7,10.6.3.8,
10.6.3.9,10.6.3.10,10.6.4.1,10.6.4.2,10.6.4.3,10.6.4.4,10.6.4.5,10.6.4.6,10.6.4
.7,10.6.4.8,
10.6.4.9,10.6.4.10,10.6.5.1,10.6.5.2,10.6.5.3,10.6.5.4,10.6.5.5,10.6.5.6,10.6.5
.7,10.6.5.8,
10.6.5.9,10.6.5.10,10.6.6.1,10.6.6.2,10.6.6.3,10.6.6.4,10.6.6.5,10.6.6.6,10.6.6
.7,10.6.68,
10.6.6.9,I U.6.6. l 0, I I 10.6.7.5,10.6.7.6,I 0.6.7.7,10.6.7.8,
10.6.7. I , I 0.6.7.3,0.6.7.4,
0.6.7.2,
1510.6.7.9,10.6.7.10, 10.6.8.1,l
10.6.8.4,10.6.8.5,10.6.8.6,10.6.8.7,10.6.8.8,
I 0.6.8.2, 0.6.8.3,
10.6.8.9,10.6.8.10,10.6.9.1,I0.6.9.2,10.6.9.3,10.6.9.4,10.6.9.5,10.6.9.6,10.6.9
.7,10.6.9.8,
10.6.9.9,10.6.9.10,10.6.10.1,I0.6.10.2,10.6.10.3,10.6.
10.4,10.6.10.5,10.6.10.6,10.6.10.7,
10.6.10.8,10.6.10.9,10.6.10.10,10.7.1.1,10.7.
1.2,10.7.1.3,10.7.1.4,10.7. 1.5,10.7.1.6,10.7.1.7,
10.7.1.8,10.7.1.9,10.7.1.10,10.7.2.1,10.7.2.2,10.7.2.3,10.7.2.4,10.7.2.5,10.7.2
.6,10.7.2.7,
2010.7.2.8,10;7.2.9,
10.7.2.10,10.7.3.2,10.7.3.3,10.7.3.4,10.7.3.5,10.7.3.6,10.7.3.7,
10.7.3.1,
10.7.3.8,10.7.3.9,
10.7.3.10,10.7.4.2,10.7.4.3,10.7.4.4,10.7.4.5,10.7.4.6,10.7.4.7,
10.7.4.1,
I0.7.4.8,10.7.4.9,10.7.4.10,10.7.5.1,10.7.5.2,10.7.5.3,10.7.5.4,10.7.5.5,10.7.5
.6,10.7.5.7,
10.7.5.8,10.7.5.9,
10.7.5.10.7.6.2,10.7.6.3,10.7.6.4,10.7.6.5,10.7.6.6,10.7.6.7,
I 0, 10.7.6.1,
10.7.6.8,10.7.6.9,10.7.6.10,10.7.7.1,10.7.7.2,10.7.7.3,10.7.7.4,10.7.7.5,10.7.7
.6,10.7.7.7,
2510.7.7.8,10.7.7.9,10.7.7.10,10.7.8.1,10.7.8.2,10.7.8.3,10.7.8.4,10.7.8.5,10.7
.8.6,10.7.8.7,
10.7.8.8,10.7.8.9,10.7.8.10,10.7.9.1,10.7.9.2,10.7.9.3,10.7.9.4,10.7.9.5,10.7.9
.6,10.7.9.7,
10.7.9.8,10.7.9.9,10.7.9.10,10.7.10.1,10.7.10.2,10.7.10.3,10.7.10.4,10.7.10.5,1
0. 7.10.6,
10.7.10.7,10.7.10.8,10.7.10.9,10.7.10.10,10.8.1.1,10.8
.1.2,10.8.1.3,10.8.1.4,10.8 .1.5,10.8.1.6,
10.8.1.7,10.8.1.8,
10.8.1.9,10.8.2.1,10.8.2.2,10.8.2.3,10.8.2.4,10.8.2.5,10.8.2.6,
10.8.1.10,
30IO.R.2.7,10.8.2.8,
10.8.2.9,10.8.3.1,10.8.3.2,10.8.3.3,10.8.3.4,10.8.3.5,10.8.3.6,
10.8.2.10,
10.8.3.7.10.8.3.8,
10.8.3.9,10.8.4.1,10.8.4.2,10.8.4.3,10.8.4.4,10.8.4.5,10.8.4.6,
10.8.3.10,
10.8.4.7,10.8.4.8,10.8.4.9,10.8.4.10,10.8.5.1,10.8.5.2,10.8.5.3,10.8.5.4,10.8.5
.5,10.8.5.6,
10.8.5.7,10.8.5.8,10.8.5.9,10.8.5.10,10.8.6.1,10.8.6.2,10.8.6.3,10.8.6.4,10.8.6
.5,10.8.6.6,
10.8.6.7,10.8.6.8,10.8.6.9,10.8.6.10,10.8.7.1,10.8.7.2,10.8.7.3,10.8.7.4,10.8.7
.5,10.8.7.6,
3510.8.7.7,10.8.7.8,I0.8.7.9,10.8.7.10,10.8.8.1,10.8.8.2,10.8.8.3,10.8.8.4,10.8
.8.5,10.8.8.6,
10.8.8.7,10.8.8.8,10.8.8.9,10.8.8.10,10.8.9.1,10.8.9.2,10.8.9.3,10.8.9.4,10.8.9
.5,10.8.9.6,
10.8.9.7,10.8.9.8, 10.8.9.9,10.8.10.1, 2, 10.4, .10.5,
10.8.9.10, 10.8.10.10.8.10.3, 10.8
10.8.
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10.8.10.6,10.8.10.7,10.8.10.8,10.8.10.9,10.8.10.10,10.9.1.1,10.9.1.2,10.9.1.3,1
0.9.1.4,
10.9.1.5,10.9.1.6,10.9.1.7,10.9.1.8,10.9.1.9,10.9.1.10,10.9.2.1,10.9.2.2,10.9.2
.3,10.9.2.4,
I 0.9.2.5, I 0.9.2.6, ! 0.9.2.7, 10.9.2.8, l 0.9.2.9, 10.9.2.10, 10.9.3. I , I
0.9.3.2, 10.9.3.3; I 0.9.3.4,
10.9.3.5,10.9.3.6,10.9.3.7,10.9.3.8,10.9.3.9,10.9.3.10,10.9.4.1,10.9.4.2,10.9.4
.3,10.9.4.4,
10.9.4.5,10.9.4.6,10.9.4.7,10.9.4.8,10.9.4.9,10.9.4.10,10.9.5.1,10.9.5.2,10.9.5
.3,10.9.5.4,
10.9.5.5, 10.9.5.6, 10.9.5.7, 10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6,1,
10.9.6.2, 10.9.6.3, 10.9.6.4,
' .
10.9.6.5,10.9.6.6,10.9.6.7,I0.9.6.8,10.9.6.9,10.9.6.10,10.9.7.1,10.9.7.2,10.9.7
.3,10.9.7.4,
10.9.7.5,10.9.7.6,10.9.7.7,10.9.7.8,10.9.7.9,10.9.7.10,10.9.8.1,10.9.8.2,10.9.8
.3,10.9.8.4,
10.9.8.5, 10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1,
10.9.9.2, 10.9.9.3, 10.9.9.4,
10.9.9.5,10.9.9.6,10.9.9.7,10.9.9.8,10.9.9.9,10.9.9.10,10.9.10.1,10.9.10.2,10.9
.10.3,10.9.10.4,
10.9.10.5,10.9.10.6,10.9.10.7,10.9.10.8,10.9.10.9,10.9.10.10,10.10.1.1,10.10.1.
2,10.10.1.3,
10.10.1.4,10.10.1.5,10.10.1.6,10.10.1.7,10.10.1.8,10.10.1.9,10.10.1.10,10.10.2.
1,10.10.2.2,
10.10.2.3, 10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9,
10.10.2.10, 10.1.3.1,
10.10.3.2,10.10.3.3,10.10.3.4,10.10.3.5,10.10.3.6,10.10.3.7,10.10.3.8,10.10.3.9
,10.10.3.10,
10.10.4.1,10.10.4.2,10.10.4.3,10.10.4.4,10.10.4.5,10.10.4.6,10.10.4.7,10.10.4.8
,10.10.4.9,
10.10.4.10,10.10.5.1,10.I0.5.2,10.10.5.3,10.10.5.4,10.10.5.5,10.10.5.6,10.10.5.
7,10.10.5.8,
10.10.5.9,10.10.5.10,10.10.6.1,10.10.6.2,10.10.6.3,10.10.6.4,10.10.6.S,I0.10.6.
6,10.10.6.7,
10.10.6.8,10.10.6.9,10.10.6.10,10.10.7.1,10.10.7.2,10.10.7.3,10.10.7.4,10.10.7.
5,10.10.7.6,
10.10.7.7,10.10.7.8,10.10.7.9,10.10.7.10,10.10.8.1,10.10.8.2,10.10.8.3,10.10.8.
4,10.10.8.5,
10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9, 10.10.8.10, 10.10.9.1, 10.10.9.2,
10.10.9.3, 10.10.9.4,
10.10.9.5,10.10.9.6,10.10.9.7,10.10.9.8,10.10.9.9,10.10.9.10,10.10.10.1,10.10.1
0.2,10.10.10.3,
10.10.10.4,10.10.10.5,10.10.10.6,10.10.10.7,10.10.10.8,10.10.10.9.10.10.10.10
Additional exemplary formula 1 compound groups include the following groups as
disclosed below.
C:ruup 2. Group 2 compounds are as named in 'fable 13, i.e., Itz, R,A, Y and X
substituents
are as defined in Table A, but they are bonded to the steroid nucleus shown in
formula 5, which is
the same as the formula 4 steroid nucleus, except that the 5-6 double bond is
absent and hydrogen is
present at the 5-position in the a-configuration
Rz
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Thus, the group 2 compound named 1.2.1.1 has the structure
~u_ O
H
group 2, compound 1.2.1.1.
Group 3. Group 3 compounds are as named in Table B, i.e., R2, R1A, Y and X
substituents
are as defined in Table A, but they are bonded to the steroid nucleus shown in
formula 6, which is
the same as the formula 4 steroid nucleus, except that the S-6 double bond is
absent and hydrogen is
present at the 5-position in the /configuration
R2
6.
Thus, the group 3 compound named 1.2.1.1 has the structure
H
group 3, compound 1.2.1.1.
Group 4. Group 4 compounds are as named in Table B, i.e., R2, R,A, Y and X
substituents
are as defined in Table A, but they are bonded to the steroid nucleus shown in
formula 7, which is
the same as the formula 4 steroid nucleus, except that Q3 is
-CHzOH
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R2
7.
Thus, the group 4 compound named 1.2.1.1 has the structure
group 4, compound I .2.1.1.
Group 5. Group 5 compounds are as named in Table B, i.e., R2, R,A, Y and X
substituents
are as defined in Table A, but they are bonded to the steroid nucleus shown in
formula 8, which is
the same as the formula 4 steroid nucleus, except that the 5-6 double bond is
absent and hydrogen is
present at the 5-position in the a-configuration and Q3 is -CHzOH
R2
a.
Thus, the group 5 compound named 1.2.1.1 has the structure
group 5, compound 1.2.1.1.
Group 6. Group 6 compounds are as named in groups 1-5, except that Q6 in
formulas 4-8
is -CI-Iz01-( instead of methyl. In group G, thcrc arc S subgroups of group 6
compounds. The first
subgroup, subgroup 6-1, has the same steroid nucleus with the substituents as
defined for group 1
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compounds while the second, subgroup 6-2, has the same steroid nucleus with
the substituents as
defined for group 2 compounds. Subgroups 6-3 through 6-5 have the same steroid
nucleus with the
substitucnts as defined for group 3 through 5 respectively. Thus, for example,
the subgroup 6-1
compound named 1.2.1.1 has the structure
H
,
and the subgroup 6-2 compound named 1.2.1.1 has the structure
Grdup 7. Group 7 compounds are as named in groups 1-5, except that the Y
moiety in
formulas 4-8 is in the /3-configuration instead of in the a-configuration.
Group 7 comprises 5
subgroups, wherein the compounds are named essentially as described for group
6 compounds,
except that the Y group is in the (3-configuration.
Group 8. Group 8 compounds are as named in groups 1-5, except that the X
moiety in
formulas 4-8 is in the a-configuration instead of in the (3-configuration.
Group 8 comprises 5
I S subgroups, wherein the compounds are named essentially as described for
group 6 compounds,
except that the X group is in the a-configuration.
Group 9. Group 9 compounds are as named in groups 1-5, except that the Rz
moiety in
formulas 4-8 is in the a-configuration instead of in the (configuration. Group
9 comprises 5
subgroups, wherein the compounds are named essentially as described for group
6 compounds,
except that the Rz group is in the a-configuration. -
Group 10. Group 10 compounds are as named in groups 1-9, except that RZ
moieties 1
through I U in 'fable A are replaced with the following moieties.
1 -S-C(O)-CH3
2 -S-C(O)-CHz-C6H3
3 -O-S(O)-O-CH3 '
4 -O-S(O)-O-CHZ-C6H5
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-U-S(U)(U)-U-CH3 _
6 -O-S(O)(O~O-CHZ-C6Hs
7 -O-C(O~NH-CH3
8 -O-C(O~NH-C6Hs
5 9 -O-C(S)-CH3
-O-C(SrCHz-C6H5
_ Group 10 comprises 25 subgroups of compounds. The first, subgroup 10-1, has
the same
steroid nucleus with substituents as defined for group 1, except that the R~
moieties or groups listed
replace those in Table A above. The subgroup 10-1 compound named 1.2.1.1 has
the structure
H3C
10 O
the subgroup 10-2 compound named 1.2.1.1 has the structure
H3C"
~II(O
the subgroup 10-6-1 compound named 1.2.1.1 has the structure
H3C S
O
and the subgroup 10-6-2 compound named 1.2.1.1 has the structure
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HOC
' 'OBI "
Group 11. Group 11 compounds are as named in groups 1-9, except that Rz
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -S-C(O)-CHZCHZ-O-CH2CH3
2 -S-C(O)-CH2-C6I~OCH3
3 -O-S(O)-O-CHZCHZ-O-CHzCH3
4 -O-S(O~O-CHZ-C6H40CH3
5 -O-S(OHO)-O-CI-IzCI~IZ-O-CFhCI-I,
6 -O-S(O)(O)-O-CHz-C6H40CH3
7 -O-C(O)-NH-CHZCH2-O-CH2CH3
8 -O-C(O~NH-C6H40CH3
9 -O-C(S)-CHZCHZ-O-CHZCH3
10 -O-C(S)~CHZ-C6H40CH3
Group I 1 comprises 25 subgroups, wherein the compounds are named essentially
as
described for group 10 compounds, except that the RZ group is given above.
Group 12. Group l2 compounds are as named in groups 1-9, except that RZ
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -S-C(O)-CHZCHZ-O-CH2C(O)OH
2 -S-C(O)-CHZ-C6H4F
3 -O-S(O)-O-CHzCHZ-O-CHiC(O)OH
4 -O-S(O)-O-CHz-C6H,F
5 -O-S(O)(O)-O-CHiCHz-O-CHzC(O)OH
6 -O-S(O)(O)-O-CHZ-C6H4F
7 -O-C(O)-NH-CHZCHZ-O-CHZC(O)OH
8 -O-C(O)-NH-C6HaF
9 -O-C(S)-CHzCH2-O-CHiC(O)OH
10 -O-C(S)-CHZ-C6H,F
Group I3. Group 13 compounds are as named in groups I-9, except that Rz
moieties 1
through 10 in Table I\ are replaced with the following moieties.
1 -S-C(O)-CHZCH~-O-CHZCHiOH
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2 -S-C(O)-CHZ-CsH,CH3 '
3 -O-S(O~O-CHZCHz-O-GHZCHZOH
4 -O-S(O)-O-C1-h-C~,Ii,,CI-1,
-O-S(O)(O~O-CHzCHi-O-CHZCHzOH
5 6 -O-S(O)(O}-O-CHz-CsH,CH3
7 -O-C(O)-NH-CHzCHz-O-CHzCHZOH
- 8 -O-C(O)-NH-CsH,CH3
9 -O-C(S)-CH2CHZ-O-CHzCHZOH
-O-C{S)-CH2-CsH,CH3
IU (:ruup 14. Group 14 wmpuunds arc us named in groups 1-9, except that R2
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -S-C(O)-CH2CH2-O-CHzCHZOR~'R
2 -S-C(O)-CI-IZ-CsIV,OR~R
3 -O-S(O)-O-CHZCHZ-O-CHZCHZORPR
4 -O-S(O)-O-CHz-CsH,ORpR
5 -O-S(O)(O)-O-CH2CHZ-O-CHZCHzORpR
6 -O-S(O)(O~O-CHz-CsH,ORPR
7 -O-C(O)-NH-CHZCHZ-O-CH2CHZORPR
8 -O-C(O)-NH-C~,H,ORPR
9 -O-C(S)-~HzCH2-O-CHzCHiORPR
IO -O-C(S)-CHZ-CsH,ORPR
Group 15. Group I S compounds are as named in groups 1-9, except that RZ
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -S-C(O)-CHzCH2-O-CH~CHZNHRPR
2 -S-C{O)-CHz-C6H3(ORPR)z
3 -O-S(O)-O-CH~CHZ-O-CH~CHzNHRPR
4 -O-S(O)-O-CH2-C6H3(ORPR)2
5 -O-S(O)(O)-O-CHZCHZ-O-CHiCH~NHRPR
6 -O-S(O)(O)-O-CHi-CsH,(ORPR)z
7 -O-C(O)-NH-CH2CH2-O-CH2CHZNHRPR
8 -O-C(O)-NH-C6H3(ORPR)z
9 -O-C(S)-CHzCHi-O-CH2CHZNHRPR
lO -O-C(S)-CHZ-C6H3(ORPR)z
Group 16. Group 16 compounds are as named in groups 1-9, except that RZ
moieties 1-
through 10 in Table A are replaced with the following moieties.
I -S-C(O)-(CHz)~-CHs
2 -S-C(O)-CHZ-C6H,
s
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3 -O-S(O)-O-(CHz)o.~-CHs
4 -O-S(O)-O-CHZ-C6Hs
-O-S(O)(O)-O-(CHz)o~-CH3
6 -O-S(O)(O)-O-CHZ-C6Hs
5 7 -O-C(O)-NH-(CHZ)o.b-CH3
8 -O-C(O)-NH-(CHZ)o.~-C6Hs
9 -O-C(S)-(CHz)o.~-CH3
-O-C(S)-CHi-CHs
Group 17. Group 17 compounds are as named in groups 1-9, except that Rz
moieties 1
10 through l0 in Tablc A arc rcplaccd with the following moieties.
1 -S-C(O)-CHzCH2-(O-CH~CHz),.so-H
2 -S-C(O)-CHZ-C~i,OCH3
3 -O-S(O)-O-CHZCHz-(O-CHZCHz),.so-H
4 -O-S(O)-O-CH2-C~OCH3
5 -O-S(O)(O)-O-CH=CHZ-(O-CHZCHz),.so-H
6 -O-S(O)(O)-O-CHZ-C6H40CH3
7 -O-C(O~NH-CHiCHZ-(O-CHzCH2),.so-H
8 -O-C(O)-NH-C6H40CH3
9 -O-C(S)-CH2CHi-(O-CH2CHZ)i.so-H
10 -O-C(S~'CHZ-C6H,OCH3
Group 18. Group 18 compounds are as named in groups 1-9, except that Rz
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -O-C(O)-CH2CH2-(O-CH2CHz),.so-H
2 -O-C(O)-CHi-C~,H,OCH,
3 -U-C(U)-(CHi)o.b-CH3
4 -O-C(O)-CHz-C6H4NOz
5 -O-C(O)-CH~CHz-(O-CHZCH2),_so-H
6 -O-C(U)-C1~~-C,,Hs
7 -O-C(O~CHzCH2-O-CHZCH3
8 -O-C(O)-C6Hs
9 -O-C(OrCHzCH2-S-CH2CH3 _
10 -O-C(O)-CHz-C6H,F
Group 19. Group 19 compounds are as named in groups 1-9, except that RZ
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -O-CHzCH2-(O-CH2CHi)i_so-H
2 -O-CHz-CsH,OCH3 ,
3 -O-(CH2)o.~-CH3
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4 -O-CHI-C6H,NOZ
-O-CHZCHZ-(O-CHzCH~),.so-H
6 -O-CHZ-C6H,
7 -O-CHzCHz-O-CH2CH3
5 8 -O-C6H5
9 -O-CHZCHz-S-CHzCH~
- _ 10 -O-CHz-C~H,F
Group 20. Group 20 compounds are as named in groups 1-9, except that Ri
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -C(O)-O-CHZCHz-(O-CHZCH2),.SO-H
2 -C(O)-O-CHZ-C6H,OCH3
3 -C(O~O-(CHZ)o.~-CH3
4 -C(O)-O-CHz-C6H,NOz
S -C(O)-O-CHzCHz-(O-CHzCH2),_so-H
t 5 6 -C(O)-O-CHz-C6H3
7 -C(O~O-CH2CHZ-O-CHZCH3
8 -C(O~O-C6Hs
9 -C(O~O-CHZCHz-S-CHiCH3
10 -C(O)-O-CHz-C6H,F
Grdup 21. Group 21 compounds are as named in groups 1-9, except that Rz
moieties 1
through 10 in Table A are replaced with the following moieties.
I -C(O)-O-G 12
2 -O-C(O)-G 12
3 -C(O)-S-G 12
4 -S-C(O)-G 12
5 -C(S)-O-G 12
6 -O-C(S~G12
7 -O-C(O)-NH-G 12
8 -NH-C(O)-O-GIZ
9 -C(O~O-CHZ-G12
10 -O-C(O)-CHz-G 12
Thus, the group 21-1 compound named 1.2.1.1 has the structure
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G12 ~
,
while the group 21-2 compound named 1.2.1.1 has the structure
G12
H
the group 21-3 compound named 1.2.1.1 has the structure
G12
H
,
the group 21-4 compound named 1.2.1.1 has the structure
G12
,
the group 21-6-I compound named 1.2.1.1 has the structure
r~
G12
the group 21-6-2 compound named 1.2.1.1 has the structure
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G12
- H
and the group 21-6-3 compound named 1.2.1.1 has the structure
G12 ~ '
G12 in Group 21 is an organic moiety comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 10,
11 or 12 carbon
atoms and 0, 1, 2, 3, 4, 5, 6, 7 or 8 independently selected O, S, N, P, or Si
atoms, but, if a Si or P
atom is present, only one Si or P is present, wherein the organic moiety is
optionally selected from
C,.,~ alkyl, EZ.,2 alkenyl, CZ.,z alkynyl, aryl, a Cz.9 heterocycle or a
substituted derivative of any of
these comprising 1, 2, 3, 4 or more substituents, wherein each substituent is
independently chosen
and is selected from -O-, -S-, -NRPR- (including -NH-), -C(O}-, =O, =S, -
N(RPR)2 (including -NHz),
-C(O)ORPR (including -C(O)OH), -OC(O)RpR (including -O-C(O)-H), -ORPR
(including -OH), -
SRPR (including -SH), -NOz, -CN, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -O-A8, -
S-A8, -C(O)-
A8, -OC(O)-A8, -C(O)O-A8, =N-, -N=, =N-OH, -OPO3(RPR}2, -OS03H2 and halogen
moieties or
atoms, where each RJR is -H, an independently selected protecting group or
both RrR together
comprise a protecting group, and A8 is C,_8 alkyl, CZ.~ alkenyl, Ci.B alkynyl,
C,.~ alkyl-aryl (e.g.,
benzyl), aryl (e.g. phenyl) or C,a alkyl-CZ.~ heterocycle. G 12 moieties
include -CHI, -CzHt, -C,H,,
-C4H.,, -C~H", -CHz-CHs, -CzHq-C~f-1S, -C,H~-CHs, -CHs, -CHz-heterocycle, -CHi-
CH~-
heterocycle and a heterocycle, any of which are substituted with one, two,
three or more
independently selected -O-, -S-, -F, -Cl, -Br, -I, -NH-, =O, -CN, -OCH3, -
OC2H5, -OC4H9, -NO2, -
NHZ, -COOH, or -NH-C(O)- moieties.
Other embodiments include the use of any formula 4 compound or genus of
formula 4
compounds that are named in any of the foregoing groups for any of the
therapeutic or other
applications described herein. This includes the use of any named formula 4
compound or genus
Ibr any of those applications wherein (i) RZ is in the a-conligurutiun, (ii)
(~4 is -CIU(halugen)-, (iii)
X is in the a-configuration and the -H at the 17-position is in the (3-
configuration, (iv) Y is in the (3-
64
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wo oor~im~ PcTnrs99nsosi
configuration and the -H at the 16-position is in the a-configuration or (v)
R,A is in the a-
configuration and the -H at the 7-position is in the ~i-configuration.
Embodiments also include formula 1 compounds (e.g.,. formula 4 compounds)
wherein R4
is optionally substituted C,~ alkyl, optionally substituted C2.8 alkenyl,
optionally substituted C2.~
alkynyl, optionally substituted aryl, optionally substituted heterocycle,
optionally substituted C»
alkyl-aryl, optionally substituted C,.B alkyl-heterocycle or optionally
substituted -CH=-C,.e organic
moiety (where the organic moiety is as described for esters), wherein any of
the foregoing are
independently substituted with 1, 2, 3, 4, 5 or 6 or more -O-, -S-, -NH-, -NH-
C(O)- (i.e., -NH-C(O)-
or -C(O)-NH-), =O, =NOH, -NOZ, -CN, -F, -Cl, -Br, -1, -OH, -SH, or -NH2. Such
R, moieties
include -CH2-C,.~ optionally substituted alkyl, -CHZ-Cz.~ optionally
substituted alkenyl, -CHZ-C,.~ -
optionally substituted aryl and -CHz-CZ.9 optionally substituted heterocycle.
Plasma concentration-enhancing, Compounds. An aspect of the invention
comprises
administering an effective amount of a plasma concentration-enhancing
compound, e.g., a'
compound of formula 2A or 2B compound with a formula 1 compound to facilitate
preventing or
treating one or more togavirus infections (including flavivirus, alphavirus,
pestivirus or rubivirus) in
a subject. In addition to the formula 2A and 2B compounds, the plasma
concentration-enhancing
compounds include bavachinin A, didymin (isosakuranctin-7-rutinosidc or
ncoponcirin),
flavanomarein (isookanine-7-glucoside), flavanone azine, flavanone
diacetylhydrazone, flavanone
hydrazone, silybin, which has the structure
silychristin, which has the structure
ral
isosilybin, which has the structure -
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and a compound having the structure (E)
N3
(E).
Collectively, these compounds and the formula 2A and 2B compounds are referred
to as the
"plasma concentration-enhancing compounds".
The formula 2A and 2B compounds encompass a number of natural and synthetic
flavonoids, including certain flavones, flavans, and their iso analogs. The
presence of a formula 2A
or 2B compound in compositions comprising a formula 1 compound has been found
to enhance the
systemic bioavailability of formulations that comprise a formula 1 compound.
The presence of a
formula 2A or 2B compound, e.g., naringin or naringenin, results in enhanced
plasma
concentrations of the formula 1 compound. The formula 2A or 2B compound need
not be present
1 S in a formulation that contains a formula 1 compound. The formula 2A or 2B
compound can also be
administered, e.g., about 1-4 hours, before or after, preferably before, the
formula 1 compound is
66
silandrin, which has the structure
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WO 00/32177 PCT/US99IZ8082
administered. In these embodiments, one will administer an oral or parenteral
formulation that
contains a formula 1 compound and a formula 2A or 2B compound.
The plasma concentration-enhancing compounds include compounds of formulas SO-
65
Rn
8 8
Rat Roc
Re Ra
50 51
a RB
Rya F
Z8
Ra
52 53
Ra
Roc Roc
~8
Re Rp
54 55
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B g ,
Roc Roc
R~ RE
56 57
Roc g F g
Re
58 59
R~u Re F a
Re ~e
60 61
Rio Rya
Re Re
Re Re
Re R8
_ Re
62 63
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F
Ra RB
Re Re
~4 65
wherein
R8 at the 6-position independently are -H, -OH, -F, -C1, -Br, -I, C,~ alkyl,
C,.~ alkoxy,
glucuronide, a C,_z5 fatty acid, glucoside, -CH2CH=C(CH3)Z or a group having
the structure (B);
R8 at the 8-position independently are -H, -OH, -F, -Cl, -Br, -I, C,.~ alkyl,
C,~ alkoxy,
glucuronide, a C,_zs fatty acid, glucoside, -CHZCH=C(CH3)2 or the residue of a
formula 50-65
compound where a hydrogen atom is removed to form the formula 50-65 radical;
ReA independently are -H, -OH, -F, -Cl, -Br, -I, C,.~ alkyl, C,.~ alkoxy,
glucuronide, a C,.zs
fatty acid, glucoside, -CHiCH=C(CH3)2 or a group having the structure (C);
the remaining Rd independently are -1-f, -OH, -F, -CI, -Br, -I, C,.~ alkyl,
C,.6 alkoxy,
glucuronide, a C,.ZS fatty acid or -CHz-CH=C(CH3)i; and
R,o (i) is -OH or -F, -Cl, -Br, -I, C,.~ alkyl, C,.6 alkoxy, neohesperidoside,
apioglucoside,
rutinoside, $lucoside, galactoside, rhamnoside, arabinoside, or a
stereoisomer, hydrate, analog,
derivative or metabolite of any of these moieties, any of which are optionally
independently
substituted at one or more hydrogen atoms with -OH, -F, -Cl, -Br, -I, C,.~
alkyl, C,.~ alkoxy,
glucuronide or a C,.zs fatty acid, or (ii) R,a is the radical of bavachinin A,
didymin, flavanomarein,
flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silybin,
silychristin, isosilybin,
silandrin, a moiety of structure (E) or a stereoisomer, hydrate, analog,
derivative or metabolite of
any of these moieties.
Additional therapeutic embodiments. In accordance with another preferred
aspect of the
present invention, there is provided a method of treatment of one or more of
the conditions
described above, e.g., togavirus infections, comprising administering a
combination therapy
including one or more of the compounds of the present invention administered
simultaneously or
sequentially with one or more macrophage stimulating factor (and optionally
further co-
administering one or more plasma concentration-enhancing compounds).
Macrophage stimulating
factors are well known to those of skill in the art, examples including GM-CSF
(see, e.g., Callard et
al., The Cytokine Facts Book, Academic Press, 1994, p. 139, which is
inco~orated herein by
reference) and Interleukin-4 (sold by Immunex as "Leukine" and by Schering
Plough as "Prokine").
In another preferred aspect of the present invention, the compounds of the
present invention
can be co-administered with one or more oxidation agent (optionally further
together with a plasma
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WO 00/32177 PCT/US99128082
concentration-enhancing compound and/or a macrophage stimulating factor), or
the patient may be
given oxygen ventilation to increase oxidative steroids in the plasma.
In addition, the present invention is further directed to a combination
therapy for the
treatment of patients suffering from hepatitis C and/or hepatitis G,
comprising administering to the
patient, simultaneously or sequentially, one or more of the compounds of the
present invention
together with ribavirin and/or alpha interferon, and optionally further
together with one or more
plasma concentration-enhancing compound, one or more macrophage stimulating
factor, one or
more oxidation agent, and/or oxygen ventilation. In addition, the present
invention is further
directed to a combination therapy as discussed above in this paragraph for the
treatment of patients
suffering from or susceptible to any type of togavirus infection.
The invention also includes the use of combinations of compounds as disclosed
herein in
the manufacture of a medicament for use in the treatment of a togavirus or a
flavivirus, in
particular, HCV.
The components of any of the combination therapies disclosed herein can be
administered
simultaneously (in a combination formulation), essentially simultaneously
(e.g., administration of
each compound a few minutes or a few hours apart), or they can be administered
sequentially, e.g.,
several days apart, or more than a week apart. For example, a compound of the
present invention
and a plasma-concentration-enhancing compound (and/or a macrophage stimulating
factor) can be
administered together, or essentially simultaneously, e.g., administration of
each compound a few
minutes or ~~few hours apart, or can be administered sequentially, e.g.,
several days apart, or more
than a week apart (optionally together with simultaneous or sequential
administration of oxidizing
agent or oxygen ventilation). All such variations in administration of the
combination therapy are
encompassed within the scope of the invention.
The invention alsu includes phannaccutical formulations containing any
combination that is
described herein.
The present invention is also directed to the use of compounds of the present
invention in
the manufacture of a medicament for therapeutic treatments as described
herein, e.g., for treatment
of a togavirus infection such as HCV.
The present invention is also directed to administering compounds of the
present invention
(optionally together with one or more combination compounds) to provide a
prophylactic treatment
of a patient to prevent, e.g., togavirus infections. _
Articles of manufacture. The present invention also provides articles of
manufacture
comprising, for example, packaging material, at least one unit-dosage of a
compound according to
the present invention (optionally together with one or more unit-dosage of a
compound which can
be administered in a combination therapy) and a label or package insert
indicating that the
compound can be used in a method disclosed herein.
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In one embodiment, an article of manufacture comprises packaging material, at
least one _
unit dose of a 17-ketosteroid compound (a formula 1 compound) and a label or
package insert
indicating that the 17-ketosteroid compound (a formula 1 compound) can be used
in a method as
described herein. The packaging material can be made from one or more
generally known
materials, e.6., foam, cardboard, fiberboard, polystyrene and polypropylene,
and is of a size suitable
to contain the compounds) accompanying the packaging material. A label or
package insert can be
a tag or label secured to the packaging material, a label printed on the
packaging material or a label
inserted within the packaging material. The label indicates that the 17-
ketosteroid can be used in a
therapy as disclosed herein, e.g., in combination with a plasma concentration-
enhancing compound,
a macrophage stimulating factor, ribavirin and/or alpha interferon. The label
can also indicate that
the compounds) have received approval from an official agency, for example,
the U.S. Food and
Drug Administration, for medical or veterinary use according to the method.
The label may also
indicate suitable administration routes, dosage regimen, and the like. If
desired, the article ntay
contain additional components such as at least one unit dose of a plasma
concentration-enhancing
I S compound, macrophage stimulating factor, ribavirin and/or alpha
interferon.
Methods of administration and formulations. The, dosage of a formula 1, 2A or
2B
compound for a particular patient will vary depending on factors such as the
overall health of the
patient, the method, route and dose of administration and the severity of side
effects (if any).
Determination of the appropriate dose is made by the clinician using
parameters known in the art.
Generally, the -dose begins with an amount somewhat less than the optimum dose
and it is
increased by small increments thereafter until the desired or optimum effect
is achieved. The
dosage of the compounds of the invention is suitably determined depending on
the individual cases
taking symptoms, age and sex ofthe subject and the like into consideration.
With respect to the
duration of treatment, it is typical for skilled clinicians to monitor
patients in order to determine
when inhibition is providing therapeutic benefit, and to determine whether to
increase dosage,
decrease dosage, discontinue therapy, resume therapy or alter therapy.
The therapeutically effective dosage of any specific compound of the invention
will vary
somewhat from compound to compound and patient to patient. As a general
proposition, a dosage
in the range of from about 0. I to about 500 mg/kg will have therapeutic
effccacy. Typically, a
dosage in the range of from about 0.5 mg/kg to about 500 mg/kg will be
employed. A daily dosage
of a formula 1 compound will typically comprise about 10 to about 750 mg,
usually about 20 to
about 400 mg, which may be administered as a single dose or as two or more
subdoses. Such doses
or subdoses may be administered at one or more sites or by one or more than
one route of
administration. The duration for the treatment is usually once per day for a
sufficient length of time
for the patient to become asymptomatic, or for symptoms to abate noticeably.
Depending upon the
severity of the infection in the individual patient, this may last several
days, weeks, or longer.
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W ith regard to the frequency and duration of treatment, it is well known that
it is within the '
skill of the ordinary physician to monitor a patient's condition and to make
appropriate decisions
with regard to discontinuing, interrupting and resuming treatments.
The dosages used in accordance with the invention are suitably determined
depending on the
S individual cases, taking symptoms, age and sex of the subject and the like
into consideration. In
addition, it is well known that it is within the skill of ordinary artisans to
determine suitable dosages
based on the above and other factors.
In accordance with the present method, a compound of the present invention may
be
administered orally, intramuscularly (IM); intravenously (IV), or
subcutaneously (SC), with
I U iWruvenuus udmiuiatrutiun bvin6 espcciully prcfcrrvd. nlthuugh usher
routes of uJministrutiun cuu
be used, it has been Found that intravenous administration provides surprising
et~ectiveness. l:or
oral administration, the use of a plasma concentrationenhancing compound may
be of great
importance. Alternatively, a formula 1 compound or salt may also be
administered intravenously or
intramuscularly as a liposomal suspension. Such administration may comprise a
cyclodextrin
I S formulation (given orally, SC, IV or IM). Compounds of the invention and
their pharmaceutically
or physiologically, acceptable salts, are thus administered by any route
suitable to the condition to
be treated, including oral, rectal, nasal, topical (including ocular, buccal
or sublingual), vaginal,
parenteral (including subcutaneous, intramuscular, intravenous,
intraperitoneal, intradermal,
intrathecal, intradural and epidural) and pulmonary by aerosol. Generally, the
compounds of the
20 invention aqe administered parenterally, orally or topically. If an
embodiment is not sufficiently
orally bioavailable it can be administered by the other routes noted above.
Embodiments include formulations that comprise a liposome or lipid complex
that
comprises a formula I compound. Such formulations are prepared according to
known methods,
e.g., U.S. patents 4427649, 5043165, 5714163, 5744158, 5783211, 5795589,
5795987, 5798348,
25 5811118, 5820848, 5834016 and 5882678, all of which are incorporated herein
by reference. The
liposomes may optionally comprise an additional therapeutic or other agent(s),
e.g., a compound of
formula 2A or 2B. The liposomes can be delivered to a subject by any standard
route, e.g., oral,
aerosol or parenteral (e.g., SC, IV, IM).
Most often, the pharmaceutical compositions useful in the present invention
will comprise a
30 compound of formula 1, or a pharmaceutically acceptable salt thereof, in
any pharmaceutically
acceptable carrier. If a solution is desired, water is the carrier of choice
with respect to water-
soluble compounds or salts. In other embodiments, an organic vehicle, such as
glycerol, ethanol,
propylene glycoi, polyethylene glycol, DMSO, DMS02, vegetable or mineral oils,
ethanol, benzyl
benzoate, or mixtures thereof, may be suitable. In general, the solutions in
any instance should be
35 sterilized in a suitable manner, preferably by filtration through a 0.22
micron filter. The
compositions useful in the practice of the present invention may be provided
in the form of vials,
ampoules, and the like.
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In some embodiments, the formula 1 compound that is present in the
compositions or that is
used in the methods disclosed herein is completely dissolved in non-aqueous
excipients. However,
in some embodiments, e.g., transient compositions or some formulations, the
formula 1 compound
is partially dissolved while the remaining portion is present as a solid,
which can be a suspension or
a colloid. In related embodiments, the formula 1 compound is incompletely
dissolved and is
present as a suspension or gel.
' _ In addition to compounds of formula 1, or their salts, the pharmaceutical
compositions may
contain usher additives, such us pl-I adjusting additives, in particular,
agents such us acids, buses, or
buffers, including sodium lactate, sodium acetate, and sodium gluconate.
Further, such
compositions may contain microbial preservatives, such as methylparaben,
propylparaben, benzyl
alcohoi and benzyl benzoate. If a multiple use vial is supplied, the
pharmaceutical composition
should likewise include such a microbial preservative. The formulations may be
lyophilized, using
techniques well known in the art.
The formulations include those suitable for the foregoing administration
routes. The
formulations may conveniently be presented in unit dosage form and may be
prepared by any of the
methods welt known in the art of pharmacy. Techniques, excipients and
formulations generally are
found in, e.g., Remingtorr's Pharmaceutical Sciences, Mack Publishing Co.,
Easton, PA 1985, 1 T"
edition, Nema et al., PDA J. Pharm. Sci. Tech. 1997 51:166-171, both of which
are incorporated
herein by reference. Methods to make invention formulations include the step
of bringing into
association ~ formula I compound with one or more excipients or carriers. In
general, the
formulations are prepared by uniformly and intimately bringing into
association the formula 1
compound with liquid excipients or finely divided solid excipients or both,
and then, if appropriate,
shaping the product.
Formulations of the present invention suitable for oral administration may be
presented as
discrete units such ;ts capsules, cachets or tnhlets each containing a
predetermined amount of the
formula 1 or formula 2A or 2B compound; as a powder or granules; as solution
or a suspension in
an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil
liquid emulsion. The formula I or formula 2A or 2B compound may also be
presented as a bolus,
electuary or paste.
A tablet may be made by compression or molding, optionally with one or more
excipients.
Compressed tablets may be prepared by compressing in a suitable machine the
formula 1 or
formula 2A or 2B compound in a free-flowing form such as a powder or granules,
optionally mixed
with a binder, lubricant, inert diluent, preservative, surface active or
dispersing agent. Molded
tablets may be made by moulding in a suitable machine a mixture of the
powdered compound
moistened with an inert liquid diluent. The tablets may optionally be coated
or scored and may be
formulated so as to provide slow or controlled release of the formula 1 or
formula 2A or 2B
compound therein
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The oily phase of the emulsions of this invention may be constituted from
known
ingredients in a known manner. While the phase may comprise merely an
emulsifier (otherwise
known as an emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an
oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is
included together with a
lipophiiic emulsifier, which acts as a stabilizer. It is also preferred to
include both an oil and a fat.
Together, the emulsifiers) with or without stabilizers) make up the
emulsifying wax, and the wax
together with the oil and fat make up the emulsifying ointment base.which
forms the oily dispersed
phase of the cream formulations. Emulgents and emulsion stabilizers suitable
for use in
formulations comprising a formula 1 or a formula 2A or 2B compound include
Tween~ 60, Span~
80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-
stearate and sodium lauryl
sulfate.
Formulations suitable for buccal administration include lozenges comprising n
formula 1 or
formula 2n or 2B compound in a flavored basis, usually sucrose and acacia or
tragacanth; ~fastiiles
comprising the formula 1 or formula 2A or 2B compound in an inert basis such
as gelatin and
glycerin, or sucrose and acacia.
Formulations for rectal administration may be presented as a suppository with
a suitable
base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration will have a
particle size
for example in the range of 0.01 to 200 microns (including particle sizes in a
range between 0.01
and 500 miorons in increments of 0.1 microns such as 0.1, 0.2, 0.3, 0.4, 0.5,
1, 2, 5, 30 microns, 35
microns, etc.), which is administered by inhalation through the nasal passage
or by inhalation
through the mouth so as to reach the various bronchi or alveolar sacs.
Formulations suitable for
aerosol or dry powder administration may be prepared according to conventional
methods and may
be delivered with other therapeutic agents such as compounds heretofore used
in the treatment or
prophylaxis of togavirus, flavivirus or retrovirus other infections.
Inhalation therapy is readily
administered by metered dose inhalers.
Formulations suitable for vaginal administration may be presented as
pessaries, tampons,
creams, gcls, pastes, foams or spray formulations containing in addition to
the formula 1 compound
such ctirricrs or excipients as are known in the art to be appropriate.
Formulations suitable for parenterai administration are sterile and include
aqueous and non-
aqueous injection solutions which may contain anti-oxidants, buffers,
bacteriostats and solutes
which render the formulation isotonic with the blood of the intended
recipient; and aqueous and
non-aqueous sterile suspensions which may include suspending agents and
thickening agents. The
formulations may be presented in unit-dose or multi-dose containers, for
example sealed ampoules
and vials with elastomeric stoppers, and may be stored in a freeze-dried
(lyophilized) condition
requiring only the addition of the sterile liquid carrier, for example water
for injections,
immediately prior to use. Extemporaneous injection solutions and suspensions
may be prepared
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from sterile powders, granules and tablets of the kind previously described.
Unit dosage
formulations will typically contain a daily dose or unit daily sub-dose, as
recited above, or an
appropriate fraction thereof, of a formula 1 or formula 2A or 2B compound.
In some embodiments, the formula 1 compounds will be administered on an
intermittent
S basis. In these embodiments, the formula 1 compound, e.g., a dose that
comprises about 5-500 mg
of a formula 1 compound (typically about 25-400 mg, or about ~50-350 mg), is
administered to a
subject for at least one day, followed by no dosing for at least one day (at
least 24 hours), optionally
followed by at (east one more daily dose of, e.g., about 50-500 mg.
Intermittent dosing methods
may comprise dosing (l, 2, 3 or 4 doses per week) based on a weekly schedule,
e.g., dosing on
t0 Monday, Wednesday and Friday, or on Tuesday, Thursday Saturday for about l,
2, 3, 4, 6, 8 or
more weeks, followed by periods of about 2, 3, 4, 5, 30, 45, 60, 90 or more
days with no dosing,
optionally followed by dosing again on Monday, Wednesday and Friday for about
1, 2, 3, 4, 6, 8 or
more weeks. Weekly dosing methods may comprise administration of the formula 1
compound to a
subject 1, 2, 3, 4 or 5 times per week for l, 2, 3, 4, or more weeks.. In
related embodiments, dosing
15 may be administered to a subject daily for 2, 3, 4, 5, 6, 7 or more days,
followed by a period of
about 1, 2, 3, 4, 5, 7, 14, 30, 45 60, 90 or more days, optionally followed by
another course of daily
dosing. These embodiments may further comprise treatment with a formula 2A or
2B compound
or another treatment as described herein.
To the extent not already indicated, it will be understood by those of
ordinary skill in the art
20 that any one of the various specific embodiments herein described and
illustrated may be further
modified to incorporate features shown in any of the other embodiments
disclosed herein.
Therapeutic applications. For therapeutic applications, the compositions
disclosed herein
will typically comprise one or more compounds of formula l, and, the methods
disclosed herein
will utilize such compositions, which will contain one, two or more of such
compounds, usually
25 one. While it is possible for the compounds of the invention to be
administered as pure compounds
it is preferable to present them as pharmaceutical formulations. The
formulations of the present
invention comprise at least one formula 1 compound together with one or more
acceptable carriers
or excipients and optionally other therapeutic agents, e.g., a formula 2A or
2B compound(s), aIFN,
ribavirin, a macrophage stimulating factors) and/or an oxidation agent(s). The
one or more can; iers
30 or excipients must be "acceptable" in the sense of being compatible with
the other ingredients of the
formulation and not deleterious to the patient. _
The compounds of this invention are useful in the treatment or prophylaxis of
one or more
flaviviral or togaviral infections in man or animals. Togavirus and flavivirus
infections that can be
treated with the formula 1 compounds include HCV, California encephalitis
virus, St. Louis
35 encephalitis virus, western equine encephalitis virus, eastern equine
encephalitis virus, Colorado
tick fever virus, Lacrosse encephalitis virus, Japanese encephalitis virus,
yellow fever virus,
V°.nezuelan equine encephalitis virus, Murray valley fever virus, tick-
borne encephalitis viruses,
CA 02352205 2001-05-23
WO 00/32177 PCT/US99/28082
GB virus A, GB virus B, GB virus C, Dengue virus 1, Dengue virus 2, Dengue
virus 3, Dengue
virus 4, Semliki Forest virus and Sindbis virus. The rubiviruses include human
rubella virus.
Pestiviruses include mucosal disease viruses such as bovine virus diarrhea
virus, hog cholera virus
and sheep border disease virus. The formula 1 compounds are also useful to
treat hepatitis G virus.
In addition to preventing or treating togaviral infections, the some of the
formula 1
compounds can be used to treat subjects who are coinfected with a togavirus
and another virus,
such as a retrovirus or a second togavirus. Retroviruses such as a human
immunodeficiency virus,
e.g., HIV 1 or HIV2, a simian immunodeficiency virus, a recombinant human-
simian
immunodeficiency virus (SHIV), a feline immunodeficiency virus or a feline or
murine leukemia or
sarcoma virus can be treated with formula 1 compounds. Coinfections with
hepatitis viruses may
be treated using the compounds of the invention, e.g., a HCV and HIV
coinfection. In these
embodiments, the subject will typically be one who has been tested to
determine that (i) one or
more togavirus infections is present (HCV, etc.) and (ii) a second virus
infection is present(e.g.,
human herpes simplex virus 1, human herpes simplex virus 2, or a retrovirus
such as HIV 1, HIV2,
etc.).
In other embodiments, a dosing regimen for a formula 1 compound will comprise
the use of
a relatively high induction dose, e.g., about 150-750 mg per day or about 150-
750 mg per day using
an intermittent dosing schedule (such as described herein), followed by lower
maintenance dosing,
e.g., about 50-250 mg per day or about 50-250 mg per day on an intermittent
dosing schedule.
These embodiments may further comprise treatment with a formula 2A or 2B
compound or another
treatment as described herein.
Parenteral formulations may comprise a cyclodextrin, e.g., an a-cyclodextrin,
a (3-
cyclodextrin (e.g., (3-hydroxypropylcyclodextrin) or a y-cyclodextrin, which
are typically employed
in aqueous formulations, which optionally comprise one or more of a buffer, a
salt (NaCI, etc.) to,
c.g., render the solution isotonic, a bacteriosti~t or other excipients as
known in the art and a formula
1 compound at a concentration of, e.g., about 5-25 mg/mL, typically about 10-
20 mg/mL.
Parenteral formulations that comprise a formula 1 compound and one or more
excipients may be
diluted into, e.g., sterile saline and infused into a subject. Parenteral
formulations are typically
administered by, e.g., intravenous, topical or oral delivery to a subject such
as a human. For non-
aqueous formulations, one or more solvents such as propylene glycol, a PEG,
e.g., PEG 300 or PEG
400, ethanol, and benzyl benzoate may be employed. Typical aqueous and non-
aqueous
formulations will contain about 5 to about 400 mg/mL of a formula 1 compound,
usually about 10
to about 200 mg/mL. Such parentcral formulations may be delivered ornlly, or
by intramuscular,
intravenous or subcutaneous injection.
In preparing compositions that comprise a fotlrtula 1 compound (and optionally
one or
more excipients), one may optionally mill or otherwise granulate the compound
to obtain a desired
particle size, before or after the formula 1 compound is contacted with one or
more excipients. For
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example, one may mill a formula 1 compound such as 16a-bromoepiandrosterone,
to obtain an
average particle size (or diameter) of about O.S-25 EtM or about 1-10 p.M
(e.g., about 2, 5 or 10 IrM
average particle size or diameter) before contacting the milled formula 1
compound with a liquid or
solid excipient. Milled formula 1 compound is useful to facilitate dissolution
or suspension of the
S formula 1 compound in one or more liquid excipients (e.g., a PEG such as PEG
300, propylene
glycol or benzyl benzoate) or to facilitate uniformly distributing drug
substance when the milled
compound is contacted with one or more solid excipients (e.g., a filler, a
binder or a lubricant).
The compositions and formulations disclosed herein are useful in the treatment
of, or
ameliorate one or more symptoms associated with, the conditions or infections
disclosed herein.
These compositions and formulations may also be used to treat, or ameliorate
one or more
symptoms associated with, a retroviral infection such as a HIV 1 or HIV2
infection in humans, or
Malaria in humans. As used herein, phrases such as "amelioration of one or
more symptoms
associated with" means that such compounds or formulations may be used to
reduce replic2tion of
an infectious agent or to reduce the number of infectious agents that are
present in a subject or to
I S ameliorate one or more symptoms associated with, or caused by, the
condition or infection (e.g.,
reduced fever, a shortened duration or degree of pain, or a noticeable
reduction of or elimination of
diarrhea or fatigue).
In addition to the ingredients particularly mentioned above the formulations
of this
invention may include other agents conventional in the art having regard to
the type of formulation
in question,~for example those suitable for oral administration may include
flavoring or coloring
agents.
The present invention further provides veterinary compositions comprising at
least one
formula 1 or formula 2A or 2B compound together with a veterinary carrier
therefor. Also, the
formula I compound may be present in the animal's feed or water. Excipients
for veterinary
applications may include compounds, e.g., small amounts of chloroform, that
may not be generally
suitable for human use.
Veterinary carriers are materials useful for the purpose of administering the
composition to
cats, dogs, horses, mice, rats, hamsters, rabbits and other animals and may be
solid, liquid or
gaseous materials that are otherwise inert or acceptable in the veterinary art
and are compatible with
the formula 1 or formula 2A or 2B compound. These veterinary compositions may
be administered
orally, parenterally or by any other desired route, e.g., as described herein.
In an exemplary embodiment, human patients infected with HCV are given an
aqueous
isotonic a-cyclodextrin or ~i-cyclodextrin (e.g., ~3-hydroxypropyl
cyclodextrin) formulation
containing about S-30 mg/mL of dehydroepiandrosterone or l6a-
bromoepiandrosterone, e.g., about
10-20 mg/mL. The formulation is delivered intravenously in a single daily dose
or two subdoses
per day. The patients are dosed with 1 to 10 mg/kg/day for 4 to 10 days,
followed by no dosing for
5 to 30 days, followed by dosing again with the cyclodextrin formulation for 4
to 10 days. The
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WO 00/32177 PCT/US99/Z8082
dosing regimen is repeated one, two or more times. Clinical markers for HCV
infection are
followed during treatment, e.g., viral nucleic acid in the blood or plasma,
liver enzyme levels in the
blood or plasma (aminotransferase). For these patients, a standard anti-HCV
treatme~t(s), e.g.,
interferon and/or ribavirin, is optionally started or continued according to
the recommendations of
S the patient's doctor and with the patient's informed approval. In some of
these embodiments, a
formula 1 compounds) is administered daily continuously as a component in an
oral or parenteral
composition or formulation, e.g., for a formula 1 compounds) that is a new
compound per se. The
dehydroepiandrosterone or 16a-bromoepiandrosterone is optionally also
administered systemically
using, e.g., the formulation of example I to deliver I-5 mg/kg/day every other
day for about 1 to 4
months, or an oral formulation to deliver about 5-40 mg/kg/day every other day
for about 1 to 4
months.
Embodiments of formula 1 compounds include or exclude any subset of compounds
within
the definition of formula 1, provided that at least one compound remains. For
example, a sflbset of
formula 1 compounds that are generally preferred and are usually included, for
example are
aqueous or nonaqueous formulations comprising 16a-bromoepiandrosterone. A
subset compounds
or applications for compounds that are optionally excluded from formula 1
compounds or their uses
in any embodiment or claim herein comprises, e.g., the use of one or more
compounds (or their use)
that are disclosed in one or more prior art references or publications, to the
extent that the disclosed
compounds or uses renders any claim or embodiment unpatentable for novelty,
obviousness and/or
inventive slap reasons. /~ItOtIICr SlIl7SCl of the farmuln 1 compounds
excludes one or more fonnuln
I cotnpuunds with corticustcruid uc;tivity, e.g., unc; ur more fornulu 1
compuunds wherein the; 3-
position comprises =O, a double bond at the 4-5 positions, a hydroxyl group (-
OH) is bonded to the
11-position, -C(O)-CHZOH and -H or -C(O)-CHZOH and -OH or =O is bonded to the
17-position,
Q6 is -CH3 or -CH20H, Q3 is -CH3, and the remaining positions (R,) comprise,
e.g., -H and 0, 1 or 2
hydroxyl groups.
In other embodiments, a formula 1 compound may be linked to an oligonucleotide
or an
oligonucleotide analog to facilitate delivery of the oligonucleotide or analog
into cells. Typically
the formula I compound will be linked to the steroid nucleus through a
terminal hydroxyl group at
a 5', 3' or 2' position of the oligonucleotide. Oligonucleotides and analogs
of oligonucleotides are
known and have been described, e.g., U.S. patents 4725677, 4973679, 4997927,
4415732, 4458066,
5047524, 4959463, 5212295, 5386023, 5489677, 5594121, 5614622, 5624621; and
PCT
publication Nos. WO 92/07864, WO 96/29337, WO 97/14706, WO 97/14709, WO
97/31009 and
WO 98/04585, WO 98/04575 all of which are incorporated herein by reference.
Synthesis methods. The compounds employed in the present invention in general
may be
synthesized in manners known and readily understood by those skilled in the
art. Therefore, there is
no need to explain in great detail the methodology used for the synthesis of
most such compounds.
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WO 00/32177 PCT/US99/28082
Formula 1 compounds that comprise a thioacetaf moiety, sulfate ester, sulfite
ester, _
carbamate or thioester moiety at R2 (the 3-position) are prepared essentially
according to methods
known in the art. Suitably protected intermediates will be used as is
apparent. See, for example,
U.S. patent 5198432; European patent publications EP 57691 S and EP 576914; C.
Christians et al.,
J. Chem. Soc. Chem. Commun. 1991 vol 22, C. Christians et al., J. Chem. Soc.
Chem. Commun.
1991 19:1403-1405, H.N. Abramson et al., J. Pharm. Sci. 197766:602-603, E.J.
Corey et al., J. Am.
' _ Chem. Soc. 1996 118:8765-8766, A.G.M. Barrett et al., J. Org. Chem. 1989
54:227, D.H.R. Barton
et al., J. Chem. Soc. Perkin Trans. I 1976 19:2112-2116, D.H.R. Barton et al.,
J. Chem. Soc. Perkin
Traps. I 1975 16:1574-I 585 and W.T. Smith et al., Traps. KentuckyAcad. Sci.
1984 45:76-77, all
of which arc incorporated herein by reference.
Enumerated embodiments. Aspects of the invention include the following
enumerated
embodiments, which further illustrate the invention and preferred aspects
thereof or related subject
matter.
1. A method of treating hepatitis virus C in a patient in need of such
treatment,
comprising administering to said patient an effective amount of at least one
compound selected
from the group consisting of the compounds of the present invention.
2. A method as recited in embodiment 1, further comprising administering to
said
patient at least one plasma concentration-enhancing compound.
3. A method as recited in embodiment 2, wherein said at least one compound
according tq'the present invention and said at Least one plasma concentration-
enhancing compound
are administered simultaneously.
4. A method as recited in embodiment 2, wherein said at least one compound
according to the present invention and said at least one plasma concentration-
enhancing compound
are administered sequentially.
5. A method as recited in any one of embodiments I - 4, further comprising
administering to said patient ribavirin and/or alpha interferon.
6. A method as recited in any one of embodiments 1 - 5, further comprising
administering to said patient at least one macrophage stimulating factor.
7. A method as recited in any one of embodiments 1 - 6, further comprising
administering to said patient one or more oxidation agent and/or oxygen
ventilation.
8. A method as recited in any one of embodiments 1 - 7, wherein said patient
is a
mammal.
9. A method as recited in embodiment 8, wherein said patient is a human.
10. A method as recited in any one of embodiments I - 9, wherein said
administering is
by injection.
11. A method as recited in any one of embodig~ents 1 - 9, wherein said
administering is
by infusion.
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WO 00/32177 PCT/US99/28082
12. A method as recited in any one of embodiments 1 - 9, wherein said
administering is
by intravenous injection.
13. A method as recited in embodiment 2, wherein said plasma concentration-
enhancing compound is naringin or naringenin.
14. A method of reducing at least one aminotransferase levei in a patient
suffering from
hepatitis virus C in a patient in need of such treatment, comprising
administering to said patient an
. effective amount of at least one compound selected from the group consisting
of the compounds of
the present invention.
I5. A method as recited in embodiment 14, further comprising administering to
said
patient at least one plasma concentration-enhancing compound.
16. A method as recited in embodiment 14, wherein said at least one compound
according to the present invention and said at least one plasma concentration-
enhancing compound
are administered simultaneously.
17. A method as recited in embodiment 15, wherein said at least one compound
according to the present invention and said at feast one plasma concentration-
enhancing compound
are administered sequentially.
18. A method as recited in any one of embodiments 14 - 17, further comprising
administering to said patient ribavirin and/or alpha interferon.
19. A method as recited in any one of embodiments 14 - 18, further comprising
administericlg to said patient at least one macrophage stimulating factor.
20. A method as recited in any one of embodiments 14 - 19, further comprising
administering to said patient one or more oxidation agent andlor oxygen
ventilation.
21. A method as recited in any one of embodiments 14 - 20, wherein said
patient is a
mammal.
22 A method as recited in embodiment 21, wherein said patient is a human.
23. A method as recited in any one of embodiments 14 - 22, wherein said
administering
is by injection.
24. A method as recited in any one of embodiments 14 - 22, wherein said
administering
is by infusion.
25. A method as recited in any one of embodiments 14 - 22, wherein said
administering
is by intravenous injection.
26. n method w recited in em hodiment 15, wherein said ~l~sma concentrati~n-
enhancing compound is naringin or naringenin.
27. A method of treating a togavirus in a patient in need of such treatment,
comprising
administering to said patient an effective amount of at least one compound
selected from the group
consisting of the compounds of to the present invention. .
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28. A method as recited in embodiment 27, further comprising administering to
said
patient at least one plasma concentration-enhancing compound.
29. A method as recited in embodiment 28, wherein said at least one compound
according to the present invention and said at Least one plasma concentration-
enhancing compound
are administered simultaneously.
30, n method as recited in embodiment 2fi, wherein said nt Icast one compound
_ according to the present invention and said at (cast one plasma
concentration-enhancing compound
are administered sequentially.
31. A method as recited in any one of embodiments 27 - 30, further comprising
administering to said patient ribavirin and/or alpha interferon.
32. A method as recited in any one of embodiments 27 - 31, further comprising
administering to said patient at least one macrophage stimulating factor.
33. A method as recited in any one of embodiments 27 - 32, further comprising
administering to said patient one or more oxidation agent and/or oxygen
ventilation.
34. A method as recited in any one of embodiments 27 - 33, wherein said
patient is a
mammal.
35. A method as recited in embodiment 34, wherein said patient is a human.
36. A method as recited in any one of embodiments 27 - 35, wherein said
administering
is by injection.
37. ;' A method as recited in any one of embodiments
21 - 35, wherein said administering
is by infusion.
38. A method as recited in any one of embodiments
27 - 35, wherein said administering
is by intravenous
injection.
39. A method as recited in embodiment 28, wherein
said plasma concentration-
enhancing
compound
is naringin
or naringenin.
40. A method according to embodiment 27, wherein
said togavirus is an alphavirus.
41. A method according to embodiment 27, wherein
said togavirus is a flavivirus.
42. A method according to embodiment 41, wherein
said flavivirus is hepatitis G.
43. A method according to embodiment 41, wherein
said flavivirus is yellow fever
virus.
44. A method acwrding to embodiment 27, wherein said togavirus is a rubivirus.
45. A method according to embodiment 44, wherein said rubivirus is the rubella
virus.
46. A method according to embodiment 27, wherein said togavints is a
pestivirus.
47. A method according to embodiment 46, wherein said pestivirus is bovine
virus
diarrhea virus (BVDV).
48. The method of any of embodiments 1-47 wherein the compound of the
invention is
a formula 1 compound or a metabolite thereof.
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49. The method of embodiment 48 wherein the fornr~la 1 compound is a compound
named in compound groups 1-21, or in any formula 1 (e.g., any formula 4)
compound or genus
disclosed or named herein, or a metabolite of any of these.
50. A composition comprising 16a-bromoepiandrosterone, and 2, 3, 4 or 5
excipients
selected from polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl
alcohol and
propylene glycol; wherein the composition comprises less thawabout 3% v/v, or
less than about 1%
v/v, or less than about 0.5% v/v of water, or less than about 0.1 % v/v of
water.
51. The composition of embodiment 50 wherein the composition comprises (i) 16a-
bromoepiandrosterone at a concentration of about 45-55 mg/mL, (ii) 20-30% v/v
polyethylene
glycol 300, polyethylene glycol 400 or a mixture of polyethylene glycol 300
and 400, (iii) 10-15%
v/v dehydrated ethyl alcohol, 2.5-7.5% v/v benzyl benzoate, and (iv) 55-60%
v/v propylene glycol.
52. The composition of embodiment 51 wherein the composition comprises 16a
bromoepiandrosterone at a concentration of about 50 mg/mL, about 25% v/v
polyethylene glycol
300, about 12.5% v/v dehydrated ethyl alcohol, about 5% v/v benzyl benzoate,
about 57.5% v/v
propylene glycol and less than about 0.5% v/v water.
53. The composition of embodiment 50 wherein the composition comprises 16a-
bromoepiandrosterone at a concentration of about 50-105 mg/mL, about 27-33%
w/w benzyl
benzoate, about 27-33% w/w polyethylene glycol 300, about 25-30% w/w propylene
glycol and
about I-3% w/w benzyl alcohol.
2() 54. ~I~11C CUnIpUSItIUn UI~CnIbU(11n1C11t 53 wherein LhC CUInpU51t1U11
CUIlIprISeS IGa-
bromoepiandrosterone at a concentration of about I OU mg/mL (about l0% w/w),
about 30.4% w/w
berry! benzoate, about 30.7% w/w polyethylene glycol 300, about 28% w/w
propylene glycol and
benzyl alcohol about 1.9% w/w.
55. A product produced by the process of contacting 16a-bromoepiandrosterone
and a
liquid excipient, wherein the product contains less than about 3% water,
provided that the liquid
excipient is not chloroform, dimethylsulfoxide, olive oil, or a vegetable oil.
56. The product of embodiment 55 wherein the liquid excipient is polyethylene
glycol,
dehydrated ethanol, benzyl benzoate, benzyl alcohol and propylene glycol,
wherein the product
comprises less than about 3% v/v, or less than about I% v/v, or less than
about 0.5% v/v of water.
57. The use of a formula 1 compound for making a medicament for the treatment
of an
infection caused by one or more togaviruses in a subject.
58. The use of embodiment 57 wherein the formula 1 compound is a compound
named
in compound groups 1-21, or a metabolite thereof.
59. A method to enhance the oral bioavailability of a therapeutic agent
comprising
administering to a subject an effective amount of a compound of formula 2A or
2B.
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60. The method of embodiment 59 wherein the therapeutic agent is a steroid, a
steroid
analog an antibiotic, an antiviral agent (e.g., a nucleoside, nucleoside
analog, nucleotide analog,
protease inhibitor or a polymerase inhibitor) or an antifungal agent (e.g.,
amphotericin B).
61. The method of embodiment 59 wherein the therapeutic agent is a compound of
formula 1.
62. A method comprising administering an effective amount of a composition of
any of
- _ embodiments 50-54 to a subject having, or susceptible to, a togavirus
infection (e.g., HCV).
63. The method of embodiment 62 wherein the subject is a human and the human
is
s
optionally coinfcctcd with a rotrovirus (c.g., I IIV 1 or I-ITV2).
64. A method to ameliorate or reduce one or more symptoms associated with a
togavirus infection in a subject, or to reduce replication of a togavirus in a
subject infected with a
togavirus, comprising administering to the subject an effective amount of a
compound of formula 1.
65. The method of embodiment 64 wherein the formula 1 compound is a compound
or
within a genus of compounds as disclosed herein, e.g., a compound or genus
named in compound
groups 1-21 or in the claims as originally filed, or the formula 1 compound is
present in a
composition comprising one or more pharmaceutical excipients, e.g., any of the
formulations
disclosed or described herein.
66. A composition comprising a formula I compound wherein the formula I
compound is
a compound or within a genus of compounds as disclosed herein, e.g., a
compound or genus named
in compound groups 1-21 or in the claims as originally filed, and at least one
excipient and a local
anesthetic, wherein the local anaesthetic is optionally selected from
procaine, benzocaine and
lidocaine.
67. A product produced by the process of contacting a compound of formula 1,
e.g., any
compound named in compound groups 1-21, and a first excipient with a second
excipient wherein
the product optionally further comprises a local anesthetic, wherein the local
anaesthetic is
optionally selected from procaine, benzocaine and Iidocaine.
68. A product produced by the process of contacting a compound of formula 1,
e.g., any
compound named in compound groups 1-21, and a first nonaqueous liquid
excipient with a second
nonaqueous liquid excipient wherein the product comprises less than about 3%
w/w water, or less
than about 0.5% w/w water, or less than about 0.1% w/w water, and wherein the
first or the second
nonaqueous liquid excipient optionally excludes one or more of
dimethylsulfoxide, chloroform,
dioxane, a vegetable oil and olive oil, and wherein the product optionally
further comprises a local
anesthetic, whcrcin the local nnncsthclic iv olionnlly xclcctcd from procaine,
benzocuinc and
I iducuinc.
69. A method comprising administering an effective amount of the composition
of
embodiment 66 or the product of embodiments 67 or 68 to a subject having an
infection or
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condition described herein, e.g., HCV, whereby the infection or condition, or
a symptom thereof, is
eliminated, reduced, treated, improved or ameliorated.
70. The method of embodiment 69 wherein the formula 1 compound is 16a-
haloepiandrosterone or 16a-halodehydroepiandrosterone.
EXAMPLES
The following examples further illustrate the invention' and are not to be
construed as
limiting the invention.
Eaamplc 1. 16a-Bromocpiandrostcronc formulation 1. Two lots of a non-aqueous
formulation was made at a 16a-bromoepiandrosterone ("BrEA") concentration of
50 mg/mL in
25% polyethylene glycol 300, 12.5% dehydrated ethyl alcohol, 5% benzyl
benzoate, and 57.5%
propylene glycol, hereafter "formulation 1 ", as follows. BrEA was obtained
from Procyte, Inc.
The remaining excipients are shown below.
Excipient SpecificationSupplier Final Product
Lot No. Concentration
Propylene glycolUSP Arco Chemical 57.5% (v:v)
HOC-61220-01104
Polyethylene NF Union Carbide 25% (v:v)
glycol 300
695752
Dehydrated alcoholUSP McCormick Distilling12.5% (v:v)
(ethanol) 97K10
Benzyl benzoate USP Spectrum 5% (v:v)
Pharmaceuticals
MG025
The formulation was prepared by suspending BrEA in polyethylene glycol 300,
and
sequentially adding propylene glycol, benzyl benzoate, and dehydrated ethyl
alcohol to form a
solution, which was diluted to the final desired volume with additional
propylene glycol. The
procedure is described below.
The calculated amount of polyethylene glycol 300 was added to a compounding
vessel.
Then, while mixing, the calculated amount of BrEA was added to the vessel, and
mixed for at least
5 minutes to form a smooth, creamy liquid. Propylene glycol was added to the
vessel, and mixed
for a minimum of 5 minutes to form a uniform suspension. The calculated amount
of benzyl
benzoate is added to the vessel, and mixed for approximately 5 minutes to form
a translucent liquid
suspension. Dehydrated alcohol was added to the vessel, and mixed for
approximately 5 minutes to
form a clear, colorless solution. Propylene glycol was then added to achieve
the desired final
formulation, and mixed for approximately 5 minutes. The drug solution was
transferred to a
volume-dispensing device set to deliver 1.2 mL per vial. Under nitrogen
pressure, the solution was
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filtered through two 0.2 ~tm polyvinylidene fluoride filters in series before
dispensing into 2 cc
amber galss vials. The vials were capped with Teflon-coated, butyl-rubber
stoppers and crimp
sealed. '
Materials used in the product vials arc listed below.
Material Sourcc Product Description
Codc
Vial Wheaton 2702-BS Tubing vial, 2 mL/13 mm,
1BA glass, type 1 amber
Stopper OmniflexV9239 FM257/213 mm, Teflon coated, butyl
rubber stopper
Seal West 4107 Flip seal, I3 mm, mist gray
bridge
Example 2. BrEA formulation 2. A formulation containing 100 mg/mL of BrEA, 10%
w/w, in benzyl benzoate (USP) 30.4% w/w, polyethylene glycol 300 (NF) 30.7%
w/w, propylene
glycol (USP), qs, about 28% w/w and benzyl alcohol (NF) 1.9% w/w, hereafter
"formulation 2",
was prepared as follows. A desired amount of BrEA ( I .0 kg) was suspended in
PEG 300 (about 3.0
L) in a compounding vessel and mixed for at least 5'minutes at room
temperature to form a smooth
creamy liquid. The needed amount of propylene glycol (about 1.5 L) was then
added and mixing
was continued for at least 5 minutes to form a uniform suspension. Benzyl
benzoate (about 3.0 L)
was then added and the vessel contents were mixed for about Sminutes to form a
translucent
suspension. Benzyl alcohol (about 200 mL) was then added and the mixing was
continued for
about 5 minutes to form a clear, colorless solution. Propylene glycol was then
added to achieve the
desired fina~'formulation volume (about 1.5 L) and mixing was continued for
about 5 minutes. The
drug solution was transferred to a volume-dispensing device, which was set to
deliver 1.2 mL per
vial (2 mL, glass, type 1 amber vials). The formulation was filtered under
nitrogen pressure (about
3 atm) through two 0.2 pm polyvinylidine fluoride filters in series. The vials
were capped using
Teflon-coated, butyl rubber stoppers and then crimp sealed essentially as
described in example 1.
The vials were stored in the dark at reduced temperature (about 2-
8°C).
Example 3. Human clinical trial. A clinical trial protocol that incorporates
about 15-20
patients is designed. For the phase I or I/II trial, the patients are mildly
infected with one or more
togaviruses, e.g., t-ICV and they are mildly to moderately symptomatic. The
patients are
administered treatment for l, 2 or 3 weeks. In 2 or more dose groups, e.g.,
25, SO or 100 mg/day of
16a-bromoepiandrosterone (BrEA), or an ester thereof, is administered
parenterally, e.g., by
intramuscular or intravenous injection, on 3, 4 or 5 days of the weeks when
dosing occurs. Dosing
is on consecutive days or on an intermittent schedule, e.g., 2, 3 or 4 doses
with one dose
administered every other day. The formulation containing BrEA is as described
herein, e.g., the
foztnulation of example 1 or 2, preferably the formulation of example 2.
During the week of
treatment and far 1, 2, 3, or more weeks thereafter, blood samples are taken
periodically for
evaluation of the infection or its symptoms, pharmacokinefics, plasma
cytokines (e.g., IL-2, IL-4,
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IL-10, IGFI, yIFN, GM-CSF), and intracellular cytokines (e.g., IL-2, IL-4, IL-
10, IGF1, yIFN, GM-
CSF). The patients are optionally treated again at about 2 to 12 weeks after
the initial dosing, using
the same or a similar protocol as that used in the initial dosing protocol.
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