Note: Descriptions are shown in the official language in which they were submitted.
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
USE OF I7-KETOSTEROID COMPOUNDS AND DERIVATIVES,
METABOLITES AND PRECURSORS THEREOF IN TREATMENT OF
TOXOPLASMOSIS AND IN THE TREATMENT OF CRYPTOSPORIDIOSIS
BACKGROUND OF THE INVENTION
The present invention is directed to the use of 17-ketost:eroid compounds, as
well as
derivatives, metabolites and precursors of such compounds, andl
pharmaceutically acceptable salts
of any of these compounds, collectively defined herein as the "c;ompounds of
the present
invention" in treatment of toxoplasmosis and/or in treatment of
cryptosporidiosis The present
invention is also directed to the use of such compounds in combination with
one or more additional
compound (as described herein) in such treatments. The present. invention is
further directed to the
use of such compounds (or combinations of compounds) for the manufacture of
pharmaceutical
formulations for treatment of such conditions.
Cryptosporidium is an intestinal parasite that is the etiologic agent of
cryptosporidiosis.
This parasite is a protozoan that has been found in humans and animals, and
has been found to
cause severe diarrhea (sometimes fatal). Cryptosporidiurn has been found to be
extremely resistant
to many known antibiotics. Persons with normal immune systems can suffer from
cryptosporidiosis, which is the apparent cause of many cases of diarrhea, and
such persons usually
recover within two weeks. Persons with serious immune deficiency, such as AIDS
patients, may
never recover from Cryptosporidiosis. This disease can spread from person to
person or from
animals to persons, and the incubation period appears to be two weeks or less.
The Toxoplasma gondii protozoan is the etiologic agent of Toxoplasmosis. This
sporozoa
is an intracellular parasite that resides inside macrophages and leas evolved
a mechanism to avoid
being killed by intracellular oxygen, metabolites and Iysosomal enzymes.
The live parasite, Toxoplasma gondii, when ingested by a macrophage, forms a
membrane
bound vesicle called a phagosome. This phagosome containing t:he Toxoplasma
parasite can inhibit
the fusion of lysosomes to the phagosome, which would cause ita digestion and
elimination.
However, if dead Toxoplasma parasites are ingested by macrophages, the
phagosome thus
resulting cannot prevent lysosome fusion, and parasite digestion. It is the
function of the
biosynthetic machinery of the parasite to synthesize molecules that block the
ability of the
lysosome to fuse with the Toxoplasma phagosome.
A number 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, 573Ei537, 5843932,
5837700, 5824671,
5807849, 5798347, 5780460, 5776923, 5728688, 5610150, 5593981, 5372996,
5110810, 5807848,
i
~ CA 02352387 2001-05-25
WO 00/32176 PCT/t7S99J28080 . .
5707983, 5641766, 5585371, 5506223, 5424463, 5296481, 5252730, 5776921,
5641768, 5559107, ..
5478566, 5461042, 5407684, 5387583, 5277907, 5206008, 50 i'7284, 5162198,
5660835, 5527789,
5756482, 5709878, 5804576, 5744462, 5714481, 5700793, 5696106, 5656621,
5175154, 5157031,
5028631, 5001119, 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.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention,. it now has been
discovered that
toxopiasmosis and cryptosporidiosis may be effectively treated with compounds
(or
pharmaceutically acceptable salts thereof} of the following formula 1 (and
metabolites, analogs and
precursors thereofj:
R~
R~ Q8
R~ ;
12
R~ R' R~ I1 13 17
Q3 I4
IS
...1 9 I
04~ 2 10 g R~ ~R
v
RZ 3 4 I,,S. .,,' b 7 Q R' Rt
R1 ~ ~s
R' R~ 1
wherein
Q 1 is -C(R 1 )2- or -C(O)-;
Q2 is -C(Rl )2'~ -C(R1 )(~')-~ -C(Y)- or -CH2-CH2-;
Q3 is -H or -C(R 1 )3-;
Q4 is -C(R1)2-, -C(O)-, hydroxyvinylidine (-CH(CH=CHOH)-) or methyl methylene
(-
CH(CH)3-);
Q5 is -C(R1)2- or -C(O)-;
X and Y independently are -OH, -H, lower alkyl (e.g., C 1 _6 alkyl), -O-C(O)-
R5,
-C(OrORS, halogen (i.e., -F, -Cl, -Br or -I) or =O;
each R1 independently is -H, -F, -Cl, -Br, -I, -OH, Cl_~5 alkoxy, or C1_6
alkyl;
R2 is -H, -OH, -F, -CI, -Br, -I, C1_6 alkyl, CI_6 alkoxy, -OR3, an ester
(e.g., -O-C(O)-R4
or -C(O)-O-R4), a thioester (e.g., -O-C(S)-R4 or -C(S)-O-R4), a thioacetal
(e.g., -S-C(O)-R4 or
C(O)-S-R4), a sulfate ester (e.g., -O-S(O)(O)-O-R4), a sulfonal:e ester (e.g.,
-O-S(O)-O-R4) or a
2
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
carbamate (e.g., -O-C(O)-NH-R4 or -NH-C(O)-O-R4) or R2, together with the Rl
that is bonded to
the same carbon atom is =O;
R3 is -S(O)(O}-OM, -S(O)(O)-O-CH2-CH(O-C(O)-R6)-CH2-O-C{O)-R6,
-P(O)(O)-O-CH2-CH(O-C(O)-R~)-CH2-O-C(O)-R~, a glucuronide group of structure
(A)
COOH
H3C o
OH
I
OH
CH3 (A),
or R3 is C 1 _ 1 g alkyl, C2_ 1 g alkenyl, C2_ 1 g alkynyl, a C 1 _ 1 g ester
or a C 1 _ 1 g thioester, where any
of the foregoing C 1_ 1 g or C2_ 1 g moieties are optionally substituted at
one or more hydrogen atoms
with one or more independently selected -ORPR, (including -OIEI), -NHRPR,
(including -NH2) or -
SRPR, (including -SH) groups, or R3 is a C1_lg fatty acid, C2_:l0 alkynyl,
(J)n-phenyl-C~-5-alkyl,
(J)n-phenyl-C2_5-alkenyl;
R4 is -H, a protecting group, optionally substituted C 1_ 1 g alkyl,
optionally substituted C2_
1 g aIkenyl, optionally substituted C2_ 1 g alkynyl, optionally substituted
aryl, optionally substituted
aryl-C1_6 alkyl, optionally substituted aryl-C2_6 alkenyl, optionally
substituted aryl-C2_6 alkynyi,
optionally substituted heterocycle-C1-6 alkyl, optionally substituted C2_6
aikenyl-heterocycle,
1 S optionally substituted C2_6 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 -NH2), -SRPR (including -SH),
=O, =S, =N-
OH, -CN, -N02, -F, -Cl, -Br or -I groups or atoms;
each RS independently is straight or branched C1_14 alkyl;
each R6 independently is straight or branched C1_14 ali';yl;
each R~ independently is straight or branched C 1 _ 14 alkyl or a glucuronide
group of
structure {A);
each RPR independently is -H or an independently sele<;ted protecting group;
2S n is 0, l, 2 or 3;
each J independently is -F, -Cl, -Br, -I, C1_4 alkyl, C1-q~ alkenyl, C1_4
alkoxy, carboxy,
nitro, sulfate, sulfonyl, a C1_6 carboxyl ester or a C1_6 sulfate ester;
M is hydrogen, sodium, -S(O)(O)-O-CH2-CH(O-C(O)-:EZ6)-CH2-O-C(O)-R6, -P(O)(O)-
O-
CH2-CH(O-C(O)-R~}-CH2-O-C(O)-R~ or a glucuronide group of structure (A); and
the dotted lines in formula 1 represent an optional double bond, provided that
there are not
double bonds at both the 4-S and S-6 positions and provided that when a double
bond is present,
CA 02352387 2001-05-25
WO 00!32176 PCT/US99/28080
zero or 1 RI group is bonded to carbon atoms at the I-, 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
collectivety referred
herein to as the "compounds of the invention" or the "compounds of the present
invention".
Accordingly, the present invention provides a method fir treating these
parasitic infections
which comprises administering to an afflicted host a therapeutically effective
amount of a
compound (or a pharmaceutically acceptable salt thereof) having the structure
of formula I, or a
metabolite or precursors thereof, as defined herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein and unless otherwise stated or implied by context, the
following terms have
the meanings defined here.
A "patient" 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,
1 S 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 1-C 1 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 -C'.H3, -CH2CH3,
-CH2CH2CH3, -
CH(CH3)2, -CH2CH2CH2CH3, -CH2CI-I(CH3)2, -CH(CH3)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)CH2GH(CH3)2,
C{CH3){CH2CH3}2, -CH(CH2CH3)CH(CH3)2, -C{CH3)2CH{CH3)2, -CH(CH3)C(CH3)3,
eyclopropyl, cyclobutyl, cyclopropylmethyl, cyciopentyl, cyclobutylmethyl, 1-
cyclopropyl-I-ethyl,
2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyl, I-cyclobutyl-1-ethyl, 2-
eyelobutyl-I-ethyl,
1-cyclopropyl-1-propyI, 2-cyclopropyl-I-propyl, 3-cyclopropyl-1-propyl, 2-
cyclopropyi-2-propyi,
and 1-cyclopropyl-2-propyl.
"Alkenyl" as used herein, unless stated to the contrary, is C2-C I g
hydrocarbon comprising
I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 I, 12, 13, 24, 15, 16, 17 or 18 carbon atoms
in the form ofnormal,
4
CA 02352387 2001-05-25
WO 00/32176 PCTIUS99I28080
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=C(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)CFi=CHCH3, -
CH(CH3)CH2CH=CH2, -CH2CH=C(CH3)2, 1-cyclopent-I-en.yl, I-cyclopent-2-enyl, 1-
cyciopent-
3-enyl, 1-cyclohex-I-enyl, 1-cyclohex-2-enyl, and I-cyclohex-:3-enyl.
"Alkynyl" as used herein, unless stated to the contrary, is C2-C 1 g
hydrocarbon comprising
I, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, I7 or 18 carbon atoms
in the form of normal,
secondary, tertiary, cyclic or mixed structures and comprising 1, 2, 3 or more
triple bonds between
adjacent carbon atoms. Examples are -CCH, -CCCH3, -CH2C(:H, -CCCH2CH3, -
CH2C>rCH3, -
CH2CH2CCH, -CH(CH3)CCH, -CCCH2CH2CH3, -CH2CCCH2CH3, -CH2CH2CCCH3 and -
CH2CH2CH2CCH.
"Halogen" or "halo" means fluorine (-F}, 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, PEG100, PEG115, PEG 200, PEG 300, PEG400, PEG500, PEG600,
PEG
1000, PEG1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000,
PEGI 1000, PEG12000, 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 deteterious to the patient or animal to which the
formulation is to be
administered. As used here, excipients and carriers include liquaids,
including benzyl benzoate,
cottonseed oil, N,N-dimethylacetamide, a C2_12 alcohol (e.g., eahanol),
glycerol, peanut oil, a
PEG, vitamin E, poppyseed oil, propylene glycol, safflower oil, sesame oil,
soybean oil and
vegetable oil. Excipients, as used herein may exclude solvents ;such as
chloroform, dioxane or
DMSO. Excipients comprise one or more components typically used in the
pharmaceuticaE
formulation arts, e.g., fillers, binders, disintegrants and lubricants.
5
CA 02352387 2001-05-25
WO 00/32176 PCTlUS99/28080 '.
Unless otherwise specified, expressions that refer to "a formula 1 compound",
a
"compound of the invention", a "compound of the present invention" and the
like mean
compositions or methods, e.g., methods to treat a Toxoplasmosi's or a
Cryptosporidiosis infection
as disclosed herein, where one or more than one formula 1 compound is present,
typically 1, 2, 3 or
4, usually 1.
"Alcohol" as used herein, includes excipients, means an alcohol that comprises
a Cl_12
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-
butanoi, i-butanol, s-
butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexauol, n-
heptanol, n-octanoi, n-
nonanoi, n-decanol and benzyl alcohol. The carbon atoms in alcohols can be
straight, branched or
cyclic. Alcohol includes any subset of the foregoing, e.g., C2_q. alcohols
(aicohols having 2, 3 or 4
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-
12 carbon atoms)
I 5 and 0 to about 10 independently selected heteroatoms (e.g., O, :i, N, P,
Si), where the organic
moiety is bonded to a formula I steroid nucleus at R2 through f~he -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 I _20 alkyl
moieties, C2_20
alkenyl moieties, C2_20 alkynyl moieties, aryl moieties, C2_g heterocycles or
substituted
derivatives of any of these, e.g., comprising I, 2, 3, 4 or more substituents,
where each substituent
is independently chosen. Typical substitutions for hydrogen or carbon atoms in
these organic
groups include I, 2, 3, 4 or more, usually I, 2, or 3 -O-, -S-, -NRPR.
(including -NH-), -C(O)-, =O,
=S, -N(RPR)2 (including -NH2), -C(O)ORPR (including -C(O)OH), -OC(O)RPR
(including -O-
C(O)-H), -ORPR (including -OH), -SRPR (including -SH), -NO2, -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)2, -OS03H2 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 I _g alkyl,
C2_g alkenyl, C2_g alkynyi, C I _q alkyl-aryl (e.g., benzyi), aryl (e.g.
phenyl} or CO_4 alkyl-C2_9
heterocycle. Substitutions are independently chosen. The organic moiety
includes compounds
defined by the Rq 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 use:. 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)-, or one or more hydrogen atom, e.g., halogen, -NH2,
-OH or -0.
6
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
"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-I2 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 R2 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., C1_20 alkyl moieties, C2_20 alkenyl
moieties, C2_20
alkynyi moieties, aryl moieties, C2_g heterocycles or substituted derivatives
of any of these, e.g.,
comprising l, 2, 3, 4 or more substituents, where each substituent is
independently chosen.
Typical substitutions for hydrogen or carbon atoms in these organic groups
include I, 2, 3, 4 or
more, usually 1, 2, or 3 -O-, -S-, -NRPR- (including -NH-), -C(O)-, =O, =S, -
N(RPR)2 (including -
NH2), -C(O)ORPR (including -C(O)OH), -OC(O)RPR (including -O-C(O)-H), -ORPR
(including -
OH), -SRPR (including -SH), -N02, -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)2, -OS03H2 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 Cl_g alkyl, C2_g alkenyl, CZ_g
alkynyl, Cl_4
alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or CO_4 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)-, or
one or more hydrogen atom, e.g., halogen, -NH2, -OH or =O.
"Thioacetal" means a moiety that comprises a -C(O)-S- structure. Typically,
thioacetals as
used here comprise an organic moiety containing about I-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 R2 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 I,
2, 3, 4 or
more -O-C(O)NRPR- structures where RPR is -H, a pratecting group or an organic
moiety as
described for ester. Typically, carbamate groups as used here comprise an
organic moiety
containing about I-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0
to.about i0 heteraatoms
(e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1
steroid nucleus at R2
through the -O-C(O)-NRPR- structure, e.g., organic moiety-NRI'R-C(O)-O-steroid
or organic
moiety-O-C(O)-NRPR-steroid. The organic moiety is as described above for
thioesters.
7
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080 '.
"Sulfate ester" means a moiety that comprises a -O-S(O){O)-O- structure.
Typically, ,
sulfate esters as used here comprise an organic moiety containin~; 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 R2 through the -O-S(O)(O)-O-
structure, 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 I-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
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 a -NH2
group at R2 and polar moieties include -OH. Salts include pharmaceutically
acceptable salts that
I S comprise, for example, an uncharged moiety or a monovalent aniion moiety
or a monavalent cotton
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, H2S0~~ H3P04, to basic centers, typically
amines that may be
present in formula 1 compounds. Or one may use certain organic; acids, e.g.,
organic sulfanic
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_lE; alkyl
sulfonic acids such as
phenyl, a-naphthyl, (i-naphthyl, (S~-camphor, methyl, ethyl, n-propyi, 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 carboxyliic acids
such as acetic, glycolic,
lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic,
malic, malefic, hydroxymaIeic,
benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and f,-
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,
atanine, isoleucine, or
leucine. 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.
8
~~ v
CA 02352387 2001-05-25
WO 00132176 PCTIUS99/28080
Heterocycle. "Heterocycle" or "heterocyclic" includes by way of example and
not
limitation these heterocycles described in Paquette, Leo A.; "Principles of
Modem Heterocyclic
Chemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6,
7, acid 9; "The
Chemistry of Heterocyciic Compounds, A series of Monographs" (John Wiley &
Sons, New York,
1950 to present), in particular Volumes 13, I4, 16, 19, and 28; and J. Am.
Chem. Soc. 1960,
82:5566; and U.S. patents 5763483 and 5811450, all of which are incorporated
herein by reference.
Examples of heterocycles include by way of example a~ld not limitation
pyridyl, thiazolyl,
tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,
furanyi, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyi,
indolenyl, quinolinyI,
IO isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-
pyrroiidonyl, pyrrolinyl,
tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazin;yl, 2H,6H-
I,5,2dithiazinyI, thienyl,
thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyi, phenoxathiinyl,
2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyi, isoindoiyl, 3H-
indolyl, 1H-indazoIy,
15 purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxa'linyl,
quinazolinyi, cinnolinyl,
pteridinyl, 4aH-carbazolyl, carbazofyl, (3-carbolinyl, phenanthridinyl,
acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl,
isochromanyl, chromanyl,
imidazolidinyl, imidazolinyl, pyrazoiidinyi, pyrazolinyl, piperazinyI,
indolinyl, isoindolinyl,
quinuclidinyl, morphoiinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl,
oxindolyl,
20 benzoxazoIinyl, and isatinoyi.
By way of example and not limitation, carbon bonded heterocycIes are bonded at
position
2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine,
position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, ~or 5 of a
furan, tetrahydrofuran,
thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4,, or 5 of an
oxazole, imidazole or
25 thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,
position 2 or 3 of an aziridine,
position 2, 3, or 4 of an azetidine, position 2, 3, 4, S, 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, 5-
pyridazinyl, 6-pyridazinyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-
pyrazinyl, 5-pyrazinyl,
30 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 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, 1H-indazole, position 2 of a isoindole, or
isoindoline, position 4 of a
9
~.-------~--.___ _________
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
morpholine, and position 9 of a carbazole, or ~3-carboline. Typically,
nitrogen bonded heterocycles _
include 1-aziridyl, 1-azetedyl, 1-pyrroiyl, 1-imidazolyl, 1-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 oxygen
(-O-), nitrogen {-NX-) or sulfur (-S-) where X is -H, a protecting; group or C
1-6 alkyl, usually -H.
Examples are as described for heterocycle.
Protectin Qg~ rouns. Various groups that the formula 1 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 t:hiol.
Intermediates used to make
formula 1 compounds may be protected as is apparent in the art" Noncyclic and
cyclic protecting
groups and corresponding cleavage reactions are described in "frotective
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 oxidation/reduction state of the remainder of t:he molecule.
For example, the
protecting group, -X, that is bonded to a -OX or -NHX group can be removed to
form -OH or -NH-
2, 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
2S with carboxyl groups during synthesis of a formula 1 compound.. For most
therapeutic applications
amine groups should be deprotected. Protecting 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. hydrolysis, elimination or aminolysis.
Thus, simple
functional considerations will suffice to guide the selection of 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-
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
-~__._-..__._ _ _-
CA 02352387 2001-05-25
WO 00/32176 PCTIUS99/28080
Stuttgart, New York, 1994) (hereafter "Kocienski"), Section 1.1, page 2, and
Greene Chapter l,
pages 1-9; and U.S. patent 5763483 and 5811450, 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, 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 mote 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 determined by conventional. techniques, 90%
of that protecting
group has been removed by a conventional deprotection reaction, no more than
50%, preferably
1 S 2.5%, more preferably 3 0%, 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 Veriag
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, I-Iydroxyl
Protecting Groups,
pages 21-94, Chapter 3, Diot Protecting Groups, pages 95-1 I7, 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 Alkoxyaikyl Ethers (Acetats), 2.6 Reviews
(hydroxy and thiol
protecting groups), 3.2 Acetals, 3.3 Silylene Derivatives, 3.4 1,1,3,3-
Tetraisopropyldisiloxanylidene Derivatives, 3.5 Reviews (diol protecting
groups), 4.2 Esters, 4.3
2,6,7-Trioxabicyclo[2.2.2joctanes [OBO] and Other Ortho Esters, 4.4
Oxazolines, 4.5 Reviews
(carboxyl protecting groups), 5.2 O,O-Acetals, 5.3 S,S-Acatals, 5.4 O,S-
Acetals, 5.5 Reviews
(carbonyl protecting groups), 6.2 N-Acyt Derivatives, 6.3 N-Sulfonyl
Derivatives, 6.4 N-Sulfenyl
Derivatives, 6.5 N-Alkyl Derivatives, 6.6 N-Silyl Derivatives, Ei.7 Irvine
Derivatives, and 6.8
11
CA 02352387 2001-05-25
WO OOI32I76 PCTIUS99/28080
Reviews (amino protecting groups), are each incorporated with specificity
where
protection/deprotection of the requisite functionalities is discussed. Further
still, the tables "Index
to the Principai Protecting Graups" appearing on the inside front cover and
facing page,
"Abbreviations" at page xiv, and "reagents and Solvents" at page xv are each
incorporated in their
entirety herein at this location.
Typicai hydroxy protecting groups are described in Greene at pages 14-118 and
include
Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyt, Methylthiamethyl, t-
Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyi, Benzyloxymethyl, p-
Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyi, t-
Butoxymethyl, 4-
Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyf, 2,2,2-
Trichloroethoxymethyi, Bis(2-
chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-
Bromotetrahydropyranyl, Tetrahydropthiopyranyl, I-Methoxycyclohexyl, 4-
methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyt, 4-
Methoxytetrahydropthiopyranyi
S,S-Dioxido, I-[(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-
methanabenzofuran-2-yl); Substituted Ethyl Ethers (1-Ethoxyethyl, I-(2-
Chloroethoxy)ethyl, 1-
Methyl-1-methoxyethyl, 1-Methyl-I-benzyloxyethyl, 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-pic:olyl N-Oxido,
Diphenylmethyl, p,
p'-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, alpha-
Naphthyldiphenylmethyl, p-
methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyI, Trip-
methaxyphenyi)methyl,
4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4', 4"-Tris(4~,5-
dichlorophthalimidophenyl)methyl, 4,4', 4"-Tris(fevulinoyloxypheny!)methyi,
4,4', 4"-
Tris(benzoyloxyphenyl)methyl, 3-(Imidazoi-1-ylmethyl)bis(4', 4"-
dimethoxyphenyl)methyl, 1,1-
Bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyi)xanthenyl, 9-(9-
Phenyl-10-
oxo)anthryl, 1,3-Benzodithialan-2-yl, Benzisothiazolyl S,S-Diaxido); Silyl
Ethers (Trimethylsilyl,
Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl,
Diethylisopropylsily, Dimethylthexylsilyl,
t-Butyldirnethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl,
Triphenylsilyi,
Diphenyimethylsilyl, t-Butyimethoxyphenylsilyl); Esters (Formate,
Benzoylformate, Acetate,
Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,
Methoxyacetate,
Triphenylmethoxyacetate, Phenoxyacetate; p-Chlorophenoxyac:etate, p-poly-
Phenylacetate, 3-
Phenyipropionate, 4-Oxopentanoate (Levulinate), 4,4-
(Ethylenedithio)pentanoate, Pivaloate,
Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-
12
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
Trimethylbenzoate (Mesitoate); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,
2,2,2-
Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-{Phenylsulfonyl)ethyl" 2-
(Triphenylphosphonio)ethyl,
Isobutyi, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-
Dimethoxybenzyl, o-
Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate, 4-Ethoxy-1-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-
tetramethylbutylf)phenoxyacetate, 2,4-Bis(1,I-
dimethylpropyt)phenoxyacetate, Chorodiphenylacetate, lsobutyrate,
Monosuccinoate, (E)-2-
Methyl-2-butenoate (Tigloate), o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, a-
Naphthoate,
Nitrate, Alkyl N,N,N', N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate,
Borate,
Dimethylphosphinothioyl, 2,4-DinitrophenylsuIfenate); and Sulfonates (Sulfate,
Methanesulfonate
(Mesylate), Benzylsulfonate, Tosylate).
More typically hydroxy protecting groups include subtituted methyl ethers,
substituted
benzyl ethers, silyl ethers, and esters including suifonic acid esters, still
more typically, triaIkylsilyl
ethers, tosylates and acetates.
Typical 1,2- and I,3-diol protecting groups are described in Greene at pages
118-142 and
include Cyclic Acetals and Ketals (Methylene, EthyIidene, I-t-
B~utylethylidene, I-
Phenylethylidene, (4-Methoxyphenyl)ethyiidene, 2,2,2-Trichloroethylidene,
Acetonide
(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cyclohep~tylidene,
Benzylidene, p-
MethoxybenzyIidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-
Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene,
Dimethoxymethylene, I-Methoxyethylidene, I-Ethoxyethylidine, 1,2-
Dimethoxyethylidene, alpha-
Methoxybenzylidene, I-(N,N-DimethyIamino)ethylidene Derivative, alpha-{N,N-
Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); and Silyl
Derivatives (Di-t-
butylsilylene Group, I,3-{I,1,3,3-Tetraisopropyidisiloxanyiidene:) Derivative,
Tetra-t-
butoxydisiloxane-1,3-diylidene Derivative, Cyclic Carbonates, Cyclic
Boronates, Ethyl Boronate,
Phenyl Boronate).
More typically, I,2- and 1,3-dioi 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)fluoroenyImethyl, 9-
(2,7-
Dibromo)fluorenylmethyI, 2,?-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, 1-(1-Adamantyl)-1-methylethyl, 1,1-Dimethyl-2-haloethyl, I,I-
Dimethyl-2,2-
13
CA 02352387 2001-05-25
WO 00!32176 PCT/US99/28080
dibromoethyl, 1,1-Dimethyl-2,2,2-trichloroethyl, 1-Methyl-I-(~t-
biphenylyl)ethyl, I-(3,5-Di-t-
butylphenyl)-I-methylethyl, 2-(2'- and 4'-Pyridyl)ethyl, 2-(N,N-
Dicyclohexylcarboxarnido)ethyl, t-
Butyl, I-Adamantyl, Vinyl, Allyl, 1-Isopropyiallyl, Cinnamyl, 4-Nitrocinnamyl,
8-QuinolyI, N-
Hydroxypiperidinyl, Alkyldithio, Benzyl, p-Methoxybenzyl, p-:hlitrobenzyl, p-
Bromobenzyl, p-
Chorobenzyl, 2,4-Dichlorobenzyl, 4-Methylsuifinylbenzyl, 9-Anthrylmethyl,
Diphenylmethyl);
Groups With Assisted Cleavage (2-Methylthioethyi, 2-Methylsulfonylethyl, 2-(p-
Toluenesulfonyl)ethyl, [2-(1,3-DithianyI)]methyl, 4-Methylthio~phenyl, 2,4-
DimethyIthiophenyl, 2-
Phosphonioethyl, 2-Triphenylphosphonioisopropyl, I,1-Dimeth~yl-2-cyanoethyl, m-
Choro-p-
acyloxybenzyl, p-(Dihydroxyboryl)benzyl, 5-Benzisoxazolylmethyl, 2-
(Trifluoromethyl)-6-
chromonylmethyl); Groups Capable of Photolytic Cleavage (m-Nitrophenyl, 3,5-
Dimethoxybenzyl, o-Nitrobenryl, 3,4-Dimethoxy-6-nitrobenzyli, Phenyl(o-
nitrophenyl)methyl);
Urea-Type Derivatives (Phenothiazinyl-(10)-carbonyl Derivative, N'-p-
Toluenesulfonylaminocarbonyl, N'-Phenylaminothiocarbonyl); Miscellaneous
Carbamates {t-
Amyl, S-Benzyl Thiocarbamate, p-Cyanobenzyl, Cyclobutyl, C.yclohexyi,
Cyclopentyl,
CyclopropyImethyl, p-Decyloxybenzyl, Diisopropylmethyl, 2,2-
Dimethoxycarbonylvinyl, o-(N,N-
Dimethylcarboxamido)benzyl, I,I-Dimethyl-3-(N,N-dimethyic~arboxamido)propyl,
l,l-
DimethyIpropynyl, Di(2-pyridyl)methyl, Z-Furanylmethyl, 2-Io~doethyl,
Isobornyl, Isobutyl,
Isonicotinyi, p-(p'-Methoxyphenylazo)benzyl, 1-Methylcyclobutyl, I-
Methylcyclohexyl, I-Methyl-
1-cyclopropylmethyl, 1-Methyl-I-(3,5-dimethoxyphenyl)ethyl, I-Methyl-I-(p-
phenylazophenyl)ethyl, I-Methyl-1-phenylethyl, 1-Methyl-I-(4-pyridyl)ethyl,
Phenyl, p-
(Phenylazo)benzyl, 2,4,6-Tri-t-butylphenyl, 4-(Trimethylammonium}benzyl, 2,4,6-
Trimethyibenzyl); Amides (N-Formyl, N-Acetyl, N-Choroacetyi, N-Trichoroacetyl,
N-
Trifluoroacetyl, N-Phenylacetyl, N-3-Phenylpropionyl, N-Picoliinoyl, N-3-
Pyridylcarboxamide, N-
Benzoylphenyialanyl Derivative, N-Benzoyl, N-p-Phenylbenzoyl); Amides With
Assisted
Cleavage (N-o-Nitrophenyiacetyi, N-o-Nitrophenoxyacetyl, N-Acetoacetyl, (N'-
Dithiobenzyloxycarbony(amino)acetyl, N-3-(p-Hydroxyphenyi)propionyl, N-3-(o-
Nitrophenyl)propionyl, N-2-Methyl-2-(o-nitrophenoxy)propionyl, N-2-Methyl-2-(0-
phenyiazophenoxy)propionyl, N-4-ChIorobutyryl, N-3-Methyl-'.3-nitrobutyryl, N-
o-
Nitrocinnamoyl, N-Acetylmethionine Derivative, N-o-Nitrobenzoyl, N-o-
(Benzoyloxymethyl)benzoyl, 4,5-biphenyl-3-oxazolin-2-one); Cyclic Imide
Derivatives (N-
Phthalimide, N-Dithiasuccinoyl, N-2,3-Diphenylmaleoyl, N-2,5-Dimethylpyrrolyl,
N-I,I,4,4-
Tetramethyldisilylazacyclopentane Adduct, 5-Substituted I,3-Dimethyl-1,3,5-
triazacycIohexan-2-
one, 5-Substituted i,3-Dibenzyl-1,3,5-triazacyclohexan-2-one, I-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-vitro-2-oxo-3-pyriotin-3-yl), Quaternary
Ammonium Salts,
14
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
N-Benryl, N-Di(4-methoxyphenyl)methyl, N-5-Dibenzosuberyil, N-Triphenylmethyl,
N-(4-
Methoxyphenyi)diphenylmethyl, N-9-Phenylfluorenyl, N-2,7-Dichloro-9-
fluorenylmethylene, N-
Ferrocenylmethyl, N-2-Picolylamine N'-Oxide); Imine Derivatives (N-l,I-
Dimethylthiomethylene,
N-Benrylidene, N-p-methoxybenylidene, N-Diphenylmethylene, N-(2-
Pyridyi)mesityl]methylene,
N,(N',N'-Dimethylaminomethylene, N,N'-Isopropylidene, N-p-Nitrobenzylidene, N-
Salicylidene,
N-S-Chlorosalicylidene, N-(5-Chloro-2-hydroxyphenyl)phenylrnethyiene, N-
CyclohexyIidene);
Enamine Derivative (N-(5,5-Dimethyl-3-oxo-1-cyclohexenyl)); N-Metal
Derivatives (N-Borane
Derivatives, N-Diphenyiborinic Acid Derivative, N-
jPhenyl(pentacarbonylchrornium- or -
tungsten)]carbenyl, N-Copper or N-Zinc Chelate}; N-N Derivatives (N-Nitro, N-
Nitroso, N-
Oxide); N-P Derivatives {N-Diphenyiphosphinyl, N-Dimethylthiophosphinyl, N-
Diphenylthiophosphinyl, N-Dialkyl Phosphoryl, N-Dibenzyl Ph.osphoryl, 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-vitro-4-
methoxybenzenesulfenyl, N-Triphenylmethylsulfenyl, 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; Tetramethyl-4-
methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6-
Trimethylbenzenesulfonyl, N-
2,6-Dimethoxy-4-methylbenzenesulfonyi, N-2,2,5,7,8-Pentamethylchroman-6-
sulfonyl, N-
Methanesulfonyl, N-.beta: TrimethylsiIyethanesuifonyl, N-9-Anthracenesu(fonyl,
N-4-(4', 8'-
Dimethoxynaphthylmethyl)benzenesulfonyl, N-Benzylsulfonyl, N-
Trifluoromethylsulfonyl, N-
Phenacylsulfonyl).
More typically, amino protecting groups include carbamates and amides, still
more
typically, N-acetyl groups.
Stereoisomers. The formula 1 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 isolateod 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, R1,
3 0 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 approximateh~ their order of
preference, i.e.; one
ordinarily should employ stereospecific synthesis from chiral precursors
before chromatographic
resolution before spontaneous crystallization.
IS
______~.___.._____-..____- _
CA 02352387 2001-05-25
WO 00/32176 PCTIUS99/28080 . .
Stereospecific synthesis is described in the examples. Methods of this type
conveniently '
are used when the appropriate chiral starting material is availablLe 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 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 experimentation then those skilled in the art would turn to other
methods. One method of
general utility is chromatographic resolution of enantiomers on chirai
chromatography resins.
These resins are packed in columns, commonly called Pirkle 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
Pirkle Covalent D-
phenylglycine, Regis Pirkle Type lA, Astec Cyclobond II, Astec Cyclobond III,
Servo Chiral D-
DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate
column,
Astec Cyclobond I-Beta, or Regis Pirkle 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
functionaiities such as
carboxyl are not esterified or amidated.
Another 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 ~tereospecific
cleavage, so it is frequently
16
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
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 enatiomeric mixture separates from solution or a melt as a
conglomerate, i.e., a
mixture of enantiomericaliy 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.
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. WiIen (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 Satt-
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 S. i .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.
Embodiments 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, ben;ryi 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% wlw water, e.g., less than O.S% w/w
water, can comprise
about 0.0001-99% w/w of a formula 1 compound such as I 6a-bromoepiandrosterone
and one or
more excipients. These transient compositions are interinediate;s that
necessarily arise when one
17
-._____~__.___-_.__
i
CA 02352387 2001-05-25 '
WO 00/32176 PCT/US99/28080
makes an invention composition or formulation and they are included in
invention embodiments to
the extent that they are patentabie.
Formula 1 compounds. The formula 1 compounds, or tlhe "compounds of the
invention",
are useful to treat a subject having, or prevent infection of a subject with,
one or more
Toxoplasmosis or Cryptosporidium parasites. The present invention provides a
new method for
treating toxoplasinosis and/or cryptosporidiosis by administering compounds of
the present
invention, as discussed above, including compounds of formula 1 and
pharmaceutically acceptable
salts thereof.
For preferred formula 1 compounds, the R2 moiety bonded to the steroid ring is
generally
in the ~3-configuration, two Rl are bonded to Q2 and X is a double bonded
oxygen moiety (=O).
Typically, one of the Rl bonded to Q2 is hydrogen in the ~3-configuration, the
other R1 bonded to
Q2 is hydrogen or a halogen, usually bromine, in the a-configuration and a
double bond is present
at the 5-6 positions. Such preferred compounds include dehydroepiandrosterone
("DHEA") and
16a-bromodehydro-epiandrosterone ("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, Q2 is -CH2- or -
CHBr-, R2 is -H, or -
OR3 wherein R3 is -S(O)(O)-OH; -S(O)(O)-ONa, -S(O)(O)-O-t:H2-CH{O-C(O)-R6)-CH2-
O-
C{O)-R6 (where R6 independently is C 1 _ 14 straight or branched alkyl), -
P(O)(O)-0-CH2-CH(O-
C(O)R7)-CH2-O-C{O)-R7 (where R7 independently is a glucuronide group or C 1 _
14 straight or
branched alkyl) or R2 is a glucuronide group. Other preferred compounds
include compounds
having the formulas 20-43
Rt R~ X Rt Rt X
R Rt Qs Rt I~ Rt Qs
t Rt t Rt
R~ R~~ 1 Rt ~ / 'R Rt RtV 1 Rt ~ / "R
R2 \Rt'1 Rt Rt Rz
Rt R~ I ! 'R WRt Rt
t R~ Rt Rt t Rt Rt Rt
20 21
18
CA 02352387 2001-05-25
WO X0/32176 PCT/U599/28080
RtR~ X R~ R~
X
..
R~ as R R~ Q s
~
R~ Y R,~ Y
R~ R~ R~ R~
R~ R~
R' Q3 R Rf .Q3 '
1 R
R1 R~ ~ R~ R~ \ R~~R
~ -
R2 R~ R' R2 R~
R
R~ ~ I 1 Rt ~ ~
~ R~ 'Rt
R~ Rt ~ R~
I~~
_ R~ R~ R~ Rt R~ Ri
R~ R~
22 23
R'R~ X _ o
R~ Qs Rt
R~
R, R1
R~
R~ Y
Q3
R~ R' ~ R~
R2 R~ R~
R, ~ I ~ 1
Rt
R~ Rt
R1 Rt R~
R~
24 25
R
R~ R~~ X R~ Rt
Qs X
R R~ Rt Q s
,
R~ R~ R~~ R
R R
Rt ~ ~ R R' R~
Q R,
R R R (~3
~''
R
~ ~ R~ R~ R ~
~
R
R2 ~ t R~ R w
Rt
R1
R
R~ R 2 ~ ~
~ w
I R1 R~ ~ R~
R R~ R
R ~ R~ R~
R~
26 2~
19
CA 02352387 2001-05-25
WO 00/32176 PCTIUS99/28080
RZ R~ X .
R~ G~~ Rt R' .
X
_ _ Rt R~ R Q
~ s
Y R~
R~ R~ R~ Y
R~
R~ Q3 R R~ R
R t
R~ R t ~ C!s R
_
R~ R~ R~
R ~R~ ~ . ~
R R~
z ~ R ~ R R~
.
2
R~ ~ ~ 1 R~ ~ ~
R~ 1
R~
R R1 R
1 R~ R~ R~
R~
28 29
R1 R, X R' R'
R1 QsR R~ Q 6 X
~
R~ R~.
R1 R' R~ R'
R~ Y R;~ Y
R~ Q3 R~ Q3
R~ R~ ~R~ R~ R~ ~R~
Rz ~ R~ R9 R2 ~ R~ R~
'
R~ ~ ~ R~ ~ ~
R~ ~
R~
~ R~ R~
R~ R~ R~ R~
R~ R1
30 3i
R~ R~ X Rt Rt X
R~ QgR1 RZ Q
R~ R~ R1 R~
R~ R~ R~ Rt
R~ R1
R' Q R R~ C! R
3 3
R~ R~ ~R~ R1 R~ ~R~
Rz R R' Rz R R~
1 ~
R~ ~ I ~ ~~O Rt ~ ~~O
I
R~ R~ R~ R,
R~ R~
R~ R1
R~ R'
32 33
__~________._-_-
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
Ri Ri X ..
. R1 Qs R1 _
R1 Y
R1 R1 R1
. R1 Q R R
3
R1 ~1 ~Ri
R2 R1 \Ri
Ri ~ I ~ w0
R1
. R1 R1 R1 R1 ,
34 35
R1 R1 X _
R1 Qs R1
R1
R R1 R1 R1 Y
1 Q
3
R1 R1 ~ R1 R
R2 Ri R1 R
R1 O
/ \ R1
R1 R1 R~ R1
s 3s 3~
_ o
R R
Ri R Rt
1
R2
R
K~ R1 R1
38 39
21
CA 02352387 2001-05-25
WO 00/32176 PCT/I3S99128080
Rt Rt X . .
- , Rt as Rt
R~
R Rt R~ Rt Y
Qs ~R
Rt Rt ~Rt
R2 ~ Rt Rt
Rt ~ ~ ~ O
Rt Rt Rt Rt Rt Ht
40 41
R
Rt Rt t Qs X Rt
Rt
Rt R,
Rt
Rx ~ Rt t Rt Rt
R, ~~n
Rt Rt Rt
42 43
wherein for each of structures 20-43
Q3 and Q6 are each -C(Rl)3 wherein each Rl is independently selected;
X and Y independently are -OH, -H, lower alkyl (e.g., (:1-6 alkyl), -C(O)-O-
R5, -O-C(O)-
R5, halogen or, X and Y together with the Rl at the same position
independently are a ketone
(=O);
each R1 is independently selected and has the definition given above; and
R2 and RS have the definitions given above.
In some embodiments, the formula 1 compound has the structure 20-43 and 2, 3,
4, 5 or 6
Rl groups independently are -OH, halogen or alkoxy, and the remaining R1 are
all hydrogen; R2 is
-OH, an ester a thioester or a carbamate, or R2, together with the R1 at the 3-
position comprises
=O; Y is -H, -OH, a halogen or -O-C(O)-R5, or Y, together with the R1 at the
16-position
comprises =O; X is -OH or -O-C(O)-R5, or X, together with the; R1 at the 17-
position comprises
=O; and Q3 and Q6 independently are -CH3 or -CH20H. Such embodiments include
structure 20-
43 compounds where two -OH are present at the 3-position, the 16-position or
at the 17-position.
22
_~~ _--__. _-
- CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
Preferred invention-embodiments include compounds having the formula 44
Y
- 44
wherein Y is hydrogen or bromine, R44 is -H, -S(O)(O)-OH, -S(O)(O)-ONa, -
S(O)(O~O-CH2-
CH(O-C(O)-R6)-CH2-O-C(O)-R6, -P(O)(O)-O-CH2-CH(O-C((7)-R7)-CH2-O-C(O)-R7 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 R44 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-
brornoepiandrosterone. Other
preferred compounds are (i) 16a-bromodehydroepiandrosterone;, (ii)
dehydroepiandrosterone-3-
sulfate (Y is -H and R44 is -S(O)(O)-OM in formula 44 are both hydrogen and
the double bond at
the 5-6 position is present) and (iii) 5(3-androstan-3(3-oI-17-one. Related
embodiments comprise
compounds related to formula 44 compounds comprise the forn;mla 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, -CI, -F, -I, -OCH3 or -OC2H$ atoms or groups.
In other embodiments, the I7-ketosteroids of formula 1 are
dehydroepiandrosterone where
R44 in formula 44 is a -S(O)(O)-O-CH2-CH(O-C(O)-R6)-CH2-~O-C(O)-R5, -P(O)(O)-O-
CH2-
CH(O-C(O)-R7)-CH2-O-C(O)-R7 or a glucuronide group of structure (A), Y is
hydrogen and the
5-6 double bond is present. Other formula 44 compounds include conjugates of
dehydroepiandrosterone wherein Y is hydrogen, a double bond is present at the
5-6 position and
R44 is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoyl
sulfate, O-
dihexadecylglycerol sulfate, hexadecane sulfonate, dioctadecanoylglycerol
phosphate or O-
hexadecylglycerot phosphate.
23
, r . ' CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
In another preferred aspect of the invention, the steroid of formula 1 is a
compound of
forrrtula 45
Q__
1~5t
R49 n50 4.5
wherein R$p is -H, -OH or =O; RS 1 is -Br, -Cl, -F or -I; R52 is -~DH or =O;
R49 is -H, -OH, or -
OR53; and R53 is C 1 _ 1 g alkyl, C2_ 1 g alkenyl, CZ_ I g alkynyl, a C 1 _ I
8 ester, a C ~ _ 1 g thioester,
wherein any of the foregoing C 1 _ 1 g or C2_ 1 g groups is substitutc;d at
one or more hydrogen atoms
with one or more independently selected -O-, -S-, -OH, -NH2 or -SH groups or
R53 is a thioacetal,
a sulfate ester, a sulfonate ester, a carbamate or a thioester. In one
preferred aspect, R49 is-O-
C(O)-CH2-CH2-CH(Rg4)-CH(Rgs)-CH2R56 wherein R54 is -NH2, -OH, -SH, -O-P03, -
S03 or -
OS03; R55 is -H, -NH2, -OH, -SH, -O-P03, -S03 or -OS03; and Rsg is C I _ I g
alkyl, C2_ I 8
alkenyl, C2_ 1 g alkynyl, a C I _ I g ester, a C 1 _ 1 g thioester, wherein
any of the foregoing C 1 _ 1 g or
C2_1 g 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 44 compounds
comprise the formula
45 compounds wherein I, 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 IB or
1C
Y v
Z1
1B Or 1C
wherein each R1 independently is -H, -OH, a halogen, -CHCH2, -CHCHCH~, -CCH, -
CCCH3, or,
or, the other moiety that is bonded to the same carbon atom is absent and RI
is =O; R2 is -H, -OH,
a halogen, Cl_g alkoxy, -S-C(O)-(CH2}m-R4, -C(O)-S-(CH2)m-R4, -O-S(O)(O)-
{CH2)m-R4. -O-
S{O){O)-O-{CH2}m-R4~ -O-C(O)-NH-{CH2)m-R4~ -NH-C(O)-O~_(CH2)m-R4~ -O-C(S)-
{CH2}m-
R4, -C(S)-O-(CH2)m-R4~ -O-C(O)-(CH2}m-R4 or -C(O)-O-(CH2)m-R4~ R4 is -H~ -CH3~
-C2H5
-C3H~, -C2H40H, -C3HgOH, -CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH3, -CH2-CH2-O-CH2-
CH2~H, a C3_6 alkenyl group, a C3_6 alkyny! group, benzyl or phenyl, wherein
the phenyl or
benzyl groups are optionally substituted with 1, 2, or 3 independently
selected halogen, CI-4
24
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
aikoxy, -OH, -SH, -O- or -NH- moieties; and Q3 and Q6 independently are -H, -
CH3 or -CH20H;
and Q2 is -C(R1)2- or -CH2-CH2-. In these embodiments, Q3 atnd Q6 are usually
both in the (3-
configuration, typically they are -CH3, Q2 usually comprises -C:H2-, -C(O)-, -
CH(Br)-, -CH(I)-, or
-CH(OH)- with the Br, I or OH moieties in the a-configuration, or Q2 comprises
=O, and RI at the
7-position is -H, -OH or =O. Related embodiments comprise compounds related to
formula 44
compounds comprise the formula IA or IB compounds wherein. 1, 2, 3, 4, 5 or b
hydrogen atoms
that are bonded to the steroid nucleus are substituted with independently
selected -OH, -Br, -CI, -F,
-I, -OCH3 or -OC2H5 atoms or groups.
The formula 1 compounds can exist in a crystalline or polymorphic form.
Metabolites. Also 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 c'~emical
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 radiotabelled (e.g. C14 or H3) formula
1 compound,
administering it parenteraily or orally in a detectable dose (e.g. I;reater
than about 0.5 mg/kg) to an
animal such as rat, mouse, guinea pig, primate, or to a human, alflowing
sufficient 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 t:he formula 1 compounds.
Group 1. Exemplary embodiments include the formula 1 compounds named in table
B
based on the compound structure designations defined in table A,. Each
compound named in Table
B is depicted as a compound of formula 4
i;,
- CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080 . .
_ R2
4
where Q3 and Q6 are both -CH3, Q4 is -CH2- and R2, R1A, and Y and X have the
structures
designated in Table A. The compounds named according to Tables A and B are
referred to as
"group 1" compounds.
Compounds named in Table B are designated by numbers assigned to R2, R1A, Y
and X
according to the following compound naming convention, R2.R1A.Y.X, using the
numbered
chemical structures depicted in Table A. As shown in formula ~G, R2 is in the
3 (3-position and
hydrogen fills the remaining valence or R2 is double bonded to the 3 carbon,
R1A is an Rl group
at the 7(3-position or R1A is an Rl group double bonded to the i' carbon, Y is
in the 16a-position
and hydrogen fills the remaining valence or R2 is double bonded to the 16
carbon and X is in the
l7Gi-position and hydrogen fills the remaining valence or X is double bonded
to the 17 carbon.
When R2, R1 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 ~'i-
hydroxyl bonded to carbons at the 3- and 7-positions (the variable groups R2
and R1A
respectively), an a-bromine bonded to carbon 16 (the variable group Y) and
double bonded oxygen
(=O) at carbon 17 (the variable group X), i.e., having the structure shown
below.
1.2.1.1
TABLE A
R2 R1A
1 -OH 1 -H
2 ~ 2 -OH
3 -O-P(O)(O)-OH 3 =O
26
i
a - CA 02352387 2001-05-25
WO 00132176 PCTIUS99/28080
4 -O-P(O)(O)-O-CH2-CH(O-C(O)-CH3)-CH2-O-C(O)CH3 4 -CH3 '
-O-S(O)(O~OH 5 -OCH3
6 -O-S(O)(O)-O-Na+ 6 -OC2H5
7 -O-S(O)(O)-OC2H5 7 -OCH2CH2CH3
5 8 -O-S(O)(O)-O-CH2-CH(O-C(O)-CH3)-CH2-O-C(O)CH3 8 -OCH(CH3)CH3
9 -O-S(O)(O)-OCH2CH2CH2CH3 9 -OCH2CH2CH2CH3
- 10 -O-S(O)(O)-OC(CH3)3 10 -OC(CH3)3
Y X
1 -Br 1 =O
2 -CI 2 -OH
3 -I 3 -H
4 -F 4 -F
5 -H 5 -C1
6 -OH 6 -Br
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-C!O)-CH2CH2CH3 10 -O-C(O)-CH~CH2CH3
TABLE 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, 1.1.2.7, 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,
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,
2 5 1.1.4.7, 1.1.4.8, 1.1.4.9, 1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 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.I.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5, 1.1.6.6,
1.1.6.7, 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, 1.1.7.8,
1.1.7.9, 1.1.7.1 0, 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, 1.1.8.10,
1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4,
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.i.10.1,1.1.',CO.2,1.1.10.3,1
.1.10.4,1.1.10.5,
1.1.10.6,1.1.10.7,1.1.t0.8,1.1.I0.9,1.1.10.10,1.2.1.1,1.2.1.2,1.2.1.3,1.2.1.4,1
.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,
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,
1.2.3.7, 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,
3 5 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, 1.2.7.5, 1.2.7.6,
27
CA 02352387 2001-05-25
WO PCT/US99/28080
00132176
1.2.7.7,1.2.7.8,1.2.7.9,1.2.'7.i0,1.2.8.1,1.2.8.2,1.2.8.3,1.2.8:4,1.2.8.5,1.2.8
.6,1.2.8.7,1.2.8.8,
1.2.8.9,1.2.8.10, , 1.2.9.2, 1.2.9.3,
1.2.9.4,1.2.9.7,1.2.9.8,1.2.9.9,1.2.9.10,
1.2.9.1 1.2.9.5, 1.2.9.6,
1.2.10.1,1.2.10.2,1.2.I0.3,t.2.10.4,1.2.10.5,1.2.I0.6,1.2.10.T,
I.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,.3.1.9,.3.1.10,1.3.2.1,1.3.2.2,
1.3.1.7, 1.3.1.8,, 1 1
1.3.2.3,1.3.2.4,1.3.2.5,1.3.2.6, 1.3.2.7,
1.3.2.8,1.3.3.1,1.3.3.2,1.3.3.3,1.3.3.4,
1.3.2.9, I.3.2.1~0,
1.3.3.5,1.3.3.6,1.3.3.7,1.3.3.8, 1.3.3.9,
1.3.3.11.3.4.3,1.3.4.4,1.3.4.5,1.3.4.6,
0, 1.3.4.1, 1.3.4.2,
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, , 1.3.6.2, 1.3.6.3,
1.3.6.4,1.3.6.7,1.3.6.8,1.3.6.9,1.3.6.10,
1.3.6.1 1.3.6.5, 1.3.6.6,
1.3.7.1,1.3.7.2,1.3.7.3,1.3.7.4, 1.3.7.5, 1.3.7.6,
.3.7.10,1.3.8.1,1.3.8.2,
1.3.7.7, 1.3.7.8, 1.3.7.9,
1
101.3.8.3,1.3.8.4,1:3.8.5,1.3.8.6, 1.3.8.7,
1.3.8.8,1.3.9.1,1.3.9.2,1.3.9.3,1.3.9.4,
1.3.8.9, 1.3.8.10,
1.3.9.5,1.3.9.6,1.3.9.7,1.3.9.8,I.3.9.9,1.3.9.10,1.3.10.1,1.3.1Ø2,1.3.10.3,1.
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.I.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,
1.4.2.2,1.4.2.5,1.4.2.6,1.4.2.7,1.4.2.8,
1.4.2.3, 1.4.2.4,
1.4.2.9,1.4.2.10,I.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,
151.4.4.1,1.4.4.2,1.4.4.3,1.4.4.4, 1.4.4.5, 1.4.4.6,
.4.4.10,1.4.5.1,1.4.5.2,
1.4.4.7, 1.4.4.8, 1.4.4.9,
1
1.4.5.3,1.4.5.4,1.4.5.5,1.4.5.6, 1.4.5.7,
1.4.5.8,1.4.6.1,1.4.6.2,1.4.6.3,1.4.6.4,
1.4.5.9, 1.4.S.I0,
1.4.6.5,1.4.6.6,1.4.6.7,1.4.6.8, 1.4.6.9,
1.4.6.10,1.4.7.3,1.4.7.4,1.4.7.5,1.4.7.6,
1.4.7.1, 1.4.7.2,
1.4.7.7,1.4.7.8,1.4.7.9,1.4.7.10,I.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,I.4.8.8,
1.4.8.9,1.4.8.10, , 1.4.9.2, 1.4.9.3,
1.4.9.4,1.4.9.7,1.4.9.8,1.4.9.9,1.4.9.1
1.4.9.1 1.4.9.5, 1.4.9.6, 0,
201.4.10.1,1.4.10.2,1.4.10.3,1.4.10.4,1.4.10.5,1.4.10.6,1.4.10.~',
1.4.10.8,1.4.10.9,i.4.10 .10,
1.5.1.1,I.S.I.2,1.5.1.3,1.5.1.4, 1.5.1.5, 1.5.1.6,
.5.1.10,1.5.2.1,1.5.2.2,
1.5.1.7, 1.5.1.8, 1.5.1.9,
1
1.5.2.3,1.5.2.4,1.5.2.S,I.5.2.6,1.5.2.7,1.5.2.8,1.5.2.9,1.5.2.1O,I.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,
1.5.3.11.5.4.3,1.5.4.4,1.5.4.5,1.5.4.6,
0, 1.5.4.1, 1.5.4.2,
1.5.4.7,1.5.4.8,1.5.4.9,1.5.4.10, 1.5.5.1,
1.5.5.2,1.5.5.5,1.5.5.6,1.5.5.7,1.5.5.8,
1.5.5.3, 1.5.5.4,
251.5.5.9,1.5.5.10,1.5.6.1
,1.5.6.2,1.5.6.3,1.5.6.4,1.5.6.5,t.5.6.6,1.5.6.7,1.5.6.8,1.5.6.9,1.5.6.10,
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, 2.5.7.8,
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, I.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,
1.5.9.5,1.5.9.6,1.5.9.7,1.5.9.8,1.5.9.9,1.5.9.10,1.5.10.1,1.5.1Ø2,1.5.10.3,I.
S.i0.4,1.5.10.5,
1.S.I0.6,1.5.10.7,1.5.10.8,1.5.10.9,i.S.10.10,1.6.1.1,1.6.1.2,1.6.1.3,1.6.1.4,1
.6.1.5,1.6.1.6,
3 0 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,
1.6.2.9, 1.6.2.10, I.6.3.I, 1.6.3.2, 1.6.3.3, 1.6.3.4, 1.6.3.5, 1.6.3.6,
1.6.3.7, 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, 1.6.5.1 0,
1.6.6.1, 1.6.6.2, 1.6.6.3, 1.6.6.4,
1.6.6.5, 1.6.6.6, 1.6.6.7, 1.6.6.8, 1.6.6.9, 1.6.6.10, 1.6.7.1, I.6.7.2,
1.6.7.3, 1.6.7.4, 1.6.7.5, 1.6.7.6,
3 S 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,
28
CA 02352387 2001-05-25
WO PCTIUS99I28080
00/32176
1.6.8.9,1.6.8.1, , 1.6.9.2, 1.6.9.3, 1.6.9.4, 1.6.9.5,1.6.9.9,1.6.9.1 0,
0 1.6.9.11.6.9.6, 1.6.9.7, 1.6.9.8,
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.i',I.6.I0.8,1.6.10
.9,1.6.10 .10,
1.7.1.1,1.7.i.2,1.7.1.3,1.7.1.4,1.7.i.5,1.7.1.6,I.7.1.7,1.7.1.8;,1.7.L9,1.7.1.1
0,1:7.2.I,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, 1.7.2.9,1.7.3.3,1.7.3.4,
I.7.2.1~D, 1.7.3.1, 1.7.3.2,
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.
4,1.7.4.5,1.7.4.6,
1.7.4.7,1.7.4.8,1.7.4.9,1.7.4.10,1.7.5.1,I.7.5.2,i.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,I.7.6.1,1.7.6.2,1.7.6.3,I.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, 1.7.7.7,1.7.8.1,1.7.8.2,
1.7.7.8, 1.7.7.9, 1.7.7.10,
1.7.8.3,1.7.8.4,1.7.8.5,1.7.8.6, 1.7.8.7, 1.7.8.8, 1.7.8.9,1.7.9.3,1.7.9.4,
1.7.8.10, 1.?.9.1, 1.7.9.2,
101.7.9.5,I.7.9.6,1.7.9.7,1.7.9.8,1.7.9.9,1.7.9.10,1.7.10.I,1.7.i0.2,1.7.10.3,1
.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.
8.1.6,
1.8.1.7,1.8.1.8,1.8.1.9,1.8.1.10, 1.8.2.1, 1.8.2.2, 1.8.2.3,1.8.2.7,1.8.2.8,
1.8.2.4, 1.8.2.5, 1.8.2.6,
1.8.2.9,1.8.2.10, , 1.8.3.2, 1.8.3.3, 1.8.3.4, 1.8.3.5,1.8.3.9,1.8.3.10,
1.8.3.1 1.8.3.6, 1.8.3.7, 1.8.3.8,
1.8.4.1,1.8.4.2,1.8.4.3,1.8.4.4, 1.8.4.5, 1.8.4.6, 1.8.4.7,1.8.5.1,1.8.5.2,
1.8.4.8, 1.8.4.9, 1.8.4.1 0,
I51.8.5.3,1.8.5.4,1.8.5.5,1.8.5.6, 1.8.5.7, 1.8.5.8, 1.8.5.9,1.8.6.3,1.8.6.4,
1.8.5.10, 1.8.6.1, 1.8.6.2,
1.8.6.5,1.8.6.6;1.8.6.7,1.8.6.8, 1.8.6.9, 1.8.6.10, 1.8.7.1,1.8.7.5,1.8.7.6,
1.8.7.2, 1.8.7.3, 1.8.7.4,
1.8.7.7,1.8.7.8,1.8.7.9,1.8.7.10, 1.8.8.1, 1.8.8.2, 1.8.8.3,1.8.8.7,1.8.8.8,
1.8.8.4, 1.8.8.5, 1.8.8.6,
L8.8.9,1.8.8.10,1.8.9.1
,1.8.9.2,1.8.9.3,1.8.9.4,1.8.9.5,1.8.9.6,1.8.9.7,1.8.9.8,1.8.9.9,1.8.9.10,
I.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,
201.9.1.1,1.9.1.2,1.9.1.3,1.9.1.4, 1.9.1.5, 1.9.1.6, 1.9.1.7,1.9.2.1,1.9.2.2,
1.9.1.8, 1.9.1.9, 1.9.I.I0,
1.9.2.3,1.9.2.4,1.9.2.5,1.9.2.6, 1.9.2.7, 1.9.2.8, 1.9.2.9,1.9.3.3,1.9.3.4,
1.9.2.10, 1.9.3.1, 1.9.3.2,
1.9.3.5,1.9.3.6,1.9.3.7,1.9.3.8, 1.9.3.9, 1.9.3.10, 1.9.4.1,1.9.4.5,1.9.4.6,
1.9.4.2, 1.9.4.3, 1.9.4.4,
1.9.4.7,1.9.4.8,1.9.4.9,1.9.4.10, 1.9.5.1, 1.9.5.2, 1.9.5.3,1.9.5.7,1.9.5.8,
1.9.5.4, 1.9.5.5, 1.9.5.6,
1.9.5.9,1.9.5.10, , 1.9.6.2, 1.9.6.3, 1.9.6.4, 1.9.6.5,1.9.6.9,1.9.6.10,
1.9.6.1 1.9.6.6, 1.9.6.7, 1.9.6.8,
251.9.7.1,1.9.7.2,1.9.7.3,1.9.7.4,1.9.7.5,1.9.7.6,1.9.7.7,1.9.7.8,1.9.7.9,1.9.7
.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, 1.9.8.9,1.9.9.3,1.9.9.4,
1.9.8.10, 1.9.9.1, 1.9.9.2,
1.9.9.5,1.9.9.6,1.9.9.7,1.9.9.8,1.9.9.9,1.9.9.10,1.9.10.1,1.9.1,0.2,1.9.10.3,1.
9.10.4,1.9.10.5,
1.9.10.6,1.9.10.
7,1.9.10.8,1.9.I0.9,1.9.10.10,1.10.1.1,1.10.1.2,1.10.1.3,1.10.1
.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,
30
1.10.2.6,1.10.2.7,I.10.2.8,1.10.2.9,1.10.2.10,1.10.3.1,1.10.3.2,1.10.3.3,1.10.3
.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.I0.4.2,1.10.4.3,1.10.4
.4,1.10.4.5,
1.10.4.6,1.10.4.7,I.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.I0.6.1,1.10.6.2,1.10.6.3,1.10.6
.4,1.10.6.5,
I.I0.6.6,1.10.6.7,1.10.6.8,1.10.6.9,I.10.6.10,1.10.7.1,1.10.7.2,1.10.7.3,1.10.7
.4,1.10.7.5,
35
1.10.7.6,1.10.7.7,1.10.7.8,1.10.7.9,1.10.7.10,1.10.8.1;1.10.8.2,1.10.8.3,1.10.8
.4,1.10.8.5,
29
~.~_________-__~
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
1.10.8.6,1.10.8.7,1.10.8.8;1.10.8.9,I.10.8.10,1.10.9.1,1.10.9.2,1.10.9.3,1.10.9
.4,1.10.9.5,
1.10.9.6,1.10.9.7,1.10.9.8,1.10.9.9,1.10.9.10,i.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, 2.1.1.3, 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. L3.8,
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, 2.1.8.6,
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,
2.1.9.9,2.1.9.10,2.1.10.1,2.1.10.2,2.1.10.3,2.1.10.4,2.1.10.5,2.1.10.6,2.1.10.7
,2.1.10.8,
2.1.10.9,2.1.I0.10,2.2.1.1,2.2.1.2,2.2.I.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,
2.2.1.10,2.2.2.1,2.2.2.2,2.2.2.3,22.2.4,2.2.2.5,2.2.2.6,2.2.2.7,2.2.2.8,2.2.2.9
,2.2.2.10,2.2.3.1,
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,
2.3.8.1, 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.I0:1,2.3.i0.2,2.3.I0.3,2.3.10.4,2.3.10.5,2
.3.10.6,2.3.10.7,
2.3.10.8,2.3.10.9,2.3.10.10,2.4.1.1,2.4.1.2,2.4.1.3,2.4.1.4,2:4.1.5,2.4.1.6,2.4
.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,
2.4.7.9,2.4.7.10,2.4.8.1,2.4.8.2,2.4.8.3,2.4.8.4,2.4.8.5,2.4.8.6,2.4.8.7,2.4.8.
8,2.4.8.9,2.4.8.10,
CA 02352387 2001-05-25
WO 00/32176 PCTIUS99/28080
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,
2.4.9.9, 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, 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.S.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.:10,2.5.6.1,2.5.6.2,2.5.6.3,2.5.6.4,2.5.6.5,2.5.6.6,2.5.6.7,2.5.6.8,2.5.6
.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,
2.5.9.6,2.5.9.7,2.5.9.8,2.5.9.9,2.5.9.10,2.5.10.1,2.5.10.2,2.5.10.3,2.5.10.4,2.
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. i
.4, 2.6.1.5, 2.6.1.6, 2.6.1.7,
2.6.1.8, 2.6.1.9, 2.6.1.1 0, 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.?,
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, 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, 2.7.1.2, 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, 2.7.2.10"
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, 2.7.3.9, 2.7.3.1 0, 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.?.10.6, 2.7.10.7, 2.7.10.8, 2.7.14.9, 2.7.10.10, 2.8.1.1, 2.8.1.2, x:.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.$.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, 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,
3 5 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,
31
CA 02352387 2001-05-25
WO 00132176 PCT/US99/28080
2.8.10.1,2.8.10.2,2.8.10.3;2.8.10.4,2.8.i0.5,2.8.10.6,2.8.10.7,2.8.10.8,2.8.10.
9,2.8.10.10,
2.9.1.1, 2.9.1.2, 2.9.1.3, 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, 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,
2.9.8.3, 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.i0.1.7,2.10.1.8,2.10.1.9,2.10.1.10,2.10.2.1,2.10.2.2,2.10.2.3,2.10.2
.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.x,
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.:',2.10.4.3,2.10.
4.4,2.10.'4.5,
2.10.4.6,2.10.4.7,2.10.4.8,2.10.4.9,2.10.4.10,2.10.5.1,2.10.5.x,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.'.?,
2.10.8.3, 2.10.8.4, 2.10.8.5,
2.10.8.6,2.10.8.7,2.10.8.8,2.10.8.9,2.10.8.10,2.20.9.1,2.10.9.:?,2.10.9.3,2.10.
9.4,2.10.9.5,
2.10.9.6, 2.10.9.7, 2.10.9.8, 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, 3.1.2.10, 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, 3.1.5.6, 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, 3.1.7.10, 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.I0,3.2.2.1,3.2.2.2,3.2.2.3,3.2.2.4,3.2.2.5,3.2.2.6,3.2.2.7,3.2.2.8,3.2.2.
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, 3.2.7.2, 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.i0,3.2.8.1,3.2.8.2,3.2.8.3,3.2.8.4,3.2.8.5,3.2.8.6;3.2.8.7,3.2.8.8,3.2.8.
9,3.2.8.10,3.2.9.1,
32
CA 02352387 2001-05-25
WO 00132176 PCT/US99/28080
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.I0.7,3.2.10.8,3.2.10.9"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, 3.3.1.?, 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,
3.3.2.5,3.3.2.6,3.3.2.7,3.3.2.8,3.3.2.9,3.3.2.10,3.3.3.1,3.3.3.2,,3.3.3.3,3.3.3
.4,3:3.3.5,3.3.3.6,
S
3.3.3.7,3.3.3.8,3.3.3.9,3.3.3.10,3.3.4.I,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, 3.3.6.3, 3.3.6.4, 3.3.6.5, 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.I0.1,3.3.10.2,3.3.10.3,3.3.10.4,3.3.10.5,3
.3.10.6,3.3.10.7,
3.3.10.8,3.3.10.9,3.3.I0.10,3.4.1.1,3.4.1.2,3.4.1.3,3.4.I.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.f»,3:4.2.7,3.4.2
.8,3.4.2.9,3.4.2.10,
3.4.3.1,3.4.3.2,3.4.3.3,3.4.3.4,3.4.3.5,3.4.3.6,3.4.3.7,3.4.3.8,3.4.3.9,3.4.3.1
0,3.4.4.1,3.4.4.2,
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, 3.5.L6, 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, 3.5.8.10, 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.?,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.I0.7,3.5.10.8,3.5.10.9,3.5.10.I0,3.6.1.1,3.6.1.2,3.6.1.3,3..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,
3.6.2.10,3.6.3.1,3.6.3.2,3.6.3.3,3.6.3.4,3.6.3.5,3.6.3.6,3.6.3.T,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.I0, 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,
3.6.6.6, 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, 3.6.7.10, 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.T,
3.6.9.8, 3.6.9.9, 3.6.9.10,
33
CA 02352387 2001-05-25
WO 00132176 PCT/(JS99/28080
3.6.10.I,3.6.10.2,3.6.I0.3,3.6.10.4,3.6.10.5,3.6.10.6,3.6.10.7,3.6.10.8,3.6.10.
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, 3.7.6.5, 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.?.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,
3.7.9.5,3.7.9.6,3.7.9.7,3.7.9.8,3.7.9.9,3.7.9,10,3.7.10.1,3.7.I0.2,3.7.10.3,3.7
.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, 3.8.1.9, 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.I0.3, 3.8.10.4, 3.8.10.5, 3.8.10.6, 3.8.10. 7,
3.5.10.8, 3.8.10.9, 3.8.10.10,
3.9.1.1,3.9.I.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,
2 0 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.I~D,
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.I,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, 3.9.5.2, 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, 3.9.6.5,
3.9.6.7, 3.9.6.8, 3.9.6.9, 3.9.6.10,
3.9.7.I, 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, 3.1 O.I ..2,
3.10.1.3, 3.10. I .4, 3.10.1.5,
3.10. I .6, 3.10.1.7, 3.10.1.8, 3.10. I .9, 3. I 0.1. I 0, 3.10.2. I ,
3.10.2..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,
3.10.5.6,3.10.5.7,3.10.5.8,3.10.5.9,3.10.5.10,3.10.6.1,3.10.6..2,3.10.6.3,3.10.
6.4,3.10.6.5,
3.10.6.6,3.10.6.7,3.10.6.8,3.10.6.9,3.10.6.10,3.10.7.1,3.10.72,3.10.7.3,3.10.7.
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,
34
CA 02352387 2001-05-25
WO 00132176 PCTIUS99I28080 . .
3.10.9.6,3.10.9.7,3.10.9:8;3.10.9:9,3.10.9.10,3.10.10.1,3.10.10.2,3.10.10.3,3.1
0.10.4, ,
3.10.10.5,3.10.10.6,3.10.10.7,3.10.10.8,3.10.10.9,3.10.10.1(1,4.1.1.1,4.1.1.2,4
.1.1.3,4.1.1.4,
4.1.1.5,4.1.1.6,4.1.1.7,4.1.1.8,4.1.1.9,4.1.1.10,4.1.2.1,4.1.2.2,4.1.2.3,4.I.2.
4,4.1.2.5,4.L2.6,
4.1.2.7, 4.1.2.8, 4.1.2.9, 4.1.2.1 0, 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, 4.1.6.1.0,
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,
4.1.9.9,4.1.9.10,4.1.10.1,4.1.10.2,4.1.10.3,4.1.10.4,4.1.10.5,4.1.10.6,4.1.10.7
,4.1.10.8,
4.1.10.9,4.1.10.10,4.2.1.1,4.2.1.2,4.2.1.3,4.2.1.4,4.2.1.5,4.2.1.6,4.2.1.7,4.2.
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, 4.2.8.7,
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, 4.2.9.5,
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,
4.3.6.1,4.3.6.2,4.3.6.3,4.3.6.4,4.3.6.5,4.3.6.6,4.3.6.7,4.3.6.E.,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, 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.i.4,4..4.1.5,4.4.1.6,4.
4.1.7,4.4.1.8,
4.4.1.9, 4.4.1.1 0, 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, 4.4.2.1 0,
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, 4.4.86,
4.4.8.7, 4.4.$.8, 4.4.8.9, 4.4.8.10,
4.4.9.I,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,
CA 02352387 2001-05-25
WO 00132176 PCTIUS99I28080
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,
4.5.1.1 0, 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, 4.5.3.10, 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,
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,
4.6.8.1 0, 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, 4.6.9.1 0,
4.6.10.1,4.6.10.2,4.6.I0.3,4.6.10.4,4.6.10.5,4.6.10.6,4.6.10.7,4.6.10.8,4.6.10.
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, 4.7.1 ().2,
4.7.10.3, 4.7.10.4, 4.7.10.5,
4.7.14.6,4.7.10.7,4.7.10.8,4.7.10.9,4.7.10.10,4.8.1.1,4.8.1.2,4.8.1.3,4.8.1.4,4
.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,
3 0 4.8.4.1, 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.I0.4,4.8.10.5,4.8.10.6,4.8.10.7,4.8.10.8,4.8.10.
9,4.8.10.10,
36
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
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,
4.9.3.5,4.9.3.6,4.9.3.7,4.9.3.8,4.9.3.9,4.9.3.10,4.9.4.1,4.9.4.2,4.9.4.3,4.9.4.
4,4.~J:4.S,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.IU,
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.I0,4.9.10.1,4.9.10.2,4.9.10.3,4.9
.10.4,4.9.10.5,
4.9.10.6,4.9.10.7,4.9.10.8,4.9.10.9,4.9.10.10,4.10.1.1,4.10.1.2,4.10.1.3,4.10.I
.4,4.10.I.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.I0.2.9,4.10.2.10,4.I0.3.1,4.10.3.2,4.10.3.3,4.10.3
.4,4.10.3.5,
4.10.3.6,4.10.3.7,4.10.3.8,4.10.3.9,4.10.3.10,4.10.4.1,4.10.4.2,4.10.4.3,4.10.4
.4,4.10.4.5,
4.10.4.6,4.10.4.7,4.10.4.8,4.10.4.9,4.10.4.10,4.10.5.1,4.10.5.2,4.10.5.3,4.10.5
.4,4.10.5.5,
4.10.5.6,4.10.5.7,4.10.5.8,4.10.5.9,4.10.5.10,4.10.6.1,4.10.6.2,4.10.6.3,4.10.6
.4,4.10.6.5,
4..10.6.6, 4.10.6.7, 4.10.6.8, 4.10.6.9, 4.10.6.10, 4.10.7.1, 4.10.7.2,
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. I , 4.10.8.2, 4. 3
0.8.3, 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.I,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.I0,4.10.10.1,4.10.1Ø2,4.10.10.3,4.
10.10.4,
4.10.10.5, 4.10.10.6, 4.10.10.7, 4.10.10.8, 4.10.10.9, 4.10.10.10, 5.1.1.1,
5.1.1.2, 5.1.1.3, 5.1.1.4,
5.1.1.5, 5.1.1.6, S.1.I.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, 5.1.2.6,
5.1.2.7, 5.1.2.8, 5.1.2.9, 5.1.2.10, S.I.3.I, 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.I.4.5,5.1.4.fi,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, S.I.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,S.I.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, S.I.9.1, 5.1.9.2, 5.1.9.3, 5.1.9.4E,
S.i.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.I,5.1.10.2,5.1.10.3,5.1.10.4,5.I.10.5,5.1.10.6,5.1.10.7
,5.1.10.8,
5.1.10.9,5.1.10.I0,5.2.1.1,5.2.1.2,5.2.1.3,5.2.1.4,5.2.1.5,5.2.1.6,5.2.1.7,5.2.
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, 5.2.2.10, 5.2.3.1,
3 0 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.?, 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, 5.2.9.1,
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,
37
CA 02352387 2001-05-25
WO 00132176 PCTNS99/28080
5.2.10.3, 5.2.10.4, 5.2.10.5, 5.2.10.6, S.2.I0.7, 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, S 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 ~l,
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.S.ti,
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, 5.3.7.8,5.3.8.2,5.3.8.3,
5.3.7.9, 5.3.7.14), 5.3.8.1, 5.3.8.4,
5.3.8.5,5.3.8.6,5.3.8.7, 5.3.8.8, 5.3.8.9, 5.3.8.10,5.3.9.4,5.3.9.5,
5.3.9.1, 5.3.9.2, 5.3.9.3, 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,
10S.3.I0.8,5.3.10
.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.ti,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, 5.4.4.1,
5.4.3.7, 5.4.3.8, 5.4.3.9, 5.4.3.10, 5.4.4.2,
5.4.4.3,5.4.4.4,5.4.4.5, 5.4.4.6, 5.4.4.7, 5.4.4.8,5.4.5.2,5.4.5.3,
5.4.4.9, 5.4.4.10, 5.4.5.1, 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,
155.4.6.7,5.4.6.8,5.4.6.9,5.4.6.10,5.4.7.1,5.4.7.2,5.4.7.3,5.4.7~I,5.4.7.5,5.4.
7.6,5.4.7.7,5.4.7.8,
5.4.7.9,5.4.7.10, 5.4.8.8,5.4.8.9,
5.4.8.1, 5.4.8.10,
5.4.8.2,
5.4.8.3,
5.4.8.4,
5.4.8.5,
5.4.8.6,
5.4.8.7,
5.4.9.1,5.4.9.2,5.4.9.3, 5.4.9.4, 5.4.9.5, 5.4.9.6,.4.9.10,5.4.10.1,
5.4.9.7, 5.4.9.8, 5.4.9.9, 5
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.I0.8,5.4.10.9,
5.4.10.10,5.5.1.1,
5.5.1.2,S.S.1.3,5.5.1.4, 5.5.1.5, 5.5.1.6, 5.5.1.7,5.5.2.1,5.5.2.2,
5.5.1.8, 5.5.1.9, 5.5.1.10, 5.5.2.3,
205.5.2.4,5.5.2.5,5.5.2.6, 5.5.2.7, 5.5.2.8, 5.5.2.9,5.5.3.3,S.S.3.4,
5.5.2.10, 5.5.3.1, 5.5.3.2, 5.5.3.5,
5.5.3.6,5.5.3.7,5.5.3.8, 5.5.3.9, 5.5.3.10, 5.5.4.1,5.5.4.5,5.5.4.6,
5.5.4.2, 5.5.4.3, 5.5.4.4, 5.5.4.7,
5.5.4.8,5.5.4.9,5.5.4.10,5.5.5.1,5.5.5.2,5.5.5.3,5.5.5.4,5.5.5.'_i,5.5.5.6,5.5.
5.7,5.5.5.8,5.5.5.9,
5.5.5.10, , 5.5.6.2, 5.5.6.3, 5.5.6.4, 5.5.6.5,5.5.6.9,5.5.6.10,
5.5.6.1 5.5.6.6, 5.5.6.7, 5.5.6.8, 5.5.7.1,
5.5.7.2,5.5.7.3,5.5.7.4, 5.5.7.5, 5.5.7.6, 5.5.7.7,5.5.8.1,5.5.8.2,
5.5.7.8, 5.5.7.9, 5.5.7.10, 5.5.8.3,
255.5.8.4,5.5.8.5,5.5.8.6, 5.5.8.7, 5.5.8.8, 5.5.8.9,5.5.9.3,5.5.9.4,
5.5.8.10, 5.5.9.1, 5.5.9.2, 5.5.9.5,
S.S.9.6,5.5.9.7,5.5.9.8,5.5.9.9,5.5.9.10,5.5.10.1,5.5.10.2,5.5.10.3,5.5.10.4,5.
5.10.5,5.5.10.6,
5.5.10.7,5.5.10.
8,5.5.10.9,S.S.10.10,5.6.1.1,5.6.I.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, 5.6.2.3,5.6.2.7,5.6.2.8,
5.6.2.4, 5.6.2.5, 5.6.2.6, 5.6.2.9,
5.6.2.10, , 5.6.3.2, 5.6.3.3, 5.6.3.4, 5.6.3.5,5.6.3.9,5.6.3.10,
5.6.3.1 5.6.3.6, 5.6.3.7, 5.6.3.8, 5.6.4.1,
3 5.6.4.2,5.6.4.3,5.6.4.4, 5.6.4.5, 5.6.4.6, 5.6.4.7,5.6.5.1,5.6.5.2,
0 5.6.4.8, 5.6.4.9, 5.6.4.10, 5.6.5.3,
5.6.5.4,5.6.5.5,5.6.5.6, 5.6.5.7, 5.6.5.8, 5.6.5.9,5.6.6.3,5.6.6.4,
5.6.5.10, 5.6.6.1, 5.6.6.2, 5.6.6.5,
5.6.6.6,5.6.6.7,5.6.6.8, 5.6.6.9, 5.6.6.10, 5.6.7.1,5.6.7.5,5.6.7.6,
5.6.7.2, 5.6.7.3, 5.6.7.4, 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.'.i,5.6.8.6,5.6
.8.7,5.6.8.8,5.6.8.9,
5.6.8.10, , 5.6.9.2, 5.6.9.3, 5.6.9.4, 5.6.9.5,5.6.9.9,5.6.9.10,
5.6.9.15.6.9.6, 5.6.9.7, 5.6.9.8,
355.6.10.1,5.6.10.2,5.6.10.3,5.6.10.4,5.6.10.5,5.6.10.6,5.6.10.7,5.6.10.8,5.6.1
0.9,5.6.10.10,
38
CA 02352387 2001-05-25
WO 001321?6 PCTIUS99/28080
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, 5.7.2.1C1,
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,
5.7.5.5, 5.7.5.6, 5:7.5.7, 5.7.5.8,
5.7.5.9, 5.7.5.10, 5.7.6.1, 5.7.6.2, 5.?.6.3, 5.7.6.4, 5.7.6.5, 5.7.6.6,
5.7.6.?, 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, 5.7.8.16,
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.I0,5.8.1.1,5.8.1.2,: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.?, 5.8.3.8, 5.8.3.9, 5.8.3.10,
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.I, 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.I0.7,5.8.10.8,5.8.10.
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,
5.9.3.5, 5.9.3.6, 5.9.3.7, 5.9.3.8, 5.9.3.9, 5.9.3.10, 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, 5.9.4.1 0, 5.9.5.1, 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.i0.1,5.9.10.2,5.9.10.3,5.9
.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,S.IO.I
.4,5.10.1.5,
5.10.1.6,5.10.1.7,5.10.1.8,5.10.1.9,5.10.1.10,5.10.2.1,5.10.2.2,5.10.2.3,5.10.2
.4,5.10.2.5,
5.10.2.6,S.I0.2.7,S.I0.2.8,S.I0.2.9,S.I0.2.10,5.10.3.I,5.10.3.2.,5.10.3.3,5.10.
3.4,5.10.3.5,
5.10.3.6,5.10.3.7,5.10.3.8,5.10.3.9,5.10.3.10,5.10.4.1,5.10.4.2,5.10.4.3,5.10.4
.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,
S.I0.5.6, S.I0.5.7, 5.10.5.8, 5.10.5.9, 5.10.5.10, 5.10.6.1, 5.10.6.2,
S.I0.6.3, 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
.4,5.10.7.5,
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,
S.i0.8.3, S.I0.8.4, 5.10.8.5,
5.10.8.6,5.10.8.7,5.10.8.8,S.I0.8.9,5.10.8.10,5.10.9.1,5.10.9.2,5.10.9.3,5.10.9
.4,5.10.9.5,
S.I0.9.6,5.10.9.7,5.10.9.8,5.10.9.9,5.10.9.10,5.10.10.1;5.10.10.2,5.10.10.3,5.1
0.10.4,
39
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
5.10.10.5,5.10.10.6,5.10.10.7,5.10.10.8,5.10.10.9,5.10.10.10,6.1.1.1,6.1.1.2,6.
1.1.3,6.1.1.4,
6.1.1.5,6.1.1.6,6.1.1.7,6.1.i.8,6.I.1.9,6.1.1.10,6.1.2.I,6.I.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, 6.1.3.6,6.1.3.7,
6.1.3.2, 6.1.3.3, 6.1.3.4, 6.1.3.5, 6.1.3.8,
6.1.3.9,6.1.3.10,6.1.4.1,6.1.4.2,6.1.4.3,6.1.4.4,6.1.4.5,6.1.4.6,6.1.4.7,6.1.4.
8,6.I.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, 6.1.6.1,
6.1.5.6, 6.1.5.7, 6.1.5.8, 6.1.5.9, 6:1.6.2,
6.1.5.10,
6.1.6.3,6.1.6.4, 6:1.6.5, 6.1.6.6, 6.1.6.7, 6.1.7.2,6.1.7.3,
6.1.6.8, 6.1.6.9, 6.1.6.10, 6.1.7.1, 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, 6.1.9.6,6.1.9.7,
6.1.9.2, 6.I.9.3, 6.1.9.4, 6.1.9.5, 6.1.9.8,
6.1.9.9,6.1.9.10,6.1.10.1,6.1.10.2,6.1.10.3,6.1.10.4,6.1.10.5,6.1.10.6,6.1.10.7
,6.1.10.8,
6.1:10.9,6.1.10.10,6.2.1.1,6.2.1.2,6.2.1.3,6.2.1.4,6.2.1.5,6.2.1.6,6.2.1
.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, 6.2.4.1,6.2.4.2,
6.2.3.7, 6.2.3.8, 6.2.3.9, 6.2.3.10, 6.2.4.3,
6.2.4.4,6.2.4.5, 6.2.4.6, 6.2.4.7, 6.2.4.8, 6.2.5.3,6.2.5.4,
6.2.4.9, 6.2.4.10, 6.2.5.1, 6.2.5.2, 6.2.5.5,
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,
I5 6.2.6.8,6.2.6.9, 6.2.6.10, 6.2.7.1, 6.2.7.2, 6.2.7.7,6.2.7.8,
6.2.7.3, 6.2.7.4, 6.2.7.5, 6.2.7.6, 6.2.7.9,
6.2.7.1 6.2.8.9,6.2.8.1
0, 0, 6.2.9.1,
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,
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.I
0.1,6.2.10.2,
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, 6.3.2.2,6.3.2.3,
6.3.t.8, 6.3.1.9, 6.3.1.10, 6.3.2.1, 6.3.2.4,
6.3.2.5,6.3.2.6, 6.3.2.7, 6.3.2.8, 6.3.2.9, 6.3.3.4,6.3.3.5,
6.3.2.10, 6.3.3.1, 6.3.3.2, 6.3.3.3, 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,
6.3.4.9,6.3.4.10, 6.3.5.1, 6.3.5.2, 6.3.5.3, 6.3.5.8,6.3.5.9,
6.3.5.4, 6.3.5.5, 6.3.5.6, 6.3.5.7, 6.3.5.10,
6.3.6.1,6.3.6.2, 6.3.6.3, 6.3.6.4, 6.3.6.5, 6.3.7.1,
6.3.6.6, 6.3.6.7, 6:3.6.8;, 6.3.6.9, 6.3.7.2,
6.3.6.10,
6.3.7.3,6.3.7.4, 6.3.7.5, 6.3.7.6, 6.3.7.7, 6.3.8.2,6.3.8.3,
6.3.7.8; 6.3.7.9, 6.3.7.1~D, 6.3.8.1, 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.I0,6.3.10.1,6.3.10.2,6.3.10.3,6.: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,
6.4.1.9,6.4.1.10,6.4.2.1,6.4.2.2,6.4.2.3,6.4.2.4,6.4.2.5,6.4.2.6,6.4.2.7,6.4.2.
8,6.4.2.9,6.4.2.10,
6.4.3.1,6.4.3.2, 6.4.3.3, 6.4.3.4, 6.4.3.5, 6.4.4.1,
6.4.3.6, 6.4.3.7, 6.4.3.8., 6.4.3.9, 6.4.4.2,
6.4.3.10,
3 6.4.4.3,6.4.4.4, 6.4.4.5, 6.4.4.6, 6.4.4.7, 6.4.5.2,6.4.5.3,
0 6.4.4.8, 6.4.4.9, 6.4.4.10, 6.4.5.1, 6.4.5.4,
6.4.5.5,6.4.5.6,6.4.5.7,6.4.5.8,6.4.5.9,6.4.5.10,6.4.6.1,6.4.6.:Z,6.4:6.3,6.4.6
.4,6.4.6.5,6.4.6.6,
6.4.6.7,6.4.b.8, 6.4.6.9, 6.4.6.10, 6.4.7.1, 6.4.7.6,6.4.7.7,
6.4.7.2, 6.4.7.3, 6.4.7.4, 6.4.7.5, 6.4.7.8,
6.4.7.9,6.4.7.10, 6.4.8.1, 6.4.8.2, 6.4.8.3, 6.4.$.8,6.4.8.9,
6.4.8.4, 6.4.8.5, 6.4.8.6, 6.4.8.7, 6.4.8.10,
6.4.9.1,6.4.9.2, 6.4.9.3, 6.4.9.4, 6.4.9.5, .4.9.10,6.4.10.1,
6.4.9.6, 6.4.9.7, 6.4.9.8., 6.4.9.9,
6
6.4.10.2,6.4.10.3,6.4.10.4,6.4.10.5,6.4.10.6,6.4.10.7,6.4.10.8.,6.4.10.9,6.4.10
.10,6.5.1.1,
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080 '.
6.5.1.2, 6.5.1.3, 6.5.1.4, 6.5.1.5, 6.5.1.6, 6.5.2.1,6.5.2.2,6:5.2.3,
6.5.1.7; 6.5.1.8, 6.5.1.9, 6.5.1.10,
6.5.2.4, 6.5.2.5, 6.5.2.6, 6.5.2.7, 6.5.2.8, 6.5.3.3,6.5.3.4,6.5.3.5,
6.5.2.9, 6.5.2.10, 6.5.3.1, 6.5.3.2,
6.5.3.6, 6.5.3.7, 6.5.3.8, 6.5.3.9, 6.5.3.10,6.5.4.5,6.5.4.6,6.5.4.7,
6.5.4.1, 6.5.4.2, 6.5.4.:3, 6.5.4.4,
6.5.4.8, 6.5.4.9, 6.5.4.1 0, 6.5.5.1, 6.5.5.2,6.5.5.7,6.5.5.8,6.5.5.9,
6.5.5.3, 6.5.5.4, 6.5.5.:5, 6.5.5.6,
6.5.5.10, 6.5.6.1, 6.5.6.2, 6.5.6.3, 6.5.6.4,6.5.6.9,6.5.6.10,
6.5.6.5; 6.5.6.6, 6.5.6.'7, 6.5.6.8, 6.5.7.1,
6.5.7.2, 6.5.7.3, 6.5.7.4, 6.5.7.5, 6.5.7.6, 6.5.8.1,6.5.8.2,6.5.8.3,
6.5.7.7, 6.5.7.8, 6.5.7.9., 6.5.7.1 0,
6.5.8.4, 6.5.8.5, 6.5.8.6, 6.5.8.7, 6.5.8.8, 6.5.9.3,6.5.9.4,6.5.9.5,
6.5.8.9, 6.5.8.10, 6.5.9.1, 6'.5.9.2,
6.5.9.6,6.5.9.7,6.5.9.8,6.5.9.9,6.5.9.10,6.5.I0.I,6.S.I0.2,6.5.,10.3,6.5.10.4,6
.5.10.5,6 .5.10.6,
6.5.10.7,6.S.I0.8,6.5.10.9,6.5.10.10,6.6.I.1,6.6.1.2,6.6.1.3,6..6.1.4,6.6.1.5,6
.6.1.6,6.6.1.7,
IO
6.6.1.8,6.6.1.9,6.6.1.10,6.6.2.1,6.6.2.2,6.6.2.3,6.6.2.4,6.6.2.:5,6.6.2.6,6.6.2
.7,6.6.2.8,6.6.2.9,
6.6.2.10,6.6.3.1,6.6.3.2,6.6.3.3,6.6.3.4,6.6.3.5,6.6.3.6,6.6.3.'7,6.6.3.8,6.6.3
.9,6.6.3.10,6.6.4.1,
5.6.4.2, 6.6.4.3, 6.6.4.4, 6.6.4.5, 6.6.4.6, 6.6.5.1,6.6.5.2,6.6.5.3,
6.6.4.7, 6.6.4.8, 6.6.4.9,. 6.6.4.10,
6.6.5.4, 6.6.5.5, 6.6.5.6, 6.6.5.7, 6.6.5.8, 6.6.6.3,6.6.6.4,6.6.6.5,
6.6.5.9, 6.6.5.10, 6.6.6.1, 6.6.6.2,
6.6.6.6, 6.6.6.7, 6.6.6.8, 6.6.6.9, 6.6.6.10,6.6.7.5,6.6.7.6,6.6.7.7,
6.6.7.1, 6.6.7.2, 6.6.7.:3, 6.6.7.4,
6.6.7.8, 6.6.7.9, 6.6.7.1 0, 6.6.8.1, 6.6.8.2,6.6.8.7,6.6.8.8,6.6.8.9,
6.6.8.3, 6.6.8.4, 6.6.8.5, 6.6.8.6,
6.6.8.10, 6.6.9.1, 6.6.9.2, 6.6.9.3, 6.6.9.4,6.6.9.9,6.6.9.10,
6.6.9.5, 6.6.9.6, 6.6.9.'7, 6.6.9.8,
6.6.10.1,6.6.10.2,6.6.10.3,6.6.10.4,6.6.10.5,6.6.10.6,6.6.I0.7,6.6.10.8,6.6.10.
9,6.6.10.10,
6.7.1.1, 6.7.1.2, 6.7.1.3, 6.7.1.4, 6.7.1.5, 6.7.2.1,6.7.2.2,
6.7.1.6, 6.7.1.7, 6.7.1.8, 6.7.I.9, 6.7.1.10,
6.7.2.3, 6.7.2.4, 6.7.2.5, 6.7.2.6, 6.7.2.7, 6.7.3.2,6.7.3.3,6.7.3.4,
6.7.2.8, 6.7.2.9, 6.7.2.10, 6.7.3.1,
6.7.3.5,6.7.3.6;6.7.3.7,6.7.3.8,6.7.3.9,6.7.3.10,6.7.4.1,6.7.4.:L,6.7.4.3,6.7.4
.4,6.7.4.5,6.7.4.6,
6.7.4.7,6.7.4.8,6.7.4.9,6.7.4.10,6.7.5.1,6.7.5.2,6.7.5.3,6.7.5~E,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, 6.7.6.3,6.7.6.8,6.7.6.9,6.7.6.10,
6.7.6.4, 6.7.6.5, 6.7.6.6, 6.7.6.7,
6.7.7.1, 6.7.7.2, 6.7.7.3, 6.7.7.4, 6.7.7.5, .7.7.10,6.7.8.1,6.7.8.2,
6.7.7.6, 6.7.7.7, 6.7.7.8, 6.7.7.9, 6
6.7.8.3, 6.7.8.4, 6.7.8.5, 6.7.8.5, 6.7.8.7, 6.7.9.2,6.7.9.3,6.7.9.4,
6.7.8.8, 6.7.8.9, 6.7.8.111, 6.7.9.1,
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;
6.8.1.7, 6.8.1.8, 6.8.1.9, 6.8.1.10, 6.8.2.1,6.8.2.6,6.8.2.7,6.8.2.8,
6.8.2.2, 6.8.2.3, 6.8.2.4, 6.8.2.5,
6.8.2.9, 6.8.2.10, 6.8.3.1, 6.8.3.2, 6.8.3.3,6.8.3.8,6.8.3.9;6.8.3.10,
6.8.3.4, 6.8.3.5, 6.8.3.Ei, 6.8.3.7,
6.8.4.1, 6.8.4.2, 6.8.4.3, 6.8.4.4, 6.8.4.5, .8.4.16.8.5.1,6.8.5.2,
6.8.4.6, 6.8.4.?, 6.8.4.8, 6.8.4.9, 6 0,
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.S.IC1,6.8.6.1,6.8.6
.2,6.8.6.3,6.8.6.4,
6.8.6.5, 6.8.6.6, 6.8.6.7, 6.8.6.8, 6.8.6.9, 6.8.7.4,6.8.7.5,6.8.7.6,
6.8.6.10, 6.8.7.1, 6.8.7.2:, 6.8.?.3,
6.8.7.7,6.8.7.8,6.8.7.9,6.8.7.10,6.8.8.1,6.8.8.2,6.8.8.3,6.8.8.4.,6.8.8.5,6.8.8
.6,6.8.8.7,6.8.8.8,
6.8.8.9, 6.8.8.10, 6.8.9.1, 6.8.9.2, 6.8.9.3,6.8.9.8,6.8.9.9,6.8.9.10,
6.8.9.4, 6.8.9.5, 6.8.9.x, 6.8.9.7,
6.8.10.1,6.8.10.2,6:8.10.3,6.8.10.4,6.8.i0.5,6.8.10.6,6.8.10.7.,6.8.10.8,6.8.10
.9,6.8.10 .10,
3 6.9.1.I, 6.9.1.2, 6.9.1.3, 6.9.1.4, 6.9.1.5, .9.1.10,6.9.2.1,6.9.2.2,
5 6.9.1.6, 6.9.1.7, 6.9.1.8, 6.9.1.9, 6
41
'- ' ~ CA 02352387 2001-05-25
WO 00132176 PCT/US99/28080
6.9.2.3,6.9.2.4,6.9.2.5,6.9.2.6,6.9.2.7,6.9.2.8,6.9.2.9,6.9.2.10,6.9.3.1,6.9.3.
2,6.9.3.3,6.9.3.4,
6.9.3.5,6.9.3.6,6.9.3.7,6.9.3.8,6.9.3.9,6.9.3.10,6.9.4.1,6.9.4.2,6.9.4.3,6.9.4.
4,6.9.4.5,6.9.4.6,
6.9.4.7, 6.9.4.8, 6.9.4.9, 6.9.4.10, 6.9.5.1, 6.9.5.2, 6.9.5.3, 6.9.5.4,
6.9.5.5, 6.9.5.6, 6.9.5.7, 6.9.5.8,
6.9.5.9, 6.9.5.10, 6.9.6.1, 6.9.6.2, 6.9.6.3, 6.9.6.4, 6.9.6.5, 6.9.6.ti,
6.9.6.7, 6.9.6.8, 6.9.6.9, 6.9.6.10,
6.9.7.1, 6.9.7.2, 6.9.7.3, 6.9.7.4, 6.9.7.5, 6.9.7.6, 6.9.7.7, 6.9.7.8,
6.9.7.9, 6.9.7.10, 6.9.8.1, 6:9.8.2,
6.9.8.3, 6.9.8.4, 6.9.8.5, 6.9.8.6, 6.9.8.7, 6.9.8.8, 6.9.8.9, 6.9.8.10,
6.9.9.1, 6.9.9.2, 6.9.9.3, 6.9.9.4,
6.9.9.5,6.9.9.6,6.9.9.7,6.9.9.8,6.9.9.9,6.9.9.10,6.9.10.1,6.9.10.2',6.9.10.3,6.
9.10.4,6.9.10.5,
6.9.10.6,6.9.10.7,6.9.10.8,6.9.10.9,6.9.10.10,6.10.1.1,6.10.1..2,6.10.1.3,6.10.
1.4,6.10.1.5,
6.10.1.6,6.10.1.7,6.10.1.8,6.10.1.9,6.10.1.10,6.10.2.1,6.10.2.2,6.10.2.3,6.10.2
.4,6.10.2.5,
6.10.2.6,6.I0.2.7,6.10.2.8,6.10.2.9,6.10.2.I0,6.10.3.1,6.10.3..2,6.10.3.3,6.10.
3.4,6.10.3.5,
6.10.3.6,6.10.3.7,6.10.3.8,6.10.3.9,6.10.3.10,6.10.4.1,6.I0.4.,2,6.10.4.3,6.10.
4.4,6.10.4.5,
6.10.4.6,6.10.4.7,6.10.4.8,6.10.4.9,6.10.4.I0,6.10.5.1,6.10.5..2,6.10.5.3,6.10.
5.4,6.10.5.5,
6.10.5.6,6.10.5.7,6.10.5.8,6.10.5.9,6.10.5.10,6.10.6.1,6.10.6..2,6.10.6.3,6.10.
6.4,6.10.6.5,
6.1 O.b.6, 6.10.6.7, 6.10.6.8, 6. I 0.6.9, 6.10.6. i 0, 6.10.7.1, 6.10.7..2,
6.10.7.3, 6.10.7.4, 6.10.7.5,
6.10.7.6,6.10.7.7,6.10.7.8,6.10.7.9,6.10.7.10,6.10.8.1,6.10.8..2,6.10.8.3,6.10.
8.4,6.10.8.5,
6.10.8.6, 6.10.8.7, 6.10.8.8, 6.10.8.9, 6.10.8.10, 6.10.9.1, 6.10.9..2,
6.10.9.3, 6.10.9.4, 6.10.9.5,
6.10.9.6,6.10.9.7,6.10.9.8,6.10.9.9,6.I0.9.10,6.10.10.1,6.10.10.2,6.10.10.3,6.1
0.10.4,
6.10.10.5, 6.10.10.6, 6.10.10.7, 6.10.10.8, 6.10.10.9, 6.10.10.10., 7.1.1.1,
7.1.1.2, 7.1.1.3, 7.1.1.4,
7.I.I.5,7.1.1.6,7.1.I.7,7.1.1.8,7.1.1.9,7.1.i.I0,7.1.2.1,7.1.2.:Z,7.1.2.3,7.1.2
.4,7.1.2.5,7.1.2.6,
7.1.2.7,7.1.2.8,7.I.2.9,7.1.2.I0,7.1.3.1,7.1.3.2,7.1.3.3,7.1.3:4,7.1.3.5,7.1.3.
6,7.1.3.7,7.1.3.8,
7.1.3.9, 7.1.3.10, 7.1.4.1, 7.1.4.2, 7.1.4.3, 7.1.4.4, 7.1.4.5, 7.I.4.6,
7.1.4.7, 7.1.4.8, 7.1.4.9, 7.1.4.10,
7.1:5.1, 7.1.5.2, 7.1.5.3, 7.1.5.4, 7.1.5.5, 7.1.5.6, 7.1.5.7, 7.1.5.8;,
7.1.5.9, 7.1.5.10, 7.1.6.1, 7.1.6.2,
7.1.6.3, 7.1.6.4, 7.1.6.5, 7.1.6.6, 7.1.6.7, 7.1.6.8, 7.1.6.9, 7.1.6.IiD,
7.1.7.1, 7.1.7.2, 7.1.7.3, 7.1.7.4,
7.1.7.5, 7.1.7.6, 7.1.7.7, 7.1.7.8, 7.1.7.9, 7.1.7.10, 7.1:8.1, 7.1.8.2,
7.1.8.3, 7.1.8.4, 7.1.$.5, 7.1.8.6,
7.1.8.7, 7.1.8.8, 7.1.8.9, 7.1.8.10, 7.1.9.1, 7.1.9.2, 7.1.9.3, 7.I.9:4,
7.1.9.5, 7.1.9.6, 7.1.9.7, 7.1.9.8,
7.1.9.9,7.I.9.10,7.1.10.1,7.I.10.2,7.1.10.3,7.1.10.4,7.1.10.5,7.1.10.6,7.1.10.7
,7.1.10.8,
7.1.10.9,7.1.10.10,7.2.1.I,7.2.1.2,7.2.1.3,7.2.I.4,7.2.I.5,7.2.1.6,7.2.1.7,7.2.
1.8,7.2.1.9,
7.2.1.10, 7.2.2.1, 7.2.2.2, 7.2.2.3, 7.2.2.4, 7.2.2.5, 7.2.2.6, 7.2.2.7,
7.2.2.8, 7.2.2.9, 7.2.2.10, 7.2.3.1,
7.2.3.2, 7.2.3.3, 7.2.3.4, 7.2.3.5, 7.2.3.6, 7.2.3.7, 7.2.3.8, 7.2.3.9,
7.2.3.1 0, 7.2.4.1, 7.2.4.2, 7.2.4.3,
3 0 7.2.4.4, 7.2.4.5, 7.2.4.6, 7.2.4.7, ?.2.4.8, 7.2.4.9, 7.2.4.10, 7.2.5.1,
7.2.5.2, 7.2.5.3, 7.2.5.4, 7.2.5.5,
7.2.5.6, 7.2.5.7, 7.2.5.8, 7.2.5.9, 7.2.5.10, 7.2.6.1, 7.2.6.2, 7.2.6.3,
7.2.6.4, 7.2.6.5, 7.2.6.6, 7.2.6.7,
7.2.6.8, 7.2.6.9, 7.2.6.10, 7.2.7.1, 7.2.7.2, 7.2.7.3, 7.2.7.4, 7.2.7.5,
7.2.7.6, 7.2.7.7, 7.2.7.8, 7.2.7.9,
7.2.7.10, 7.2.8.1, 7.2.8.2, 7.2.8.3, 7.2.8.4, 7.2.8.5, 7.2.8.6,'7.2.8.7,
7.2.8.8, 7.2.8.9, 7.2.8.10, 7.2.9.1,
7.2.9.2,7.2.9.3,7.2.9.4,7.2.9.5,7.2.9.6,7.2.9.7,7.2.9.8,7.2.9.9,7.2.9.10,7.2.10
.1,7.2.10.2,
7.2.10.3,7.2.10.4,7.2.10.5,7.2.10.6,7.2.10.7,7.2.10.8,7.2.10.5>,7.2.10.10,7.3.1
.1,7.3.1.2,
42
i
' ~ CA 02352387 2001-05-25
WO 00/32176 PCTIUS99/28080
7.3;1.3,7.3.I.4,7.3.1.5,7.3.1.6,7.3.1.7,7.3.1.8,7.3.1.9,7.3.1.10,7.3.2.1,7.3.2.
2,7.3.2.3,7.3.2.4,
7.3.2.5, 7.3.2.6, 7.3.2.7, 7.3.2.8, 7.3.2.9, 7.3.2.10, 7.3.3.1, 7.3.3..2,
7.3.3.3, 7.3.3.4, 7.3.3.5, 7.3.3.6,
7.3.3.?, 7.3.3.8, 7.3.3.9, 7.3.3.10, 7.3.4.1, 7.3.4.2, 7.3.4.3, 7.3.4..4,
7.3.4.5, 7.3.4.6, 7.3.4.7, 7.3.4.8,
7.3.4.9, 7.3.4.1 0, 7.3.5.1, 7.3.5.2, 7.3.5.3, 7.3.5.4, 7.3.5.5, 7.3.5.6,
7.3.5.7, 7.3.5.8, 7.3.5.9, 7.3.S.I 0,
7.3.6.1, 7.3.6.2, 7.3.6.3, 7.3.6.4, 7.3.6.5, 7.3.6.6, 7.3.6.7, 7.3.6.8,
7.3.6.9, 7.3.6.10, 7.3.7.1, 7.3.7.2,
7.3.7.3, 7.3.7.4, 7.3.7.5, 7.3.7.6, 7.3.7.7, 7.3.7.8, 7.3.7.9, 7.3.7.10,
7.3.8.I, 7.3.8.2, 7.3.8.3, 7.3.8.4,
7.3.8.5, 7.3.8.6, 7.3.8.7, 7.3.8.8, 7.3.8.9, 7.3.8.10, 7.3.9.1, 7.3.9..2,
7.3.9.3, 7.3.9.4, 7.3.9.5, 7.3.9.6,
7.3.9.7, ?.3.9.8, 7.3.9.9, 7.3.9.10, 7.3.10.1, 7.3.10.2, 7.3.10.3, 7..3.10.4,
7.3.I0.5, 7.3.10.6, 7.3.10.7,
7.3.10.8, 7.3.1 0.9, 7.3.1 0.10, 7.4.1.1, 7.4.1.2, 7.4.1.3, 7.4.1.4, 7.4.1.5,
7.4.1.6, 7.4.1.7, 7.4.1.8,
7.4.1.9,7.4.I.10,7.4.2.1,7.4.2.2,7.4.2.3,7.4.2.4,7.4.2.5,7.4.2.6,7.4.2.7,7.4.2.
8,7.4.2.9,7.4.2.10,
7.4.3.1, 7.4.3.2, 7.4.3.3, 7.4.3.4, 7.4.3.5, 7.4.3.6, 7.4.3.7, 7.4.3.8,
7.4.3.9, 7.4.3.10, 7.4.4.1, 7.4.4.2,
7.4.4.3, 7.4.4.4, 7.4.4.5, 7.4.4.6, 7.4.4.7, 7.4.4.8, 7.4.4.9, 7.4.4.10,
7.4.5.1, 7.4.5.2, 7.4.5.3= 7.4.5.4,
7.4.5.5, 7.4.5.6, 7.4.5.7, 7.4.5.8, 7.4.5.9, 7.4.S.i0, 7.4.6.1, 7.4.6.2,
7.4.6.3, 7.4.6.4, 7.4.6.5, 7.4.6.6,
7.4.6.7,7.4.6.8,7.4.6.9,7.4.6.10,7.4.7.1,7.4.7.2,7.4.7.3,7.4.7.4,7.4.7.5,7.4.7.
6,7.4.7.7,7.4.7.8,
7.4.7.9,7.4.7.I0,7.4.8.1,7.4.8.2,7.4.8.3,7.4.8.4,7.4.8.5,7.4.8.6,7.4.8.7,7.4.8.
8,7.4.8.9,7.4.8.10,
7.4.9.1, 7.4.9.2, 7.4.9.3, 7.4.9.4, 7.4.9.5, 7.4.9.6, 7.4.9.7, 7.4.9.8,
7.4.9.9, 7.4.9.10, 7.4.1 0.1,
7.4.10.2, 7.4.10.3, 7.4.10.4, 7.4.10.5, 7.4.10.6, 7.4.10.7, 7.4.10.fI,
?.4.10.9, 7.4.10.10, 7.5.1.1,
7.5.1.2, 7.5.1.3, 7.5.1.4, 7.5.1.5, 7.5.1.6, 7.5.1.7, 7.5.1.8, 7.5.1.9"
7.5.1.10, 7.5.2.1, 7.5.2.2, 7.5.2.3,
7.5.2.4, 7.5.2.5, 7.5.2.6, 7.5.2.7, 7.5.2.8, 7.5.2.9, 7.5.2.10, 7.5.3.1,
7.5.3.2, 7.5.3.3, 7.5.3.4, 7.5.3.5,
7.5.3.6,7.5.3.7,7.5.3.8,7.5.3.9,7.5.3.10,7.5.4.1,7.5.4.2,7.5.4.:3,7.5.4.4,7.5.4
.5,7.5.4.6,7.5.4.7,
7.5.4.8, 7.5.4.9, 7.5.4.10, 7.5.5.1, 7.5.5.2, 7.5.5.3, 7.5.5.4, 7.5.5.5,
7.5.5.6, 7.5.5.7, 7.5.5.8, 7.5.5.9,
7.5.5.10, 7.5.6.1, 7.5.6.2, 7.5.6.3, 7.5.6.4, 7.5.6.5, 7.5.6.6, 7.5.6.'7,
7.5.6.8, 7.5.6.9, 7.5.6.10, 7.5.7.1,
7.5.7.2, 7.5.7.3, 7.5.7.4, 7.5.7.5, 7.5.7.6, 7.5.7.7, 7.5.7.8, 7.5.7.9.,
7.5.7.10, 7.5.8.1, 7.5.8.2, 7.5.8.3,
7.5.8.4, 7.5.8.5, 7.5.8.6, 7.5.8.7, 7.5.8.8, 7.5.8.9, 7.5.8.10, 7.5.9.1,
7.5.9.2, 7.5.9.3, 7.5.9.4, 7.5.9.5,
7.5.9.6,7.5.9.7,7.5.9.8,7.5.9.9,7.5.9.10,7.5.10.1,7.5.10.2,7.5..10.3,7.5.10.4,7
.5.10.5,7.5.10.6,
7.5.10.7,7.5.10.8,7.5.10.9,7.5.10.10,7.6.1.1,7.6.1.2,7.6.1.3,7.6.1.4,7.6.1.5,7.
6.1.6,7.6.1.7,
7.6.1.8, 7.6.1.9, 7.6.1.1 0, 7.6.2.1, 7.6.2.2, 7.6.2.3, 7.6.2.4, 7.6.2.;i,
7.6.2.6, 7.6.2.7, 7.6.2.8, 7.6.2.9,
7.6.2.10,7.6.3.1,7.6.3.2,7.6.3.3,7.6.3.4,7.6.3.5,7.6.3.6,7.6.3.'7,7.6.3.8,7.6.3
.9,7.6.3.10,7.6.4.1,
7.6.4.2, 7.6.4.3, 7.6.4.4, 7.6.4.5, 7.6.4.6, 7.6.4.7, 7.6.4.8, 7.6.4.9,
7.6.4.10, 7.6.5.1, 7.6.5.2, 7.6.5.3,
7.6.5.4, 7.6.5.5, 7.6.5.6, 7.6.5.7, 7.6.5.8, 7.6.5.9, 7.6.5.10, 7.6.6.;1,
7.6.6.2, 7.6.6.3, 7.6.6.4, 7.6.6.5,
7.6.6.6, 7.6.6.7, 7.6.6.8, 7.6.6.9, 7.6.6.10, 7.6.7.1, 7.6.7.2, 7.6.7.x,
7.6.7.4, 7.6.7.5, 7.6.7.6, 7.6.7.7,
7.6.7.8, 7.6.7.9, 7.6.7.10, 7.6.8.1, 7.6.8.2, 7.6.8.3, 7.6.8.4, 7.6.8.:>,
7.6.8.6, 7.6.8.7, 7.6.8.8, 7.6.8.9,
7.6.8.10, 7.6.9.1, 7.6.9.2, 7.6.9.3, 7.6.9.4, 7.6.9.5, 7.6.9.6, 7.6.9.7,
7.6.9.8, 7.6.9.9, 7.6.9.10,
7.6.10.I,7.6.10.2,7.6.10.3,7.6.10.4,7.6.10.5,7.6.10.6,7.6.10.7,7.6.10.8,7.6.10.
9,7.6.10.10,
3 S 7.7.1.1, 7.7.1.2, 7.7.1.3, 7.7.1.4, 7.7.1.5, 7.7.1.6, 7.7.1.7, 7.7.1.8,
7.7.1.9, 7.7.1.10, 7.7.2.1, 7.7.2.2,
43
CA 02352387 2001-05-25
WO 00/32176 PCT/US99l28080
7.7.2.3, 7.7.2.4, 7.7.2.5, 7.7.2.6, 7.7.2.7,7.7.3.1, 7.7.3.2,
7.7.2.8, 7.7.2.9, 7.7.2.10, 7.7.3.3, 7.7.3.4,
7.7.3.5, 7.7.3.6, 7.7.3.7, 7.7.3.8, 7.7.3.9,7.7.4.3, 7.7.4.4,
7.7.3.10, 7.7.4.1, 7.7.4.2, 7.7.4.5, 7.7.4.6,
7.7.4.7, 7.7.4.8, 7.7.4.9, 7.7.4.1 0, 7.7.5.5, 7.7.5.6,
?.7.5.1, 7.7.5.2, 7.7.5.3, 7.7.5.4, 7.7.5.7, 7.7.5.8,
7.7.5.9, 7.7.5.1 0, 7.7.6.1, 7.7.6.2, 7.7.6.7, 7.7.6.8,
7.7.6.3, 7.7.6.4, 7.7.6.5, 7.7.6.6, 7.7.6.9, 7.7.6.1
0,
7.7.7.1, 7.7.7:2, 7.7.7.3, 7.7.7.4, 7.7.7.5,
7.7.7.6, 7.7.7.7, 7.7.7.8, 7.7.7.9,
7.7.7.1 0, 7.7.8.1, 7.7.8.2,
7.7.8.3, 7.7.8.4, 7.7.8.5, 7.7.8.6, 7.7.8.7,7.7.9.1, 7.7.9.2,
7.7.8.8, 7.7.8.9, 7.7.8.10, 7.7.9.3, 7.7.9.4,
7.7.9.5, 7.7.9.6, 7.7.9.7, 7.7.9.8, 7.7.9.9,.2, 7.7.10.3, 7.7.1
7.7.9.10, 7.7.1 0.1, 7.7.1 0 0.4, 7.7.1 0.5,
7.7.10.6, 7.7.10.7, 7.7.10.8, 7.7.10.9,
7.7.10.10, 7.8.1.1, 7.8.1.2, 7.8.1.3,
7.8.1.4, 7.8.1.5, 7.8.1.6,
7.8.1.7, 7.8.1.8, 7.8.1.9, 7.8.1.10, 7.8.2.5, 7.8.2.6,
7.8.2.1, 7.8.2.2, 7.8.2.3, 7.8.2:4, 7.8.2.7, 7.8.2.8,
7.8.2.9, 7.8.2.1 0, 7.8.3.1, 7.8.3.2, 7.8.3.7, 7.8.3.8,
7.8.3.3, 7.8.3.4, 7.8.3.5, 7.8.3.5, 7.8.3.9, 7.8.3.1
0,
7.8.4.1, 7.8.4.2, 7.8.4.3, 7.8.4.4, 7.8.4.5,
7.8.4.6, 7.8.4.7, 7.8.4.8., 7.8.4.9,
7.8.4.1 0, 7.8.5.1, 7.8.5.2,
7.8.5.3, 7.8.5.4, 7.8.5.5, 7.8.5.6, 7.8.5.7,7.8.6.1, 7.8.6.2,
7.8.5.8, 7.8.5.9, 7.8.5.10, 7.8.6.3, 7.8.6.4,
7.8.6.5, 7.8.6.6, 7.8.6.7, 7.8.6.8, 7.8.6.9,7.8.7.3, ?.8.7.4,
7.8.6.10, 7.8.7.1, 7.8.7.2, 7.8.7.5, 7.8.7.6,
7.8.7.7, 7.8.7.8, 7.8.7.9, 7.8.7.10, 7.8.8.5, 7.8.8.6,
7.8.8.1, 7.8.8.2, 7.8.8.3, 7.8.8.4, 7.8.8.7, 7.8.8.8,
7.8.8.9,7.8.8.10,7.8.9.I,T.8.9.2,7.8.9.3,7.8.9.4,7.8.9.5,7.8.9.ti,7.8.9.7,7.8.9
.8,7.8.9.9,7.8.9.10,
7.8.10.1,7.8.10.2,7.8.I0.3,7.8.10.4,7.8.10.5,7.8.10.6,7.8.10.7,7.8.10.8,7.8.10.
9,7.8.10.10,
7.9.1.1, 7.9.1.2, 7.9.1.3, 7.9.1.4, 7.9.1.5,.9.1.9, 7.9.1.10,
?.9.1.6, 7.9.1.7, 7.9.1.8; 7 7.9.2.1, 7.9.2.2,
7.9.2.3, 7.9.2.4, 7.9.2.5, 7.9.2.6, ?.9.2.7,7.9.3.1, 7.9.3.2,
7.9.2.8, 7.9.2.9, 7.9.2.10, 7.9.3.3, 7.9.3.4,
7.9.3.5, 7.9.3.6, 7.9.3.7, 7.9.3.8, 7.9.3.9,7.9.4.3, 7.9.4.4,
7.9.3.10, 7.9.4.1, 7.9.4.:>., 7.9.4.5, ?.9.4.6,
7.9.4.7, 7.9.4.8, 7.9.4.9, 7.9.4.10, 7.9.5.5, 7.9.5.6,
7.9.5.1, 7.9.5.2, 7.9.5.3, 7.9.5.4, 7.9.5.?, 7.9.5.8,
7.9.5.9,7.9.5.10,7.9.6.1,7.9.6.2,7.9.6.3,7.9.6.4,7.9.6.5,7.9.6.f's,7.9.6.7,7.9.
6.8,7.9.6.9,7.9.6.10,
7.9.7.1, 7.9.7.2, 7.9.7.3, 7.9.7.4, 7.9.7.5,.9.7.9, 7.9.7.1 0,
7.9.7.6, 7.9.7.7, 7.9.7.8, 7 7.9.8.1, 7.9.8.2,
7.9.8.3, 7.9.8.4, 7.9.8.5, 7.9.8.6, 7.9.8.7,7.9.9.1, 7.9.9.2,
7.9.8.8, 7.9.8.9, 7.9.8.1(), 7.9.9.3, 7.9.9.4,
7.9.9.5, 7.9.9.6, 7.9.9.7, 7.9.9.8, 7.9.9.9,
7.9.9.10, 7.9.10.1, 7.9.1 0.2, 7.9.1
0.3, 7.9.10.4, 7.9.10.5,
7.9.10.6,7.9.10.7,7.9.10.8,7.9.10.9,7.9.i0.10,7.10.1.1,7.10.1.:2,7.10.1.3,7.10.
1.4,7.10.1.5,
7:10.1.6, 7.10.1.7, 7. I 0.1.8, 7.10. 7.10.2.3, 7.10.2.4,
i .9, ?.10.1.10, 7.10.2.1, 7. I 0.2.:2, 7.10.2.5,
7.10.2.6, 7.10.2.7, 7.10.2.8, 7.10.2.9, 7.10.3.3, 7.10.3.4,
7.10.2.10, 7.10.3.1, 7.10.3.2, 7.10.3.5,
7.10.3.6,7.10.3.7,7.10.3.8,7.10.3.9,7.10.3.10,7.10.4.1,7.10.4.:2,7.10.4.3,7.10.
4.4,7.10.4.5,
7.10.4.6,7.10.4.7,7.10.4.8,7.10.4.9,7.10.4.10,7.I0.5.1,7.10.5.:2,7.10.5.3,7.10.
5.4,7.10.5.5,
7.10.5.6,7.10.5.7,7.I0.5.8,7.10.5.9,7.10.5.10,7.10.6.1,7.10.6.:2,7.10.6.3,7.10:
6.4,7.10.6.5,
7.10.6.6,7.10.6.7,7.I0.6.8,7.10.6.9,7.10.6.10,7.10.7.1,7.10.7.:2,7.10.7.3,7.10.
7.4,7.10.7.5,
7.10.7.6,7.10.7.7,7.I0.7.8,7.10.7.9,7.10.7.10,7.10.8.1,7.10.8.:2,7.10.8.3,7.10.
8.4,7.10.8.5,
7.10.8.6,7.10.8.7,7.10.8.8,7.10.8.9,7.10.8.10,7.10.9.1,7.10.9.2,7.10.9.3,7:10.9
.4,7.10.9.5,
7.I0.9.6,7.10.9.7,7.10.9.8,7.10.9.9,7.10.9.10,7.10.10.1,7.10.10.2,7.10.10.3,7.1
0.10.4,
7.10.I0.5,7.10.10.6,7.10.10.7,7.I0.10.8,7.10.10.9,7.10.10.10,8.1.1.1,8.1.1.2,8.
1.1.3,8.1.1.4,
44
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
B.I:i.5,8.1.1.6,8.1.1.7,8.1.1.8,8.1.1.9,8.1.I.10,8.1.2.I,8.1.2.2,8.1.2.3,8.1.2.
4,8.1.2.5,8.1.2.6, .
8.1.2.7,8.I.2.8,8.1.2.9,8.1.2.10,8.1.3.1,8.1.3.2,8.1.3.3,8.1.3.4,8.1.3.5,8.1.3.
6,8.1.3.7,8.1.3.8,
8.1.3.9, 8.1.3.1 0,8.1.4.1, 8.1.4.2, 8.1.4.3, 8.1.4.4, 8.1.4.5, 8.1.4.6,
8.1.4.7, 8.1.4.8, 8.1.4.9, $.1.4.10,
8.1.5.1,8.1.5.2,8.1.5.3,8.1.5.4,8.i.5.5,8.1.5.6,8.1.5.7,8.1.5.f~,8.1.5.9,8.1.5.
10,8.1.6.1,8.1.6.2,
8.1.6.3, 8.I.6.4, 8.1.6.5, 8.1.6.6, 8.1.6.7, 8.1.6.8, 8.1.6.9, 8.1.6.1.0,
8.1.7.1, 8.1.7.2, 8.1.7.3, 8.1.7.4,
8.1.7.5, 8.1.7.6, 8.1.7.7, 8.1.7.8, 8.1.7.9, 8.1.7.1 0, 8.1.8.1, 8.1.8.2,
8.1.8.3, 8.1.8.4, 8.1.8.5, 8.1.8.6,
8.1.8.7, 8.1.8.8, 8.1.8.9, 8.1.8.10, 8.1.9.1, 8.1.9.2, 8.1.9.3, 8.1.9.4,
8.1.9.5, 8.1.9.6, 8.1.9.7, 8.1.9.8,
8.1.9.9, 8.1.9.10, 8.1. I 0.1, 8.1.10.2, 8.1.10.3, 8.1.10.4, 8. i .10.5,
8.1.10.6, 8.1.10.7, 8.1.10.8,
8.1.10.9, 8.1.10.10, 8.2.1.1, 8.2.1.2, 8.2.1.3, 8.2.1.4, 8.2.1.5, 8.2.1.6,
8.2.1.7, 8.2.1.8, 8.2.1.9,
8.2.1.I0,8.2.2.1,8.2.2.2,8.2.2.3,8.2.2.4,8.2.2.5,8.2.2.6,8.2.2..7,8.2.2.8,8.2.2
.9,8.2.2.10,8.2.3.1,
8.2.3.2,8.2.3.3,8.2.3.4,8.2.3.5,8.2.3.6,8.2.3.7,8.2.3.8,8.2.3.5~,8.2.3.10,8.2.4
.1,8.2.4.2,8.2.4.3,
8.2.4.4, 8.2.4.5, 8.2.4.6, 8.2.4.7, 8.2.4.8, 8.2.4.9, 8.2.4.10, 8.2.5..1,
8.2.5.2, 8.2.5.3, 8.2.5.4, 8.2.5.5,
8.2.5.6, 8.2.5.7, 8.2.5.8, 8.2.5.9, 8.2.5.10, 8.2.6.1, 8.2.6.2, 8.2.6.3,
8.2.6.4, 8.2.6.5, 8.2.6.6, 8.2.6.7,
8.2.6.8,8.2.6.9,8.2.6.10,8.2.7.1,8.2.7.2,8.2.7.3,8.2.7.4,8.2.7.5,8.2.7.6,8.2.7.
7,8.2.7.8,8.2.7.9,
8.2.7.1 0, 8.2.8.1, 8.2.8.2, 8.2.8.3, 8.2.8.4, 8.2.8.5, 8.2.8.6, 8.2.8.7,
8.2.8.8, 8.2.8.9, 8.2.8.10, 8.2.9.1,
8.2.9.2,8.2.9.3,8.2.9.4,8.2.9.5,8.2.9.6,8.2.9.7,8.2.9.8,8.2.9.9,8.2.9.10,8.2.10
:1,8.2.10.2,
8.2.10.3,8.2.10.4,8.2.10.5,8.2.10.6,8.2.I0.7,8.2.10.8,8.2.10.9,8.2.10.10,8.3.1.
1,8.3.1.2,
8.3.i.3,8.3.1.4,8.3.i.5,8.3.1.6,8.3.1.7,8.3.I.8,8.3.1.9,8.3.1.10,8.3.2.I,8.3.2.
2,8.3.2.3,8.3.2.4,
8.3.2.5, 8.3.2.6, 8.3.2.7, 8.3.2.8, 8.3.2.9, 8.3.2.10, 8.3.3.1, 8.3.3.2,
8.3.3.3, 8.3.3.4, 8.3.3.5, 8.3.3.6,
8.3.3:7,8.3.3.8,8.3.3.9,8.3.3.10,8.3.4.1,8.3.4.2,8.3.4.3,8.3.4.4,8.3.4.5,5.3.4.
6,8.3.4.7,8.3.4.8,
8.3.4.9, 8.3.4.10, 8.3.5.1, 8.3.5.2, 8.3.5.3, 8.3.5.4, 8.3.5.5, 8.3.5.6,
8.3.5.7, 8.3.5.8, 8.3.5.9, 8.3.5.10,
8.3.6.1, 8.3.6.2, 8.3.6.3, 8.3.6.4, 8.3.6.5, 8.3.6.6, 8.3.6.7, 8.3.6.8,
8.3.6.9, 8.3.6.I0, 8.3.7.1, 8.3.7.2,
8.3.7.3, 8.3.7.4, 8.3.7.5, 8.3.7.6, 8.3.7.7, 8.3.7.8, 8.3.7.9, 8.3.7.1 0,
8.3.8.1, 8.3.8.2, 8.3.8.3, 8.3.8.4,
8.3.8.5, 8.3.8.6, 8.3.8.7, 8.3.8.8, 8.3.8.9, 8.3.8.10, 8.3.9.1, 8.3.9.2,
8.3.9.3, 8.3.9.4, 8.3.9.5, 8.3.9.6,
8.3.9.7,8.3.9.8,8.3.9.9,8.3.9.I0,8.3.10.1,8.3.10.2,$.3.i0.3,8.3.10.4,8.3.10.5,8
.3.10.6,8.3.10.7,
8.3.10.8, 8.3.10.9, 8.3.10.I0, 8.4.1.1, 8.4.1.2, 8.4.1.3, 8.4.1.4, 8.4.1.5,
8.4.1.6, 8.4.1.7, 8.4.1.8,
8.4.1.9, 8.4.1.1 0, 8.4.2.1, 8.4.2.2, 8.4.2.3, 8.4.2.4, 8.4.2.5, 8.4.2.6,
8.4.2.7, 8.4.2.8, 8.4.2.9, 8.4.2.10,
8.4.3.1, 8.4.3.2, 8.4.3.3, 8.4.3.4, 8.4.3.5, 8.4.3.6, 8.4.3.7, 8.4.3.8.,
8.4.3.9, 8.4.3.10, 8.4.4.1, 8.4.4.2,
8.4.4.3, 8.4.4.4, 8.4.4.5, 8.4.4.6, 8.4.4.7, 8.4.4.8, 8.4.4.9, 8.4.4.10,
8.4.5.1, 8.4.5.2, 8.4.5.3, 8.4.5.4,
3 0 8.4.5.5, 8.4.5.6, 8.4.5.7, 8.4.5.8, 8.4.5.9, 8.4.5.10, 8.4.6.1, 8.4.6.2,
8.4.6.3, 8.4.6.4, 8.4.6.5, 8.4.6.6,
8.4.6.7, 8.4.6.8, 8.4.6.9, 8.4.6.10, 8.4.7.1, 8.4.7.2, 8.4.7.3, 8.4.7.4,
8.4.7.5, 8.4.7.6, 8.4.7.7, 8.4.7.8,
8.4.7.9, 8.4.7.1 0, 8.4.8.1, 8.4.8.2, 8.4.8.3, 8.4.8.4, 8.4.8.5, 8.4.8.6,
8.4.8.7, 8.4.8.8, 8.4.8.9, 8.4.8.1 0,
8.4.9.1, 8.4.9.2, 8.4.9.3, 8.4.9.4, 8.4.9.5, 8.4.9.6, 8.4.9.7, 8.4.9.8.,
8.4.9.9, 8.4.9.1 0, 8.4.1 0.1,
8.4.10.2,8.4.10.3,8.4.10.4,8.4.10.5,8.4.10.6,8.4.10.7,8.4.10.8,8.4.10.9,8.4.10.
10,8.5.1.1,
3 5 8.5.1.2, 8.5.I.3, 8.5.1.4, 8.5.1.5, 8.5.1.6, 8.5.1.7, 8.5.1.8, 8.5.1.9,
8.5.1.10, 8.5.2.1, 8.5.2.2, 8.5.2.3,
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
8.5.2.4,8.5.2.5,8.5.2.6, 8.5.2.7, 8.5.2.8, 8.5.2.9,8.5.3.3,8.5.3.4,8.5.3.5,
8.5.2.1 0, 8.5.3..1, 8.5.3.2,
8.5.3.6,8.5.3.?,8.5.3.8, 8.5.3.9, 8.5.3.10, 8.5.4.1,8.5.4.5,8.5.4.6,8.5.4.7,
8.5.4.2, 8.5.4..3, 8.5.4.4,
8.5.4.8,8.5.4.9,8.5.4.1 0, 8.5.5.1, 8.5.5.2, 8.5.5.3,8.5.5.7,8.5.5.8,8.5.5.9,
8.5.5.4, 8.5.5..5, 8.5.5.6,
8.5.5.1 , 8.5.6.2, 8.5.6.3, 8.5.6.4, 8.5.6.5,8.5.6.9,8.5.6.1
0, 8.5.6.6, 8.5.6..7, 8.5.6.8, 0,
8.5.6.1 8.5.7.1,
8.5.7.2,8.5.7.3,8.5.7.4, 8.5.7.5, 8.5.7.6, 8.5.7.7,S.S.8.1,8.5.8.2,8.5.8.3,
8.5.7.8, 8.5.7.9', 8.5.7.10,
8.5.8.4,8.5.8.5,8.5.8.6, 8.5.8.7, 8.5.8.8, 8.5.8.9,8.5.9.3,8.5.9.4,8.5.9.5,
8.5.8.10, 8.5.9..1, 8.5.9.2,
8.5.9.6,8.5.9.?,8.5.9.8, 8.5.9.9, 8.5.9.10, 8.5.10.1,10.4,
8.5.10.2, 8.5.IQ.3, 8.5. 8.5.10.5,
8.5.10.6,
8.S.I0.7,S.S.10.8,8.5.10.9,8.5.10.10,8.6.1.1,8.6.I.2,8.6.1.3,1~.6.1.4,8.6.I.5,8
.6.I.6,8.6.1.7,
8.6.1.8,8.6.1.9,8.6.1.10, 8.6.2.1, 8.6.2.2, 8.6.2.3,8.6.2.7,8.6.2.8,8.6.2.9,
8.6.2.4, 8.6.2.5, 8.6.2.6,
108.6.2.I0,8.6.3.I
,8.6.3.2,8.6.3.3,8.6.3.4,8.6.3.5,8.6.3.6,8.6.3.7,8.6.3.8,8.6.3.9,8.6.3.10,8.6.4
.1,
8.6.4.2,8.6.4.3,8.6.4.4, 8.6.4.5, 8.6.4.6, 8.6.4.7,8.6.5.1,8.6.5.2,8.6.5.3,
8.6.4.8, 8.6.4.9, 8.6.4.10,
8.6.5.4,8.6.5.5,8.6.5.6,8.6.5.7,8.6.5.8,8.6.5.9,8.6.5.10,8.6.6.1,8.6.6.2,8.6.6.
3,8.6.6.4,8.6.6.5,
8.6.6.6,8.6.6.7,8.6.6.8, 8.6.6.9, 8.6.6.10, 8.6.7.1,8.6.7.5,8.6.7.6,8.6.7.7,
8.6.7.2, 8.6.7.3, 8.6.7.4,
8.6.7.8,8.6.7.9,8.6.7.10, 8.6.8.1, 8.6.8.2, 8.6.8.3,8.6.8.7,8.6.8.8,8.6.8.9,
8.6.8.4, 8.6.8.5, 8.6.8.6,
158.6.8.10, , 8.6.9.2, 8.6.9.3, 8.6.9.4, 8.6.9.5,8.6.9.9,8.6.9.10,
8.6.9.1 8.6.9.6, 8.6.9.7, 8.6.9.8,
8.6.10.1,8.6.10.2,8.6.10.3,8.6.I0.4,8.6.10.5,8.6.10.6,8.6.10.'7,8.6.10.8,
8.6.10.9,8.6.10.10,
8.7.1.1,8.7.1.2,8.7.1.3, 8.7.1.4, 8.7.1.5, 8.7.1.6,.7.1.10,8.7.2.1,8.7.2.2,
8.7.1.7, 8.7.1.8, 8.7.1.9, 8
8.7.2.3,8.7.2.4,8.7.2.5, 8.7.2.6, 8.7.2.7, 8.7.2.8,8.7.3.2,8.7.3.3,8.7.3.4,
8.7.2.9, 8.7.2.10, 8.7.3.1,
8.7.3.5,8.?.3.6,8.7.3.7,8.7.3.8,8.7.3.9,8.7.3.10,8.7.4.1,8.7.4.2,8.7.4.3,8.7.4.
4,8.7.4..5,8.7.4.6,
208.7.4.7,8.7.4.8,8.7.4.9, 8.7.4.1 0, 8.7.5.1,
8.7.5.2,8.7.5.6,8.7.5.7,8.7.5.8,
8.7.5.3, 8.7.5.4, 8.7.5.5,
8.7.5.9,8.7.5.10, 8.7.6.8,8.7.6.9,8.7.6.10,
8.7.6.1,
8.7.6.2,
8.7.6.3,
8.7.6.4,
8.7.6.5,
8.7.6.6,
8.7.6.7,
8.7.7.1,8.7.7.2,8.7.7.3, 8.7.7.4, 8.7.7.5, 8.7.7.6,.7.7.10,8.7.8.1,8.7.8.2,
8.7.7.7, 8.7.7.8, 8.7.7.9, 8
8.7.8.3,8.7.8.4,8.7.8.5, 8.7.8.6, 8.7.8.7, 8.7.8.8,8.7.9.2,8.7.9.3,8.7.9.4,
8.7.8.9, 8.7.8.10, 8.7.9.1,
8.7.9.5,8.7.9.6,8.7.9.7,8.7.9.8,8.7.9.9,8.7.9.10,8.7.10.1,8.7.10.2,8.7.10.3,8.7
. 10.4,8.7.10.5,
258.7.10.6, 7, 8.7.10.8, 8.7.10.9, 8.7.10.10, 8.1.4, 8.1.6,
8.7.10.8.8.1.1, 8.8.1.2,.8.8.1.3, 8. 8.8.1.5,
8.
8.8.1.7,8.8.1.8,8.8.1.9, 8.8.1.1 0, 8.8.2.1, 8.8.2.2,8.8.2.6,8.8.2.7,8.8.2.8,
8.8.2.3, 8.8.2.4, 8.8.2.5,
8.8.2.9,8.8.2.1, 8.8.3.1, 8.8.3.2, 8.8.3.3, 8.8.3.4,8.8.3.8,8.8.3.9,8.8.3.1
0 8.8.3.5, 8.8.3.6, 8.8.3.7, 0,
8.8.4.1,8.8.4.2,8.8.4.3, 8.8.4.4, 8.8.4.5, 8.8.4.6,.8.4.10,8.8.5.1,8.8.5.2,
8.8.4.7, 8.8.4.8, 8.8.4.9, 8
8.8.5.3,8.8.5.4,8.8.5.5, 8.8.5.6, 8.8.5.7, 8.8.5.8,8.8.6.2,8.8.6.3,8.8.6.4,
8.8.5.9, 8.8.5.10, 8.8.6.1,
3 8.8.6.5,8.8.6.6,8.8.6.7, 8.8.6.8, 8.8.6.9, 8.8.6.10,8.8.7.4,8.8.7.5,8.8.7.6,
0 8.8.7.1, 8.8.7.2, 8.8.7.3,
8.8.7.7,8.8.7.8,8.8.7.9, 8.8.7.10, 8.8.8.1, 8.8.8.2,8.8.8.6,8.8.8.7,8.8.8.8,
8.8.8.3, 8.8.8.4, 8.8.8.5,
8.8.8.9,8.8.8.1, 8.8.9.1, 8.8.9.2, 8.8.9.3, 8.8.9.4,8.8.9.8,8.8.9.9,8.8.9.1
0 8.8.9.5, 8.8.9.6, 8.8.9.7, 0,
8.8.10.1, 2, 8.8.10.3, 8.8. I 0.4, 8. 8.10.5,8.8.10.9,
8.8.10.8.8. I 0.6, 8.8. I 0.7, 8.8.10.8, 8.8.10.
I
0,
8.9.1.1,8.9.1.2,8.9.1.3, 8.9.1.4, 8.9.1.5, 8.9.I.6,.9.1.10,8.9.2.1,8.9.2.2,
8.9.1.7, 8.9.1.8, 8.9.1.9, 8
3 8.9.2.3,8.9.2.4,8.9.2.5, 8.9.2.6, 8.9.2.7, 8.9.2.8,8.9.3.2,8.9.3.3,8.9.3.4,
5 8.9.2.9,'8.9.2.1 0, 8.9.3.1,
46
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
8.9; 3.5, 8.9.3.6, 8.9.3.7, 8.9.3.8, 8.9.3.9, 8.9.3.10, 8.9.4.1, 8.9.4.2,
8.9.4.3, 8.9.4.4, 8.9.4.5, 8.9.4.6,
8.9.4.7,8.9.4.8,8.9.4.9,8.9.4.10,8.9.5.1,8.9.5:2,8.9.5.3,8.9.5.4,8.9.5.5,8.9.5.
6,8.9.5.7,8.9.5.8,
8.9.5.9, 8.9.5.1 0, 8.9.6.1, 8.9.6.2, 8.9.6.3, 8.9.6.4, 8.9.6.5, 8.9.6.6,
8.9.6.7, 8.9.6.8, 8.9.6.9, 8.9.6.10,
8.9.7.1, 8.9.7.2, 8.9.7.3, 8.9.7.4, 8.9.7.5, 8.9.7.6, 8.9.7.7, 8.9.7.8,
8.9.7.9, 8.9.7.10, 8.9.8.1, 8.9.8.2,
S 8.9.8.3, 8.9.8.4, 8.9.8.5, 8.9.8.6, 8.9.8.7, 8.9.8.8, 8.9.8.9, 8.9.8.1.0,
8.9.9.1, 8.9.9.2, 8.9.9.3, 8.9.9.4,
8.9.9.5,8.9.9.6,8.9.9.7,8.9.9.8,8.9.9.9,8.9.9.10,8.9.10.1,8.9.10.2,8.9.10.3,8.9
.10.4,8.9.10.5,
8.9.10.6, 8.9.10.7, 8.9.10.8, 8.9.10.9, 8.9.10.10, 8.10.1.1, 8.10.1
.2,'8.10.1.3, 8.10.1.4, 8.10.1.5,
8.10.1.6,8.10.1.7,8.10.1.8,8.10.1.9,8.10.1.10,8.10.2.1,8.10.2.2,8.10.2.3,8.10.2
.4,8.10.2.5,
8.10.2.6,8.10.2.7,8.10.2.8,8.10.2.9,8.10.2.10,8.I0.3.1,8.10.3'~~.2,8.10.3.3,8.1
0.3.4,8.10.3.5,
8.10.3.6,8.10.3.7,8.I0.3.8,8.10.3.9,8.10.3.10,8.10.4.I,S.I0.4..2,8.10.4.3,8.10.
4.4,8.10.4.5,
8.I0.4.6,8.10.4.7,S.I0.4.8,8.10.4.9,8.10.4.10,8.10.5.1,8.10.5.2,8.10.5.3,8.10.5
.4,8.10.5.5,
8.10.5.6,8.10.5.7,8.10.5.8,8.10.5.9,8.10.5.10,8.10.6.1,8.10.6.2,8.10.6.3,8.10.6
.4,8.10.6.5,
8.10.6.6,8.10.6.7,8.10.6.8,8.10.6:9,8.10.6.10,8.10.7.I,8.10.T.2,8.10.7.3,8.10.7
.4,8.I0.7.5,
8.10.7.6,8.10.7.7,8.10.7.8,8.i0.7.9,8.10.7.10,8.10.8.1,8.10.8.2,8.10.8.3,8.10.8
.4,8.10.8.5,
8.10.8.6,8.10.8.7,8.10.8.8,8.10.8.9,8.10.8.10,8.10.9.1,8.10.9.2,8.10.9.3,8.10.9
.4,8.10.9.5,
8.10.9.6,8.10.9.7,8.10.9.8,8.10.9.9,8.I0.9.I0,8.10.10.1,8.10.10.2,8.10.10.3,8.1
0.10.4,
8.i0.10.5,8.10.10.6,8.10.I0.7,8.10.10.8,8.10.10.9,8.10.10.10,9.1.1.1,9.1.1.2,9.
1.1.3,9.1.1.4,
9.1.1.5, 9.1.1.6, 9.1.1.7, 9.1.1.8, 9.1.1.9, 9.1.1.10, 9.1.2.1, 9.1.2.2,
9.1.2.3, 9.1.2.4, 9.1.2.5, 9.1.2.6,
9.1.2.7, 9.1.2.8, 9.1.2.9, 9.1.2.10, 9.1.3.1, 9.1.3.2, 9.1.3.3, 9.1.3:4,
9.1.3.5, 9.1.3.6, 9.1.3.7, 9.1.3.8,
9.1.3.9,9.i.3.10,9.I.4.1,9.1.4.2,9.1.4.3,9.1.4.4,9.1.4.5,9.1.4.~6,9.1.4.7,9.1.4
.8,9.1.4.9,9.1.4.10,
9.1.S.I,9.1.5.2,9.1.5.3,9.1.5.4,9.I.5.5,9.1.5.6;9.1.5.7,9.1.5:8,9.1.5.9,9.1.5.1
0,9.I.6.1,9.1.6.2,
9.1.6.3, 9.1.b.4, 9.1.6.5, 9.1.6.6, 9.1.6.7, 9.1.6.8, 9.1.6.9, 9.1.6.10,
9.1.7.1, 9.1.7.2, 9.1.7.3, 9.1.7.4,
9.1.7.5,9.1.7.6,9.1.7.7,9.1.7.8,9.1.7.9,9.1.7.10,9.1.8.1,9.1.8.2,9.1.8.3,9.1.8.
4,9.1.8.5,9.1.8.6,
9.1.8.7, 9.1.8.8, 9.1.8.9, 9.1.8.10, 9.1.9.1, 9.1.9.2, 9.1.9.3, 9.1.9:4,
9.1.9.5, 9.1.9.6, 9.1.9.7, 9.1.9.8,
9.1.9.9, 9.1.9.10, 9.1.10.1, 9.1.10.2, 9.1.10.3, 9.1.10.4, 9. I.IO.S,
9.1.10.6, 9.1.10.7, 9.1.10.8,
9.1.10.9,9.1.10.10,9.2.1.I,9.2.1.2,9.2.1.3,9.2.1.4,9.2.1.5,9.2.1.6,9.2.1.7,9.2.
1.8,9.2.1.9,
9.2.1.10, 9.2.2.1, 9.2.2.2, 9.2.2.3, 9.2.2.4, 9.2.2.5, 9.2.2.6, 9.2.2.'1,
9.2.2.8, 9.2.2.9, 9.2.2.10, 9.2.3.1,
9.2.3.2, 9.2.3.3, 9.2.3.4, 9.2.3.5, 9.2.3.6, 9.2.3.7, 9.2.3.8, 9.2.3.9,
9.2.3.10, 9.2.4.1, 9.2.4.2, 9.2.4.3,
9.2.4.4, 9.2.4.5, 9.2.4.6, 9.2.4.7, 9.2.4.8, 9.2.4.9, 9.2.4.10, 9.2.5.:1,
9.2.5.2, 9.2.5.3, 9.2.5.4, 9.2.5.5,
9.2.5.6,9.2.5.7,9.2.5.8,9.2.5.9,9.2.5.10,9.2.6.1,9.2.6.2,9.2.6.3,9.2.6.4,9.2.6.
5,9.2.6.6,9.2.6.7,
9.2.6.8,9.2.6.9,9.2.6.10,9.2.7.1,9.2.7.2,9.2.7.3,9.2.7.4,9.2.7.'.>,9.2.7.6,9.2.
7.7,9.2.7.8,9.2.7.9,
9.2.7.I0,9.2.8.1,9.2.8.2,9.2.8.3,9.2.8.4,9.2.8.5;9.2.8.6,9.2.8.7,9.2.8.8,9.2.8.
9,9.2.8.10,9.2.9.1,
9.2.9.2,9.2.9.3,9.2.9.4,9.2.9.5,9.2.9.6,9.2.9.7,9.2.9.8,9.2.9.9,9.2.9.10,9.2.10
.1,9.2.10.2,
9.2.10.3,9.2.10.4,9.2.10.5,9.2.10.6,9.2.10.7,9.2.10.8,9.2.10.9,9.2.10.10,9.3.1.
1,9.3.1.2,
9.3.I.3,9.3.1.4,9.3.1.5,9.3.1.6,9.3.1.7,9.3.1.8,9.3.i.9,9.3.1.10,9.3.2.1,9.3.2.
2,9.3.2.3,9.3.2.4,
47
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
9.3; 2.5, 9.3.2.6, 9.3.2.7, 9:3.2.8, 9.3.2.9, 9.3.2.10, 9.3.3.1, 9.3.3 .2, 9.3
.3.3, 9.3.3.4, 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.I,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,
9.3.6.1,9.3.6.2,9.3.6.3,9.3.6.4,9.3.6.5,9.3.6.6,9.3.6.7,9.3.6.8,9.3.6.9,9.3.6.1
0,9.3.7.1,9.3.7.2,
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, 9.3.7.110,
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,
9.3.9.7,9.3.9.8,9.3.9.9,9.3.9.10,9.3.10.1,9.3.10.2,9.3.10.3,9.3.10.4,9.3.10.5,9
.3.10.6,9.3.10.7,
9.3.10.8,9.3.10.9,9.3.10.10,9.4.1.I,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.F~,
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, 9.4.5.1 0, 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.?, 9.4.8.8, 9.4.8.9, 9.4.8.10,
9.4.9.1,9.4.9.2,9.4.9.3,9.4.9.4,9.4.9.5,9.4.9.6,9.4.9.7,9.4.9.8,9.4.9.9,9.4.9.1
0,9.4.10.1,
9.4.i0.2,9.4.10.3,9.4.10.4,9.4.10.5,9.4.10.6,9.4.10.7,9.4.10.8,9.4.10.9,9.4.10.
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,
9.5.5.1 0, 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, 9.5.6.1 0, 9.5.7.1,
9.5.7.2, 9.5.7.3, 9.5.7.4, 9.5.7.5, 9.5.7.6, 9.5.7.7, 9.5.7.8, 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, ~>.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,
9.6.2.10,9.6.3.1,9.6.3.2,9.6.3.3,9.6.3.4,9.6.3.5,9.6.3.6,9.6.3.7,9.6.3.8,9.6.3.
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,
3 0 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, 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,
9.6.9.8, 9.6.9.9, 9.6.9.10,
9.6.10.1,9.6.10.2,9.6.10.3,9.6.10.4,9.6.10.5,9.6.I0.6,9.6.10.7,9.6.10.8,9.6.10.
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, 9.7.1.6, 9.7.1.7, 9.7.1.8,
9.7.1.9, 9.7.1:10, 9.7.2.1, 9.7.2.2,
9.7.2.3,9.7.2.4,9.7.2.5,9.7.2.6,9.7.2.7,9.7.2.8,9.7.2.9,9.7.2.1n~,9.7.3.1,9.7.3
.2,9.7.3.3,9.7.3.4,
48
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
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, 9.7.4.1 0, 9.7:5.1, 9.7.5.2, 9.7.5.3, 9.7.5:4,
9.7.5.5, 9.7.5.6, 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,
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, 9.7.7.1 0, 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, 9.7.8.1~U,
9.7.9.1, 9.?.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, 9.7.1Ø2,
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.?.10.10,9.8.I.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, 9.8.5.7, 9.8.5.8, 9.8.5.9, 9.8.5.10,
9.8.6.1, 9.8.6.2, 9.8.6.3, 9.8.6.4,
9.8.6.5,9.8.6.6,9.8.6.7,9.8.6.8,9.8.6.9,9.8.6.1x,9.8.7.1,9.8.7.:2,9.8.7.3,9.8.?
.4,9.8.7.5,9.8.7.6,
9.8.7.7, 9.8.7.8, 9.8.7.9, 9.8.7.10, 9.8.8.1, 9.8.8.2, 9.8.8.3, 9.8.8.4,
9.8.8.5, 9.8.8.6, 9.8.8.7, 9.8.8.8,
9.8.8.9, 9.8.8.10, 9.8.9.1, 9.8.9.2, 9.8.9.3, 9.8.9.4, 9.8.9.5, 9.8.9.:1,
9.8.9.7, 9.8.9.8, 9.8.9.9, 9.8.9.10,
9.8.10.1, 9.8.10.2, 9.8.10.3, 9.8.10.4, 9.8./0.5, 9.8.10.6, 9.8.10.7,
9.8.10.8, 9.8.10.9, 9.8.10.10,
9.9.1.1, 9.9.1.2, 9.9.1.3, 9.9.1.4, 9.9.I.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, 9.9.2.2,
9.9.2.3, 9.9.2.4, 9.9.2.5, 9.9.2.6, 9.9.2.7, 9.9.2.8, 9.9.2.9, 9.9.2.10,
9.9.3.1, 9.9.3.2, 9.9.3.3, 9.9.3.4,
9.9.3.5, 9.9.3.6, 9.9.3.7, 9.9.3.8, 9.9.3.9, 9.9.3.10, 9.9.4.1, 9.9.4.2,
9.9.4.3, 9.9.4.4, 9.9.4.5, 9.9.4.6,
9.9.4.7, 9.9.4.8, 9.9.4.9, 9.9.4.2 0, 9.9.5.1, 9.9.5.2, 9.9.5.3, 9.9.5.4,
9.9.5.5, 9.9.5.6, 9.9.5.7, 9.9.5.8,
9.9.5.9,9.9.5.10,9.9.6.1,9.9.6.2,9.9.6.3,9.9.6.4,9.9.6.5,9.9.6.fi,9.9.6.7,9.9.6
.8,9.9.6.9,9.9.6.10,
9.9.7.1, 9.9.7.2, 9.9.7.3, 9.9.7.4, 9.9.7.5, 9.9.7.6, 9.9.7.7, 9.9.7.8,
9.9.7.9, 9.9.7.10, 9.9.8.1, 9.9.8.2,
9.9.8.3, 9.9.8.4, 9.9.8.5, 9.9.8.6, 9.9.8.7, 9.9.8.8, 9.9.8.9, 9.9.8.10,
9.9.9.1, 9.9.9.2, 9.9.9.3, 9.9.9.4,
9.9.9.5,9.9.9.6,9.9.9.7,9.9.9.8,9.9.9.9,9.9.9.I0,9.9.10.1,9.9.I0.2,9.9.10.3,9.9
.10.4,9.9.10.5,
9.9.10.6,9.9.10.7,9.9.10.8,9.9.I0.9,9.9.10.10,9.10.1.1,9.10.1.2,9.10.1.3,9.10.1
.4,9.10.1.5,
9.10.1.6, 9.10.1.7, 9.10.1.8, 9.I0.1.9, 9.10.1.10, 9.10.2.1, 9.10.2.2,
9.10.2.3, 9.10.2.4, 9.10.2.5,
9.10.2.6,9.10.2.7,9.I0.2.8,9.I0.2.9,9.10.2.I0,9.I0.3.1,9.10.3.2,9.10.3.3,9.10.3
.4,9./0.3.5,
9.I0.3.6,9.10.3.7,9.I0.3.8,9.10.3.9,9.10.3.10,9.10.4.1,9.10.4.2,9./0.4.3,9.10.4
.4,9./0.4.5,
9.10.4.6,9.10.4.7,9.10.4.8,9.10.4.9,9.20.4.10,9.10.5.1,9.10.5.:2,9.10.5.3,9.10.
5.4,9.10.5.5,
9.10.5.6, 9. I 0.5.7, 9.10.5.8, 9.10.5 .9, 9. I 0.5.10, 9. 2 0.6. I , 9. I
0.6.:2, 9.10.6.3, 9. I 0.6.4, 9. I 0.6.5,
9.10.6.6,9.10.6.7,9.I0.6.8,9.10.6.9,9.I0.6.10,9.10.7.I,9.10.7.:2,9.10.7.3,9.10.
7.4,9.10.7.5,
9.10.7.6,9.10.7.7,9.10.7.8,9.10.7.9,9.10.7.10,9.10.8.1,9.10.8.'.2,9.10.8.3,9./0
.8.4,9./0.8.5,
9.10.8.6, 9.10.8.7, 9.10.8.8, 9.10.8.9, 9.10.8.10, 9.10.9.1, 9.10.9.:2,
9.10.9.3, 9.10.9.4, 9.10.9.5,
9.10.9.6, 9.10.9.7, 9.10.9.8, 9.10.9.9, 9.10.9.10, 9.10.10.1, 9.10.10.2,
9.10.10.3, 9.10.10.4,
9.10.10.5, 9.10.10.6, 9.10.10.7, 9.10.10.8, 9.10.10.9, 9.10.10.10, 10.1.1.1,
10.1.1.2, 10.1.1.3,
i0.1.1.4,10.1.1.5,10.1.I.6,10.1.1.7,10.1.I.8,10.1.1.9,10.1.1.IO,IO.I.2.I,I0.1.2
.2,10.1.2.3,
49
CA 02352387 2001-05-25
WO 00/32176 PCT1US99/28080
10.1.2.4, 10.1.2.5, / 0.1.2.6, 10.1.2.7, 10.1.2.8, 10.1.2.9, 10.1.2.10,
10.1.3.1, 10.1.3.2, 10.1.3.3, _
10.1.3.4, 10.1.3.5, 10.1.3.6, 10.1.3.7, 10.1.3.8, 10.1.3.9, 10.1.3.10,
10.1.4.1, 10.1.4.2, 10. /.4.3,
I0.1.4.4,10.1.4.5,10.1.4.6,10.1.4.7,10.1.4.8,10.1.4.9,10.1.4.10,10.1.5.1,10.1.5
.2,10.1.5.3,
10.1.5.4,10.1.5.5,I0.1.5.6,10.1.5.7,10.1.5.8,10.1.5.9,10.1.5.I0,10.1.6.1,10.1.6
.2,10.I.6.3,
10.I.6.4,I0.1.6.5,10.1.6.6,10.1.6.7,10.1.6.8,10.1.6.9,10.1.6.IO,l0.I.7.1,10.1.7
.2,10.1.7.3,
10.1.7.4, 10.1.7.5, 10.1.7.6, 10.1.?.7, 10.1.7.8, 10.1.7.9, 10.1.7.,10,
10.1.8.1, 10.1.8.2, 10.1.8.3,
10.1.8.4, 10. I .8.5, i 0.1.8.6, 10.1.8.7, 10.1.8.8, 10.1.8.9, 10.1.8.,10;
10.1.9.1, 10.1.9.2, I 0.1.9.3,
10.1.9.4, 10.1.9.5, 10.1.9.6, 10.1.9.7, i 0. I .9.8, I 0. I .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.I0.7,10.1.i0.8,10.1.10.9.,10.1.10.10,10.2.1.
1,10.2.1.2,
IO
10.2.1.3,10.2.1.4,10.2.I.5,10.2.1.6,10.2.1.7,10.2.1.8,10.2.1.9,10.2.1.10,10.2.2
.1,10.2.2.2,
10.2.2.3, 10.2.2.4, 10.2.2.5, 10.2.2.6, 10.2.2.7, 10.2.2.8, 10.2.2.9,
10.2.2.10, 10.2.3.1, 10.2.3.2,
10.2.3.3,10.2.3.4,10.2.3.5,10.2.3.6,10.2.3.7,10.2.3.8,10.2.3.9,10.2.3.10,10.2.4
.1,10.2.4.2,
10.2.4.3,10.2.4.4,10.2.4.5,10.2.4.6,I0.2.4.7,I0.2.4.8,10.2.4.9,10.2.4.10,10.2.5
.1,10.2.5.2,
10.2.5.3,10.2.5.4,10.2.S.S,I0.2.5.6,10.2.5.7,I0.2.5.8,10.2.5.9,10.2.5.10,10.2.6
.1,10.2.6.2,
I5
10.2.6.3,10.2.6.4,10.2.6.5,10.2.6.6,i0.2.6.7,10.2.6.8,10.2.6.9,10.2.6.10,10.2.7
.1,10.2.7.2,
10.2.7.3,10.2.7.4,10.2.7.5,I0.2.7.6,10.2.7.7,10.2.7.8,10.2.7.9,10.2.7.10,10.2.8
.1,30.2.8.2,
10.2.8.3,10.2.8.4,10.2.8.5,10.2.8.6,10.2.8.7,F0.2.8.8,10.2.8.9,10.2.8.10,10.2.9
.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,
10.2.10.2,
I0.2.I0.3,10.2.10.4,10.2.10.5,10.2.
10.6,10.2.10.7,10.2.10.8,10.2.10.9,10.2.10.10,I0.3.1.1,
20
I0.3.1.2,I0.3.1.3,10.3.1.4,10.3.1.5,10.3.1.6,10.3.1.7,I0.3.1.8,10.3.1.9,10.3.1.
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,I0.3.3.1,
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,
10.3.5.2,10.3.5.3,10.3.5.4,10.3.5.5,10.3.5.6,10.3.5.7,10.3.5.8,10.3.5.9,
10.3.5.10,
10.3.6.1,
25
10.3.6.2,10.3.6.3,I0.3.6.4,10.3.6.5,10.3.6.6,10.3.6.7,I0.3.6.8,10.3.6.9,10.3.6.
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,I0.3.7.8,10.3.7.9,10.3.7.
10,10.3.8.1,
10.3.8.2,10.3.8.3,10.3.8.4,10.3.8.5,i0.3.8.6,10.3.8.7,10.3.8.8,10.3.8.9,10.3.8.
10,10.3.9.1,
10.3.9.2,10.3.9.3,i0.3.9.4,10.3.9.5,I0.3.9.6,10.3.9.7,10.3.9.l3,10.3.9.9,10.3.9
.10,10.3.10.1,
10.3.10.2,I0.3.10.3,10.3.10.4,10.3.10.5,10.3
.10.6,10.3.10.7,10.3.10.8,10.3.10.9,10.3.10.10,
30
10.4.1.1,10.4.1.2,10.4.1.3,10.4.1.4,10.4.I.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,I0.4.2.7,10.4.2.8,I0.4.2.
9,10.4.2.10,
i0.4.3.1,10.4.3.2,10.4.3.3,10.4.3.4,10.4.3.5,10.4.3.6,10.4.3.7,10.4.3.8,/0:4.3.
9,10.4.3.10,
10.4.4.1,i0.4.4.2,10.4.4.3,I0.4.4.4,10.4.4.5,10.4.4.6,10.4.4.7,10.4.4.8,10.4.4.
9,10.4.4.10,
10.4.S.i,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,
35
10.4.6.1,10.4.6.2,10.4.6.3,10.4.6.4,10.4.6.5,I0.4.6.6,10.4.6.7,10.4.6.8,10.4.6.
9,10.4.6.10,
' CA 02352387 2001-05-25
WO 00/32176 PCTlUS99IZ8080
10.4.7.1,10.4.7.2,10.4.7.3,10.4.7.4,10.4.7.5,I0.4.7.6,10.4.7.1',10.4.7.8,10.4.7
.9,10.4.7.10,
10.4.8.1,I0.4.8.2,10.4.8.3,10.4.8.4,10.4.8.5,10.4.8.6,10.4:8.7,10.4.8.8,10.4.8.
9,10.4.8.10,
10.4.9.1,10.4.9.2,10.4.9.3,10.4.9.4,10.4.9:5,10.4.9.6,10.4.9.~',10.4.9.8,10.4.9
.9,I0.4.9.10,
10.4.10.1,10.4.10.2,10.4.I0.3,10.4.10.4,10.4.10.5,10.4.I0.6,10.4.10.7,10.4.10.8
,I0.4.I0.9,
10.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4,10.5.1.5, 10.5.1.6,
10.5.1.7, 10.5.1.8, 10.5.1.9,
10.5.1.10,10.5.2.1,10.5.2.2,10.5.2.3,10.5.2.4,10.5.2.5,10.5.2.6,10.5.2.7,10.5.2
.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,
x10.5.3.7, 10.5.3.8, 10.5.3.9,
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, I 0.5.5.3, 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, I0.5.6.3, 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,I0.5.7.2,10.5.7.3,10.5.7.4,10.5.7.5,10.5.7.6,10.5.7.7,10.5.7
.8,10.5.7.9,
10.5.7.10,10.5.8.I,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,
10.5.8.10,i0.5.9.1,10.5.9.2,10.5.9.3,10.5.9.4,10.5.9.5,10.5.9.6,10.5.9.7,10.5.9
.8,10.5.9.9,
10.5.9.10,10.S.I0.I,10.5.10.2,10.5.10.3,10.5.I0.4,10.5.10.5,: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,I0.6.2.4,10.6.2.5,10.6.2.6,10.6.2
.7,10.6.2.8,
10.6.2.9, 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.I0,10.6.4.1,10.6.4.2,10.6.4.3,10.6.4.4,10.6.4.5,10.6.4.6,10.6.4
.7,10.6.4.8,
10.6.4.9,10.6.4.10,10.6.S.I,I0.6.5.2,10.6.5.3,10.6.5.4,10.6.5.5,10.6.5.6,10.6.5
.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, 10.6.6.8,
10.6.6.9,10.6.6.10,10.6.7.1,10.6.7.2,10.6.7.3,10.6.7.4,10.6.7.5,10.6.7.6,10.6.7
.7,10.6.7.8,
I 0.6.7.9, 10.6.7. I 0, 10.6.8. i , 10.6. 8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5,
10.6.8.6, 10.6.8.7, 10.6. 8.8,
10.6.8.9,10.6.8.10,10.6.9.1,10.6.9.2,10.6.9.3,10.6.9.4,10.6.9.5,10.6.9.6,10.6.9
.7,10.6.9.8,
10.6.9.9,10.6.9.10,I0.6.10.1,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, I0.7.2.2, 10.7.2.3, 10.7.2:4,
10.7.2.5, 10.7.2.6, 10.7.2.7,
10.7.2.8, 10.7.2.9, 10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4,
10.7.3.5, 10.7.3.6, 10.7.3.7,
10.7.3.8,10.7.3.9,10.7.3.I0,10.7.4.1,10.7.4.2,10.7.4.3,I0.7.4.4,10.7.4.5,10.7.4
.6,10.7.4.7,
10.7.4.8,10.7.4.9,10.7.4.10,10.7.5.1,10.7.5.2,10.7.5.3,10.7.5.4,10.7.5.5,10.7.5
.6,10.7.5.7,
10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4,
10.7.6.5, 10.7.6.6, 10.7.6.7,
10.7.6.8,10.7.6.9,10.7.6.10,10.7.7.i,I0.7.7.2,10.7.7.3,10.7.7.4,10.7.7.5,10.7.7
.6,10.7.7.7,
10.7.7.8,10.7.7.9,10.7.7.I0,10.7.8.1,10.7.8.2,10.7.8.3,10.7.8.4,10.7.8.5,10.7.8
.6,10.7.8.7,
10.7.8.8,10.7.8.9,10.7.8.I0,10.7.9.1,10.7.9.2,10.7.9.3,10.7.9.4,14.7.9.5,10.7.9
.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.'1.10.4,
10.7.10.5, 10.7.10.6,
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.I.3,10.8.1.4,10
.8.1.5,10.8.1.6,
S1
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
10.8.I.7,10.8.1.8,10.8.1.9,10.8.1.10,10.8.2.1,10.8.2.2,10.8.2..3,10.8.2.4,10.8.
2.5,10.8.2.6, _
10.8.2.7,10.8.2.8,10.8.2.9,10.8.2.10,10.8.3.1,10.8.3.2,10.8.3:3,10.8.3.4,10.8.3
.8,10.8.3.6,
10.8.3.7,10.8.3.8,10.8.3.9,10.8.3.10,I0.8.4.I,10.8.4.2,10.8.4..3,10.8.4.4,10.8.
4.5,10.8.4.6,
10.8.4.7,10.8.4.8,10.8.4.9,10.8.4.10,10.8.5.1,10.8.5.2,10.8.5.3,10.8.5.4,10.8.8
.8,10.8.5.6,
S 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.8.10, 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,
10.8.7.7,10.8.7.8,10.8.7.9,10.8.7.10,10.8.8.1,10.8.8.2,I0.8.8.3,10.8.8.4,10.8.8
.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, 10.8.9.10, 10.8.10.1, 10.8.10.2, 10.8.10.3,
10.8.10.4, 10. 8.10.5,
I0.8.10.6,10.8.10.7,10.8.10.8,10.8.10.9,10.8.10.10,10.9.1.1,10.9.1.2,10.9.1.3,1
0.9.1.4,
10.9.1.5,10.9.1.6,10.9.1.7,10.9.1.8,10.9.1.9,I0.9.1.10,10.9.2',..1,10.9.2.2,10.
9.2.3,10.9.2.4,
10.9.2.5,10.9.2.6,10.9.2.7,10.9.2.8,10.9.2.9,10.9.2.10,10.9.3.1,10.9.3.2,10.9.3
.3,10.9.3.4,
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,i0.9.S.2,10.9.5
.3,10.9.5.4,
1S
10.9.S.S,10.9.5.6,10.9.5.7,10.9.5.8,10.9.5.9,i0.9.S.10,10.9.6..1,10.9.6.2,10.9.
6.3,10.9.6.4,
10.9.6.5,10.9.6.6,10.9.6.7,10.9.6.8,10.9.6.9,10.9.6.10,10.9.7.1,10.9.7.2,10.9.7
.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, I0.9.9~.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.?, 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. 10.1.8, 10.10.1.6, 10.I 0.1.7, J 0.10.1.8, 10.10.1.9, I
0.10.1.10, 10.10.2.1, 10.10.2.2,
10.10.2.3,10.10.2.4,10:10.2.5,10.I0.2.6,10.10.2.7,I0.10.2.8,10.10.2.9,10.10.2.1
0,10.10.3.1,
10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5, 10.10.3.6, 10.10.3.7, I0.10.3.8,
10.10.3.9, 10.10.3.10,
10.10.4.I,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,
2S 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.I0.S.3, 10.10.5.4, 10.10.8.8,
10.10.5.6, 10.10.5.7, 10.10.5.8,
10.10.5.9,10.10.5.i0,10.10.6.1,10.10.6.2,10.10.6.3,I0.10.6.4,10.10.6.5,10.10.6.
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,I0.10.7.8,10.10.7.9,10.10.7.I0,10.10.8.1,10.10.8.2,,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. I, 10. i
0.9.2, 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,
10.10.10.2,
10.10.10.3,10.10.10.4.10.10.10.5.10.10.10.6,10.I0.10.7,10.10.10.810.10109101010
10
S2
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
Additional exemplary formula 1 compound groups include the following groups as
_
disclosed below.
Group 2. Group 2 compounds are as named in Table 13, 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
5, which is the same as the formula 4 steroid nucleus, except that the 5-b
double bond is absent and
hydrogen is present at the 5-position in the a-configuration
R2
Thus, the group 2 compound named 1.2.1.1 has the structure
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 th;3t the 5-6
double bond is absent and
hydrogen is present at the 5-position in the ~i-configuration
R2
, ~ 6.
Thus, the group 3 compound named 1.2.1.1 has the structure
53
i,,
CA 02352387 2001-05-25
WO 00132176 PCT/US99/28080 . .
H
group 3, compound 1.2.1.1.
Group 4. Group 4 compounds are as named in Tabie B, i.e., R2, Ri 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 -
CH20H
R2
7.
Thus, the group 4 compound named I .2.1.1 has the structure
group 4, compound 1.2.1.1.
i0 Group 5. Gxoup 5 compounds are as named in Table B, i.e., R2, RIA, 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 S-6
double bond is absent and
hydrogen is present at the 5-position in the a-configuration and Q3 is -CH20H
R2
54
8.
i:
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080 . .
Thus, the group 5 compound named 1.2.1.1 has the structure .
Group 6. Group 6 compounds are as named in groups 1-S, except that Q6 in
formulas 4-8
is -CH20H instead of methyl. In group 6, there are 5 subgroups of group 6
compounds. The first
subgroup, subgroup 6-1, has the same steroid nucleus with the ;substituents as
defined for group 1
compounds while the second, subgroup 6-2, has the same steroid nucleus with
the substitt~ents as
defined far group 2 compounds. Subgroups 6-3 through 6-5 have the same steroid
nucleus with the
substituents as defined for group 3 through 5 respectively. Thus, for example,
the subgroup 6-1
compound named 1.2.1.1 has the structure
and the subgroup 6-2 compound named 1.2.1.1 has the structure
Group 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 oc-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.
SS
i.,,,
CA 02352387 2001-05-25
WO OOI32176 PC'T/US99/28080
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
subgroups, wherein the compounds are named essentially as described for group
6 compounds,
except that the X group is in the a-conf guration.
Group 9. Group 9 compounds are as named in groups 1-5, except that the R2
moiety in
formulas 4-8 is in the a-configuration instead of in the (3-configuration.
Group 9 comprises 5
- subgroups, wherein the compounds are named essentially as described for
group 6 compounds,
except that the R2 group is in the a-configuration.
Group 10. Group I 0 compounds are as named in groyps 1-9, except that R2
moieties 1
through 10 in Table A are replaced with the following moieties..
1 -S-C(O)-CH3
2 _S_C(O)_CH2_C6H5
3 -O-S(O)-O-CH3
~ -O-S(O)-O-CH2-C6H5
I S 5 -O-S(O)(O)-O-CH3
6 -O-S(O)(O)-O-CH2-C6Hg
7 -O-C(O)-NH-CH3
8 -O-C(O)-NH-C5H5
9 -O-C(S)-CH3
10 -O-C(S)-CH2-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 R2
moieties or groups
listed replace those in Table A above. The subgroup I O-1 compound named
1.2.1.1 has the
structure
ru_ O
H3C S
O
the subgroup 10-2 compound named 1.2.1.1 has the structure
56
' ° - ' CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28U80
-
the subgroup 10-6-I 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 strucvture
Group 11. Group 11 compounds are as named in groups 1-9, except that R2
moieties 1
through 10 in Table A are replaced with the following moieties.
I -S-C(O~CH2CH2-O-CH2CHg
2 -S-C(O)-CH2-C6H40CH3
3 -O-S(O}-O-CH2CH2-O-CH2CH3
4 -O-S(O)-O-CH2-C6H40CH3
5 -O-S(O)(O)-O-CH2CH2-O-CH2CH3
6 -O-S(O)(O)-O-CH2-C6H40CHg
7 -O-C(O)-NH-CH2CH2-O-CH2CH3
8 -O-C(O}-NH-C6H40CH3 '
9 -O-C(S)-CH2CH2-O-CH2CH3
57
i,,
° ~ ~ CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28088
-O-C(S)-CH2-C6H40CH3
Group 12. Group 12 compounds are as 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-CH2C(O)OH
5 2 -S-C(O)-CH2-C6H4F
3 -O-S(O)-O-CH2CH2-O-CH2C(O)OH
4 -O-S(O)-O-CH2-C6H4F
5 -O-S(O)(O)-O-CH2CH2-O-CH2C(O)OH
6 -O-S(O)(O)-O-CH2-C6H4F
10 7 -O-C(O)-NH-CH2CH2-O-CH2C(O)OH
8 -O-C(O)-NH-C6H4F
9 -O-C(S)-CH2CH2-O-CH2C(O)OH
10 -O-C(S)-CH2-C6H4F
Graup I3. Group 13 compounds are as named in groups 1-9, except that R2
moieties 1
through 10 in Tabie A are replaced with the following moieties.
1 -S-C(O)-CH2CH2-O-CH2CH20H
2 -S-C(O)-CH2-C6H4CH3
3 -O-S(O)-O-CH2CH2-O-CH2CH20H
4 -O-S(O)-O-CH2-C6H4CH3
5 -O-S(O)(O}-O-CH2CH2-O-CH2CH20H
6 -O-S(O)(O}-O-CH2-C~H4CH3
7 -O-C(O}-NH-CH2CH2-O-CH2CH20H
8 -O-C(O)-NH-C6H4CH3
9 -O-C(S)-CH2CH2-O-CH2CH20H
10 -O-C(S)-CH2-C6H4CH3
Group 14. Group 14 compounds are as 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-CH2CH20RPR
2 -S-C(O)-CH2-CbH40RPR
3 -O-S(O)-O-CH2CH2-O-CH2CH20RpR
4 -O-S(O)-O-CH2-C6H40RPR
5 -O-S(O)(O)-O-CH2CH2-O-CH2CH20RPR
6 -O-S(O)(O}-O-CH2-C6H40RPR
7 -O-C(O}-NH-CH2CH2-O-CH2CH20RPR
8 -O-C(O}-NH-C6H40RPR
58
i
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
9 -O-C(S)-CH2CH2-O-CH2CH20RPR
10~ -O-C(S)-CH2-C6H40RPR .
Group 15. Group 1 S compounds are as named in groups I-9, except that R2
moieties 1
through IO in Table A are replaced with the following moieties.
S 1 -S-C(O)-CH2CH2-O-CH2CH2NHRPR
2 -S-C(O}-CH2-C6H3{ORPR)2
3 -0-S(O)-O-CH2CH2-O-CH2CH2NHRpR
4 -O-S(O)-O-CH2-C6H3(ORPR}2
S -O-S(O)(O)-O-CH2CH2-O-CH2CH2NHRPR
6 -O-S(O)(O)-O-CH2-C6H3(ORPR)2
7 -O-C(O}-NH-CH2CH2-O-CH2CH2NHRPR
8 -O-C(O}-NH-C6H3(ORPR)2
9 -O-C(S}-CH2CH2-O-CH2CH2NHRPR
10 -O-C(S)-CH2-C6H3(ORpR)2
1 S Group 16. Group 16 compounds are as named in groups 1-9, except that R2
moieties 1
through 10 in Table are replaced with the following moieties.
1 -S-C(O)-(CH2)0-6-CH3
2 -S-C(O)-CH2-C6HS
3 -O-S(O~O-(CH2)0-6-CH3
4 -O-S(O)-O-CH2-C6HS
S -O-S(O){O)-O-(CH2)0-6-CH3
6 -O-S(O){O)-O-CH2-C6HS
7 -O-C(O)-NH-(CH2)0-6-CH3
8 -O-C(O)-NH-(CH2)0-6-C6HS
2S 9 -O-C(S)-(CH2)0-6-CH3
10 -O-C{S)-CH2-C6H5
Group 17. Group I7 compounds are as 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-CH2CH2}1-SO-H
2 -S-C(O)-CH2-C6H40CH3
3 -O-S(O)-O-CH2CH2-(O-CH2CH2)1-50-H
4 -O-S(O)-O-CH2-C6H40CH3
5 -O-S(O)(O)-O-CH2CH2-(O-CH2CH2)1-SO-H
6 -O-S(O)(O)-O-CH2-C6H40CH3
3S 7 -O-C(O)-NH-CH2CH2-(O-CH2CH2)1-SO-H
S9
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080 .
8 -O-C(O)-NH-C6H40CH3
9 -O-C{S)-CHZCH2-(O-CH2CH2)I-SO-H
-O-C(S)-CH2-C6H40CH3
Group 18. Group 18 compounds are as named in groups 1-9, except that R2
moieties 1
S through 10 in Table A are replaced with the following moieties.
I -O-C(O)-CH2CH2-(O-CH2CH2)1_SO-H
- 2 -O-C(O)-CH2-C6H40CH3
3 -O-C(O)-(CH2)0-6-CH3
4 -O-C(O)-CH2-C6H4N02
10 S -O-C(O}-CH2CH2-(O-CH2CH2)I-SO-H
6 -O-C(O)-CH2-C6HS
7 -O-C(O)-CH2CH2-O-CH2CH3
8 -O-C(O)-C6H5
9 -O-C(O)-CH2CH2-S-CH2CH3
1 S 10 -O-C(O)-CH2-C6H4F
Group 19. Group 19 compounds are as named in groups 1-9, except that R2
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -O-CH2CH2-(O-CH2CH2)1-SO-H
2 -O-CH2-C6H40CH3
3 -O-(CH2)0-6-CH3
4 -O-CH2-C6H4NO2
S -O-CH2CH2-(O-CH2CH2)I-SO-H
6 -O-CH2-C6HS
7 -O-CH2CH2-O-CH2CH3
2S 8 -O-C6HS
9 -O-CH2CH2-S-CH2CH3
10 -O-CH2-C6H4F
Group 20. Group 20 compounds are as named in groups 1-9, except that R2
moieties 1
through 10 in Table A are replaced with the following moieties.
I -C(O)-O-CH2CH2-(O-CH2CH2)1-SO-H
2 -C{O)-O-CH2-C6H40CH3
3 -C(O)-O-{CH2)0-6-CH3
4 -C(O)-O-CH2-C6H4N02
S -C(O}-O-CH2CH2-(O-CH2CH2)1-SO-H
6 -C(Or0-CH2-C6HS
CA 02352387 2001-05-25
WO 00/32176 PCT/US99128080
7 -C(O)-O-CH2CH2-O-CH2CH3
8 -C(O~O-C6H5
9 -C(O)-O-CH2CH2-S-CH2CH3
-C(O)-O-CH2-CgH4F
5 Group 21. Group 21 compounds are as named in groups 1-9, except that R2
moieties 1
through 10 in Table A are replaced with the following moieties.
1 -C(O)-O-G 12
2 -O-C(O)-G12
3 -C(O)-S-G 12
10 4 -S-C(O)-G 12
5 -C(S)-O-G12
6 -O-C(S)-G 12
7 -O-C(O)-NH-G 12
8 -NH-C(O)-O-G12
9 -C(O)-O-CH2-G 12
10 -O-C(O)-CH2-G 12
Thus, the group 21-1 compound named 1.2.1.1 has the structure
G'i 2
while the group 21-2 compound named 1.2.1.1 has the structure;
G12
H
the group 2I-3 compound named 1.2.1.1 has the structure
61
i,
' CA 02352387 2001-05-25
WO 00/32176 PCT/US99128080 . .
G12
the group 21-4 compound named 1.2.1.1 has the structure
G12~
the group 21-6-1 compound named 1.2.1.1 has the structure
G12
the group 21-6-2 compound named 1.2.1.1 has the structure
G12
H
and the group 21-6-3 compound named 1.2.1.1 has the structure
62
CA 02352387 2001-05-25
wo oor~a i ~6 rc~rms99nsoso
~N.,n~+
G12~
H
G12 in Group 21 is an organic moiety comprising 1, 2, =l, 4, 5, 6, 7, 8, 9 I0,
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 G 1_ 12 alkyl, C2_ 12 alkenyl, C2_ 12 alkynyl, aryl, a C2_g
heterocycle or a substituted
derivative of any of these comprising l, 2, 3, 4 or more substitue;nts,
wherein each substituent is
independently chosen and is selected from -O-, -S-, -NRPR- (inc;luding -NH-), -
C(O)-, =O, =S, -
N(RPR)2 (including -NH2), -C(O)ORPR (including -C(O)OH), -OC(O)RPR (including -
O-C(O)-
H}, -ORPR (including -OH), -SRPR (including -SH), -N02, -CrT, -NHC(O)-, -
C{O)NH-, -OC{O)-,
-C(O}O-, -O-A8, -S-A8, -C(O)-A8, -OC(O)-A8, -C(O)O-A8, =rd-, -N=, =N-OH, -
OP03(RPRn,
OS03H2 and 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
C1_g alkyl, C2_g
alkenyl, C2_g alkynyl, C 1 _4 alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or
C 1 _4 alkyl-C2_9
IS heterocycle. G12 moieties include -CH3, -C2H5, -C3H~, -C4Hy, -C6H13, -CH2-
C6H5, -C2HQ-
C6H$, -C3H6-C6H5, -C6H5, -CH2-heterocycle, -CH2-CH2-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, -OC4H~, -N02, -NH2, -COOH, or -NH-C(O)-
moieties.
Other embodiments include the use of any formula ~l coimpound 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
for any of those applications wherein (i) R2 is in the a-configuration, (ii)
Q4 is -CH(halogen)-, (iii)
X is in the a-configuration and the -H at the i 7-position is in thc; (3-conf
guration, (iv) Y is in the
~i-configuration and the -H at the 16-position is in the a-configuration or
(v) R1A is in the a-
configuration and the -H at the 7-position is in the /3-configuration.
Embodiments also include formula I compounds (e.g., ~:ormula 4 compounds)
wherein Rø
is optionally substituted C1_g alkyl, optionally substituted C2-g alkenyl,
optionally substituted C2_
8 alkynyl, optionally substituted aryl, optionally substituted hete;rocycle,
optionally substituted C1_
g alkyl-aryl, optionally substituted C1_g alkyl-heterocycle or optionally
substituted -CH2-C1_g
organic moiety (where the organic moiety is as described for esters), wherein
any of the foregoing
63
CA 02352387 2001-05-25
WO 00132176 PCTIUS99/28080
are independently substitued 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-), -0, NOH, -N02, -CN, -F, -CI, -Br, -I, -OH, -SH, or -NH2.
Such R4
moieties include -CH2-C 1_6 optionally substituted alkyl, -CH2-C2_6 optionally
substituted
alkenyl, -CH2-C 1-6 -optionally substituted aryl and -CH2-C2_9 optionally
substituted heterocycle.
Additional theraueutic embodiments. In accordance with a preferred aspect of
the present
invention, one or more compound of the present invention is administered to a
patient who is
suffering from AIDS in order to treat cryptosporidiosis in the patient and one
or more additional
compound are administered to the patient, such additional compound being a
compound which is
used for treatment of AIDS. Such compounds for treatment of AIDS are well
known to those of
skill in the art, and it is expected that additional compounds will be
developed for treatment of
AIDS. For example, protease inhibitors which are used in the trt;atment of
AIDS include Invirase
(saquinavir, RO-31-8959), made by Hoffmann-La Roche, Norvir (ritonavir,
ABT538), made by
Abbott, Crixivan (indinavir, MK-639), made by Merck, Viracept (nelfinavir, AG-
1 343), made by
Agouron, VX-478 I41 W94, made by Glaxo-Weilcome-Vertex, ICNI-272 (kynostatin),
made by
Nikko Kyoto Pharmaceutical and National Cancer Institute, U1(13373, made by
Upjohn, CGP-
53437, made by Ciba-Geigy, Hoe/Bay-793, made by Hoechst-Bayer, and SR-41476,
made by
5anofi. In addition, reverse transcriptase inhibitors include AZT (Retrovir,
zidovudine); ddl
(Videx, didanosine); ddC (Hivid, zaicitabine); d4T (Zerit, stavudine); and 3TC
(Epivir,
Lamivudine). Also, HI'A23 has reportedly been found to inhibit HIV
replication.
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 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 compound for the treatment of AIDS can be administered together, or
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. All such
variations in administration of the combination therapy are encompassed within
the scope of the
invention.
The invention also includes pharmaceutical formulations containing any such
combination
as described herein.
Articles of manufacture. The present invention also provides articles of
manufacture
comprising, for example, packaging material, at least one unit-dosage of a
compound of 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.
64
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
In one embodiment, an article of manufacture comprises. packaging material, at
least one
unit dose of a I7-ketosteroid (a formula 1 compound) and a label or package
insert indicating that
the 17-ketosteroid (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.g., 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 compound for the treatment of
AIDS. 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 may contain additional components such as at least one unit dose
of a compound for
treatment of AIDS.
Methods of administration and formulations. The dosage for a particular
patient will vary
depending on factors such as the overall health of the patient, thc; 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 of the 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 inhibitiion 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 will vary
somewhat from
compound to compound and patient to patient. As a general proposition, a
dosage in the range of
from about 0.1 to about 500 mg/kg will have therapeutic efficacy. Typically, a
dosage in the range
of from about 0.5 mg/kg to about 500 mglkg 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.
CA 02352387 2001-05-25
WO 00/32I7b PCTIUS99/28080
With regard to the frequency and duration of treatment, it is wets 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 individual cases taking symptoms, age and sex of the subjecvt 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 l:he present invention
may be
administered orally, intramuscularly (IM}, intravenously (IV), or
subcutaneously (SC), with
intravenous administration being especially preferred. Although other routes
of administration can
be used, it has been, found that intravenous administration provides
surprising effectiveness.
Alternatively, the compound or salt may also be administered intravenously or
intramuscularly as a
liposomal suspension. The administration may also be in a cyclodextrin
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 tl~e
condition to be treated,
including oral, rectal, nasal, topical (including ocular, buccal or
sublingual), vaginal, parenteral
(including subcutaneous, intramuscuIar, intravenous, intraperitoneal,
intradermal, intrathecal,
intradural and epidurai) and pulmonary by aerosol. Generally, the compounds of
the invention are
administered parenteraliy, orally or topically. if an embodiment: is not
sufficiently orally
bioavaiIable it can be administered by the other routes noted above.
Embodiments include formulations that comprise a lipo;some or lipid complex
that
comprises a formula 1 compound. Such formulations are prepared according to
known methods,
e.g., U.S. patents 4427649, 5043165, 5714163, 5744158, 57832:11, 5795589,
5795987, 5798348,
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).
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 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 glycol, polyethylene glycol, DMSO, DMS02, vegetal'~le, mineral oils,
ethanol, benzyl
benzoate, or mixtures thereof, may be suitable. In general, the solutions in
any instance should be
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,
ampules, and the like.
66
' CA 02352387 2001-05-25
WO 00132176 PCTIUS99I28080
In some embodiments, the formula I 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 I compound is
incompletely
dissolved and is present as a suspension or gel.
In addition to compounds of formula I, or their salts, the; pharmaceutical
compositions
may contain other additives, such as pH adjusting additives, in particular,
agents such as acids,
bases, or buffers, including sodium lactate, sodium acetate, and sodium
gluconate. Further, such
I O compositions may contain microbial preservatives, such as methylparaben,
propylparaben, benzyl
alcohol and benzyl benzoate. If a multiple use vial is supplied, the
pharmaceutical composition
should likewise include such a microbial preservative. The formulations may
be, of course
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 forms and may be
prepared by any of
the methods well known in the art of pharmacy. Techniques, excipients and
formulations generally
are found in, e.g., Remington's Pharmaceutical.Sciences, Mack 1?ublishing Co.,
Easton, PA 1985,
17th edition, Nema et al., PDA J. Pharm. Sci. Tech. 1997 S 1:166-171, both of
which are
incorporated herein by reference. Methods to make invention formulations
include the step of
bringing into association a 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 as capsules, cachets or tablets each containing a
predetermined amount of the
formula 1 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 1 compound may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optio~nalIy with one or more
excipients.
Compressed tablets may be prepared by compressing in a suitable machine the
formula i
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 stow or controlled release of the formula 1 compound therein.
67
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
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
tipophilic 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 ofthe cream formulations. Emulgents and emulsion stabilizers suitable
for use in
formulations comprising a formula 1 compound include Tween~~ 60, Span~ 80,
cetostearyl
alcohol, benzyl alcohol, rnyristyl alcohol, glyceryl mono-stearate and sodium
lauryl sulfate.
Formulations suitable for buccal administration include lozenges comprising a
formula 1
compound in a flavored basis, usually sucrose and acacia or tragacanth;
pastilles comprising the
formula 1 compound in an inert basis such as gelatin and glycerin, or sucrose
and acacia.
Formulations far 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 microns 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 Toxoplasmosis or Cryptosporidium infections. Inhalation therapy
is readily
administered by metered dose inhalers.
Formulations suitable for vaginal administration may be presented as
pessaries, tampons,
creams, gels, pastes, foams or spray formulations containing in addition to
the formula 1
compound such carriers or excipients as are known in the art to be
appropriate.
Formulations suitable for parenteral 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 contai;aers, 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
68
CA 02352387 2001-05-25
WO 00/32176 PCTlUS99/28080
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 i compound.
In some embodiments, the formula i compounds will be administered on an
intermittent
S basis. In these embodiments, the formula i compound, e.g., a dose that
comprises about 5-S00 mg
of a formula 1 compound (typically about SO-400 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 least
one more daily dose of, e.g., about SO-500 mg. Intermittent dosing methods may
comprise dosing
(1, 2, 3 or 4 doses per week) based on a weekly schedule, e.g., dlosing on
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, S, 30, 4S, 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 S
times per week for l, 2, 3, 4, or more weeks.. In related embodiiments, dosing
may be administered
1 S to a subject daily for 2, 3, 4, S, 6, 7 or more days, followed by a period
of about l, 2, 3, 4, 5, ?, 14,
30, 4S 60, 90 or more days, optionally followed by another course of daily
dosing.
In accordance with an especially preferred method of the present invention, a
formulation
prepared as described below is administered subcutaneously, by intramuscular
injection or orally to
a patient. ( 1 ) To a glass vessel, add 400 mg of one or more compound of the
present invention and
2.S mL of polyethylene glycol 300 and vortex for 1 minute to form a smooth,
creamy liquid. (2)
Add 2.S mL of propylene glycol and vortex for 1 minute to forni a uniform
suspension. (3) Add
O.S mL of benzyl benzoate and vortex for 1 minute to form a semi clear liquid.
(4) Add i.25 mL of
absolute ethanol (99.5 %) and vortex to a clear and colorless solution. (S)
Make up to I O mL with
propylene glycol. (6) Store at 10 - 25 degrees C. Avoid heating of any kind.
Preferably, in such a
2S formulation, the compound of the invention is bromine epiandrosterone or
16a-
bromoepiandrosterone.
To the extent not already indicated, it will be understood by those of
ordinary skill in the
art that any one of the various specif c embodiments herein described and
illustrated rnay 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 1, and, the methods
disclosed herein
will utilize such compositions, which will contain one, two or more of such
compounds, usually
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
3S invention comprise at least one formula 1 compound together with one or
more acceptable carriers
69
-~- _--
°
CA 02352387 2001-05-25
WO 00/32176 PCTIUS99/28080 .
or excipients and optionally other therapeutic agents. The one or more
carriers or excipients must -
be "acceptable" in the sense of being compatible with the other ingredients of
the formulation and
not deleterious to the patient.
It has been found that oral administration of bromine epiandrosterone is
surprisingly
effective for the treatment of infections of Cryptosporidium parasites and/or
Toxoplasma, e.g., T.
gondii, or C. parvum, in the gastrointestinal tracts of patients.
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 dray or about
150-750 mg per day
using an intermittent dosing schedule (such as described herein), followed by
lower maintenance
dosing, e.g., about SO-250 mg per day or about 50-250 mg per day on an
intermittent dosing
schedule. These embodiments may further comprise treatment v~ith another
treatment as described
herein.
Parenteral formulations may comprise a cyclodextrin, e.g., an a-cyclodextrin,
a ~i-
cyclodextrin (e.g., (3-hydroxypropylcyclodextrin) or a y-cyciode~;trio, which
are typically employed
in aqueous formulations, which optionally comprise one or more of a buffer, a
salt (NaCI, etc.) to,
e.g., render the solution isotonic, a bacteriostat or other excipienta as
known in the art and a
formula 1 compound at a concentration of, e.g., about S-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 infeused into a subject. Paren~terat
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 parenteral formulations may be delivered orally, or
by intramuscular,
intravenous or subcutaneous injection.
In preparing compositions that comprise a formula 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 i compound is contacted with one or
more excipients. For
example, one may mill a formula 1 compound such as 16a-brom.oepiandrosterone,
to obtain an
average particle size (or diameter) of about 0.5-25 pM or about l.-10 pM
(e.g., about 2, 5 or 10 ~tM
average particle size or diameter) before contacting the milled formula 1
compound with a liquid
or solid excipient. Milted formula 1 compound is useful to faciliaate
dissolution or suspension of
the 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).
CA 02352387 2001-05-25
WO 00/32176 PCT/US99/28080
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 alsa be used to treat, or ameliorate
one or more
symptoms associated with, a retrovirai infection such as a HIV I 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 m,ay be used to
reduce replication of
an infectious agent or to reduce the number of infectious agents that are
present in a subject or to
ameliorate one or more symptoms associated with, or caused by, the condition
or infection (e.g.,
reduced fever, a shortened duration or level 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 m.ay include
flavoring or coloring
agents.
1 S The present invention further provides veterinary compositions comprising
at Least one
formula 1 compound together with a veterinary carrier therefor. Also, the
formula 1 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 compound. These veterinary compositions may be administered
orally,
parenterally or by any other desired route, e.g., as described herein.
Veterinary carriers may
include compounds that are not generally suitable for human applications,
e.g., small amounts of
chloroform.
Embodiments of formula 1 compounds include or exclude any subset of compounds
within
the definition of formula l, provided that at feast one compound remains. For
example, a subset 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 step reasons.
71
i',
' CA 02352387 2001-05-25
WO 00132176 PCT/US99/28080
In other embodiments, a formula 1 compound may be linked to an oiigonucleotide
or an
oligonucleotide analog, e.g., to facilitate delivery of the oligonucteotide or
analog into cells.
Typically the formula 1 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
oiigonucleotides are known and have been described, e.g., U.S. patents
4725677, 4973679,
4997927, 4415732, 4458066, 5047524, 4959463, 5212295, 538fi023, 5489677,
5594121, 5614622,
5624621; and PCT publication Nos. WO 92/07864, WO 96/293:37,'WO 97/14706, WO
97!14709,
WO 97/31009, WO 98104585, WO 98/04575, aEl of which are incorporated herein by
reference.
Synthesis methods. In general, 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.
Formula 1 compounds that comprise a thioacetal 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 576915 and EP 576914; C.
Christians et al.,
J. Chem. Soc. Chem. Commun. 1991 vol 22, C. Christians et al., J. Chem. Sac.
Chem. Commun.
1991 19:1403-1405, H.N. Abramson et al., J. Pharm. Sci. 1977 ii6:602-603, E.J.
Corey et al., J.
Am. Chem. Soc. 1996 118:8765-8766, A.G.M. Barrett et al., J. C>rg. Chem. 1989
54:227, D.H.R
Burton et aL, .l. Chem. Soc. Perkin Trans. 1 1976 19:2112-2116, D.H.R. Burton
et al., J. Chem.
Soc. Perkin Trans. I 1975 16:1574-1585 and W.T. Smith et al., Trans.
KentuckyAcad Sci. 1984
45:76-77, all of which are 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 cryptosporidiosis in a patient in need of such
treatment, comprising
administering to said patient an effective amount of at Least one compound of
the present
invention.
2. A method as recited in embodiment 1, wherein said patient is also infected
with a
retrovirus or is suffering from AIDS.
3. A method as recited in embodiment 2, further comprising administering to
said patient
at least one compound for treatment of AIDS.
4. A method as recited in embodiment 3, wherein said at least one compound of
the present
invention and said at /east one compound for the treatment of AIfDS are
administered
simultaneously.
72
' CA 02352387 2001-05-25
WO 00/32I76 PC'T/US99/28080
5. A method as recited in embodiment 3, wherein said at least one compound of
the present
invention and said at least one compound for the treatment of AIfDS are
administered sequentially.
6. A method as recited in any one of embodiments 1 - 5, wherein said patient
is a mammal.
7. A method as recited in embodiment 6, wherein said patient is a human, a
primate or a
feline.
8. A method as recited in any one of embodiments 1 - 7, wherein said
administering is by
oral ingestion.
9. A method as recited in any one of embodiments 1 - 7, wherein said
administering is by
subcutaneous.
10. A method as recited in any one of embodiments 1 - St, wherein said
compound of the
invention is bromine epiandrosterone or 16a-bromoepiandrosterone.
11. A method as recited in any one of embodiments 1 -10, wherein said compound
of the
invention is contained in a formulation prepared by (1) combining said
compound ofthe present
invention and polyethylene glycol and vortexing to form a smooth, creamy
liquid, (2) adding
additional propylene glycol and vortexing to form a uniform suspension, (3)
adding benzyl
benzoate and vortexing to form a semi clear liquid, (4) adding ethanol and
vortexing to a clear and
colorless solution; and (S) optionally adding more propylene glycol.
12. A method of treating toxoplasmosis 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.
13. A method as recited in embodiment 12, wherein said patient is also
infected with a
retrovirus or is suffering from AIDS.
14. A method as recited in embodiment 13, further comprising administering to
said
patient at least one compound for treatment of AIDS.
15. A method as recited in embodiment 14, wherein said at least one compound
of the
present invention and said at least one compound for the treatment of AIDS are
administered
simultaneously.
16. A method as recited in embodiment 14, wherein said at least one compound
of the
present invention and said at least one compound for the treatment of AIDS are
administered
sequentially.
17. A method as recited in any one of embodiments 12 - 16, wherein.said
patient is a
mammal. .
18. A method as recited in embodiment 17, wherein said patient is a human, a
primate or a
feline.
73
CA 02352387 2001-05-25
WO 00/32176 PCT/U899/28080 '.
19. A method as recited in any one of embodiments 12 - I8, wherein said
administering is
by oral ingestion.
20. A method as recited in any one of embodiments I2 - I 8, wherein said
administering is
by subcutaneous or intramuscular injection.
S 21. A method as recited in any one of embodiments 12 - 20, wherein said
compound of the
invention is bromine epiandrosterone.
22. A method as recited in any one of embodiments 12-s; l, wherein said
compound of the
invention is contained in a formulation prepared by (1 ) combining said
compound of the present
invention and polyethylene glycol and vortexing to form a smooth, creamy
liquid, (2) adding
additional propylene glycol and vortexing to form a uniform suspension, (3)
adding benzyl
benzoate and vortexing to form a semi clear liquid, (4) adding ethanol and
vortexing to a clear and
colorless solution; and (S) optionally adding more propylene glycol.
23. A composition comprising at least one of the compounds of the present
invention, and
at least one compound for treatment of HIV infection or for the treatment of
AIDS.
IS 24. A kit comprising one or more unit dosages of at least one of the
compounds of the
present invention, and one or more unit dosages of at least one compound for
treatment of HIV
infection or for the treatment of AIDS.
2S. The method of any of embodiments I-24 wherein thc; compound of the
invention is a
formula 1 compound or a metabolite thereof.
26. The method of embodiment 2S wherein the formula 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.
2?. A composition comprising 16a-bromoepiandrosterone, and 2, 3, 4 or 5
excipients
selected from polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl
alcohol and
2S propylene glycol, wherein the composition comprises less than about 3% v/v,
or less than about
1% v/v, or less than about O.S% vlv of water, or less than about 0.1% v/v of
water.
28. The composition of embodiment 2? wherein the composition comprises (i) 16a-
bromoepiandrosterone at a concentration of about 4S-SS mg/mL" (ii) 20-30% vlv
polyethylene
glycol 300, polyethylene glycol 400 or a mixture of polyethylene; glycol 300
and 400, (iii) 10-IS%
vlv dehydrated ethyl alcohol, 2.S-7.S% v/v benzyl benzoate, and (iv) SS-60%
v/v propylene glycol.
29. The composition of embodiment 28 wherein the composition comprises 16a-
bromoepiandrosterone at a concentration of about 50 mg/mL, about 2S% v/v
polyethylene glycol
300, about 12.5% v/v dehydrated ethyl alcohol, about S% v/v benzyl benzoate,
about 57.5% v/v
propylene glycol and less than about O.S% v/v water.
?4
' CA 02352387 2001-05-25
WO 00!32176 PCT/US99I28080 '.
30. The composition of embodiment 27 wherein the composition comprises 16a-
bromoepiandrosterone at a concentration of about 50-105 mg/rnL, about 27-33%
wlw benzyl
benzoate, about 27-33% w/w polyethylene glycol 300, about 25-30% w/w propylene
glycol and
about 1-3% w/w benzyl alcohol.
31. The composition of embodiment.30 wherein the; composition comprises 16a-
bromoepiandrosterone at a concentration of about 100 mg/mL (.about 10% w/w),
about 30.4% w/w
- benzyl benzoate, about 30.7% w/w polyethylene glycol 300, about 28% w/w
propylene glycol and
benzyl alcohol about 1.9% w/w.
32. A product produced by the process of contacting 16a-bromoepiandrosterone
and a
liquid excipient, wherein the product contains less than about
3°,i° water, provided that the liquid
excipient is not chloroform, dimethylsuifoxide, olive oil, or a vegetable oil.
33. The product of embodiment 32 wherein the liquid excipient is polyethyleye
glycol,
dehydrated ethanol, benzyl benzoate, benzyl alcohol and propylene glycol,
wherein the product
comprises less than about 3% v/v, or less than about 1% v/v, or less than
about 0.5% v/v of water.
1 S 34. The use of a formula 1 compound for making a medicament for the
treatment of an
infection caused by one or more Toxoplasma or Cryptosporidio~ris parasites in
a subject.
35. The use of embodiment 34 wherein the formula I compound is a compound
named
in compound groups 1-2I or a metabolite thereof.
36. A method comprising administering an effective: amount of a composition of
any
of embodiments 27-31 to a subject having, or susceptible to, a Toxoplasma or
Cryptosporidium
infection.
37. The method of embodiment 36 wherein the subject is a human and the human
is
optionally coinfected with a retrovirus (e.g., HIV 1 or HIV2).
38. A method to ameliorate or reduce one or more symptoms associated with a a
Toxoplasma or Cryptosporidium infection in a subject, or to reduce replication
of a Toxoplasma or
Cryptosporidium infection in a subject infected with a Toxoplasma or
Cryptosporidium parasite,
comprising administering to the subject an effective amount of a. compound of
formula I .
39. The method of embodiment 38 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 I compound is
present in a
composition comprising one or more pharmaceutical excipients, e.g., any of the
formulations
disclosed or described herein.
40. A composition comprising a formula 1 compound 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, and at least one
excipient and a local
n-.4~-~--~---m---
i,,
' CA 02352387 2001-05-25
WO 00/32176 PCT/US99128080
anesthetic, wherein the local anaesthetic is optionally selected from
procaine, benzocaine and
lidocaine.
41. 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 excipier~t with a second
excipient wherein
the product optionally further comprises a focal anesthetic, whemin the local
anaesthetic is
optionally selected from procaine, benzocaine and lidocaine.
42. A product produced by the process of contacting a c;otrlpound of formula
1, e.g., any
compound named in compound groups I-21, and a first nonaque;ous 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
dimethyisulfoxide, chloroform,
dioxane, a vegetable oil and olive oil, and wherein the product optionally
further comprises a local
anesthetic, wherein the local anaesthetic is optionally selected from
procaine, benzocaine and
Iidocaine.
43. A method comprising administering an effective amount ofthe composition of
embodiment 40 or the product of embodiments 41 or 42 to a subject having an
infection or
condition described herein, e.g., a Toxoplasma or Cryptosporidi~um parasite
infection, whereby the
infection or condition, or a symptom thereof, is eliminated, reduced, treated,
improved or
ameliorated.
44. The method of embodiment 43 wherein the formula i compound is 16a-
haloepiandrosterone or 16a-halodehydroepiandrosterone.
EXAMPLES
The following examples further illustrate the invention amd are not to be
construed as
limiting the invention.
Example 1. Human clinical trial. To a patient who had suffered two years
continuously
from diarrhea resulting from cryptosporidiosis, bromine epiandrosterone was
administered once a
day. After three days of such administration, the patient did not suffer from
diarrhea.
Example 2. 16a-Bromoepiandrosterone formulation 1. Two lots of a non-aqueous
formulation was made at a 16a-bromoepiandrosterone ("BrEA";i 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.
76
CA 02352387 2001-05-25
WO 00/32176 PCT/US99I28080
The remaining excipients are shown below.
Excipient Specifica-nonSupplier Final Product
Lot No. Concentra-tion
Propylene glycol USP Arco Chemical 57.5% (v:v)
HOC-61220-O1
I04
- Polyethylene glycol 300 NF Union Carbide 25% (v:v)
695752 .
Dehydrated alcohol USP McCormiclk Distilling12.5% (v:v)
(ethanol) 97KI0
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
filtered through two 0.2 pm poIyvinylidene fluoride filters in series before
dispensing into 2 cc
amber glass vials. The vials were capped with Teflon-coated, butyl-rubber
stoppers and crimp
sealed.
Materials used in the product vials are listed below.
Material Source Product Code Description
Vial Wheaton 2702-BS 1BA Tubing vial, 2 mL/I3 mm, glass, type 1 amber
Stopper Omniflex V9239 FM257/2 13 mm, Teflon coated, butyl rubber stopper
Seal West 4107 Flip seal, I3 mm, mist gray bridge
77
i,
CA 02352387 2001-05-25
WO 00/32I76 PC'TIUS99/28080
. Example 3. BrEA formulation 2. A formulation containing 100 mg/mL of BrEA,
9%
w/w, in benzyl benzoate (USP) 30.4% wlw, polyethylene glycol 300 (NF) 30.7%
w/w, propylene
glycol (USP), qs, about 28% w/w and benzyl alcohol (NF) 1.9°.~o w/w,
hereafter "formulation 2",
was prepared as follows. A desired amount of BrEA (1.0 kg) eras suspended in
PEG 300 (about
S 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 glycoil (about 1.S 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 S minutes to form a clear, colorless solution. Propylene glycol was then
added to achieve the
desired final formulation volume (about l.S L) and mixing was continued for
about S minutes. The
drug solution was transferred to a volume-dispensing device, wihich 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 ~m polyvinylidine fluoride filters in series. The vials
were capped using
1S Teflon-coated, butyl rubber stoppers and then crimp sealed essentially as
described in example 2.
The vials were stored in the dark at reduced temperature (about 2-8oC).
The foregoing detailed description has been provided for a better
understanding of the
invention only and no unnecessary limitation should be understood therefrom as
some
modiftcations will be apparent to those skilled in the art without deviating
from the spirit and scope
of the appended claims.
78
