Note: Descriptions are shown in the official language in which they were submitted.
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NUCLEOTIDE ANALOGS
BACKGROUND OF THE INVENTION
The present invention relates to intermediates for phosphonomethoxy
nucleotide analogs, in particular intermediates suitable for use in the
efficient
oral delivery of such analogs.
Such analogs per se and various technologies for oral delivery of these
and other therapeutic compounds are known. See WO 91/19721, WO
94/03467, WO 94/03466, WO 92/13869, U.S. 5,208,221, 5,124,051, DE 41 38 584
A1, WO 94 / 10539, WO 94 / 10467, WO 96 / 18605, WO 95 / 07920, WO 95
79/07919, WO 92/09611, WO 92/01698, WO 91/19721, WO 88/05438, EP 0 632
048, EP 0 481 214, EP 0 369 409, EP 0 269 947, U.S. Patent Nos. 3,524,846 and
5,386,030, Engel Chem. Rev. 77:349-367 1977, Farquhar et al., J. Pharm. Sci.
72:324-325 1983, Starrett et al., Antivira! Res. 19:267-273 1992, Safadi et
al.,
Pharmaceutical Research 10 9 :1350-1355 1993, Sakamoto et al., Chem. Pharm.
Bull. 32 6 :2241-2248 1984, and Davidsen et al., J. Med. Chem. 37 26 :4423-
4429
1994.
SUMMARY OF THE INVENTION
In accordance with this invention, compounds are provided having
formula (1a)
O
I
A-OCH2P(Z)2 (1a)
wherein Z is independently -OC(R2)20C(O)X(R)a, an ester, an amidate or -H,
but at least one Z is -OC(R2)20C(O)X(R)a;
A is the residue of an antiviral phosphonomethoxy nucleotide analog;
XisNorO;
R2 independently is -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-
C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any
one
of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido,
nitro
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or -OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12
aryl;
R independently is -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-
C12 alkynyl, C~-C12 alkyenylaryl, C~-C12 alkynylaryl, or C(-C12 alkaryl, any
one of which is unsubstituted or is substituted with 1 or 2 halo, cyano,
azido,
vitro, -N(R4)2 or -OR3, where R4 independently is -H or C1-Cg alkyl, provided
that at least one R is not H; and
a is 1 when X is O, or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups
can be taken together to form a carbocycle or oxygen-containing heterocycle,
{b) one N-linked R additionally can be -OR3 or (c) both N-linked R groups can
be -H;
and the salts, hydrates, tautomers and solvates thereof.
Further embodiments of the compounds of this invention are
compounds of formula (1)
R2 O
B O~O~O~OR
O~P\OR$ {1)
Rl
wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-
9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
R is independently -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12
alkynyl, C7-C12 alkenylaryl, C~-C12 alkynylaryl, or C6-C12 alkaryl, any one of
which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, vitro
or
-OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12
aryl;
Rl is hydrogen, -CH3, -CH20H, -CH2F, -CH=CH2, or -CH2N3, or Rl and
R8 are joined to form -CH2-;
R2 independently is hydrogen or C1-C6 alkyl; and
R8 is hydrogen or -CHR2-O-C(O)-OR, or R8 is joined with Rl to form
-CH2-;
and the salts, hydrates, tautomers and solvates thereof.
Other embodiments comprise orally administering to a patient infected
with virus or at risk for viral infection a therapeutically effective amount
of a
compound of formulas (1a) or {1).
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Other embodiments of this invention include a method for preparing a
compound of formula (la) which comprises reacting the diacid of a
phosphonomethoxy nucleotide analog with LC(R2)20C(O)X(R)a wherein L is
a leaving group.
In particular embodiments of this invention, a method for preparing a
compound of formula (1) is provided which comprises reacting a compound
of formula (4)
O
O p-OH
~ \OR8
R1
with LC(R2)20C(O)X(R)a .
DETAILED DESCRIPTION OF THE INVENTION
The abbreviations NMP, DMF and DMPU mean, respectively, N
methylpyrrolidinone, dimethylformamide and N,N'-dimethylpropyleneurea.
Heterocycle means aromatic and nonaromatic ringed moieties.
Heterocyclic moieties typically comprise one ring or two fused rings, where
the rings) is 5- or 6-membered and typically contains 1 or 2 noncarbon atoms
such as oxygen, nitrogen or sulfur, usually oxygen or nitrogen.
"Alkyl" as used herein, unless stated to the contrary, is C1-C12
hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in
the
form of normal, secondary, tertiary or cyclic structures. Examples are -CH3,
-CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(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)CH2CH(CH3)2.
-C(CH3)(CH2CH3)2, -CH(CH2CH3)CH{CH3)2, -C(CH3)2CH(CH3)2.
-CH(CH3)C(CH3)3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl,
cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl,
' cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-
1-
propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl, 2-cyclopropyl-2-
propyl,
and 1-cyclopropyl-2-propyl.
"Alkenyl" as used herein, unless stated to the contrary, is C1-C12
hydrocarbon containing normal, secondary, tertiary or cyclic structures.
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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)CH=CHCH3, -CH(CH3)CH2CH=CH2, -CH2CH=C(CH3)2,1-cyclopent-
1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-
2-
enyl, and 1-cyclohex-3-enyl.
"Alkynyl" as used herein, unless stated to the contrary, is C1-C12
hydrocarbon containing normal, secondary, tertiary or cyclic structures.
Examples are -CCH, -CCCH3, -CH2CCH, -CCCH2CH3, -CH2CCCH3,
-CH2CH2CCH, CH(CH3)CCH, -CCCH2CH2CH3, -CH2CCCH2CH3,
-CH2CH2CCCH3 and -CH2CH2CH2CCH.
Salts) include those derived by combination of appropriate anions
such as inorganic or organic 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
organic and inorganic acids, e.g., HF, HCI, HBr, HI, H2S04, H3P04, or from
organic sulfonic acids, organic carboxylic acids to basic centers, typically
amines. Exemplary organic sulfonic acids include C6_16 aryl sulfonic acids,
C6-16 heteroaryl sulfonic acids and Cl_16 alkyl sulfonic acids such as phenyl,
a-naphthyl, b-naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-
butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids. Exemplary
organic carboxylic acids include Cl-16 alkyl, C6-16 aryl carboxylic acids and
C4_16 heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic,
malonic, glutaric, tartaric, citric, fumaric, succinic, malic, malefic,
hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic
and 2-phenoxybenzoic. Salts also include the invention compound salts
with one or more amino acids. Many amino acids are suitable, especially
the naturally-occurring amino acids found as protein components,
although the amino acid typically is one bearing a side chain with a basic
or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group
such as glycine, serine, threonine, alanine, isoleucine, or leucine. Salts are
usually biologically compatible or pharmaceutically acceptable or non-
toxic, particularly for mammalian cells. Salts that are biologically toxic are
generally used with synthetic intermediates of invention compounds.
The salts of invention compounds may be crystalline or noncrystalline.
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A is the residue of a phosphonomethoxy nucleotide analog. The
parental compounds have the structure AOCH2P(O){OH)2. They are well
known and have demonstrated antiviral activity. Per se, they are not part of
this invention. In general, A has the structure BQ wherein B is a purine or
pyrimidine base or the aza and/or deaza analogs thereof and Q is a cyclic or
acyclic aglycon. B is linked to Q through the purine 9 or pyrimidine 1
positions. Examples of these analogs can be found in U.S. Patents 4,659,825,
4,724,233, 5,142,051 and 5,130,427, EP 369,409, EP 398,231, EP 494,370, EP
454,427,
EP 270,885, EP 269,947, EP 452,935, WO 93/07157, WO 94/03467, and
W096/23801. Typically, A will have the structure BCH2CH(CH3)- or
BCH2CH2-.
The designation "a" is an integer of 1 or 2. If X is N then a is 2 and one
R is usually H and the other is not H. If X is O then a is 1.
B generally is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-
aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-
yl.
Ordinarily, B is adenin-9-yl or 2,6-diaminopurin-9-yl. In formula (la)
compounds, one Z optionally comprises an ester or an amidate. Suitable
esters or amidates have been described, e.g., WO 95/07920. Exemplary esters
are phenyl, benzyl, o-ethoxyphenyl, p-ethoxyphenyl, 2-pyridyl, 3-pyridyl, 4-
pyridyl, N-ethylmorpholino, C1_Cg O-alkyl and C1_C8 NH-alkyl. However,
every compound of the invention will contain at least one
-C(R2)20C(O)X(R)a moiety.
R2 independently is -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl,
C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl,
any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano,
azido, vitro or -OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12
alkynyl or C5-C12 aryl. R2 is usually H or C1-C6 alkyl, and typically only
one R2 is other than H. In most embodiments R2 is H in both instances.
The carbon atom to which R2 is bonded is capable of chiral substitution, in
which case R2 is in the (R), (S) or racemic configuration. In most
embodiments, if R2 is other than H the compounds of this invention are
chirally enriched or pure at this site. In general, however, manufacturing
is somewhat less expensive if chirality at the R2 carbon can be avoided.
Thus, R2 is H when it is desired to help minimize the cost of synthesis.
X is O or N, typically O. The carbamates (where X=N) tend to be
more stable in biological environments than the carbonates. When X is O
then a is 1.
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R independently is -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-
C12 alkynyl, C~-C12 alkyenylaryl, C'7-C12 alkynylaryl, or C6-C12 alkaryl, any
one of which is unsubstituted or is substituted with 1 or 2 halo, cyano,
azido, nitro, -N(R4)2 or -OR3, where R4 independently is -H or C1-Cg alkyl,
provided that at least one R is not H. In general, R is C1-C6 secondary or
normal alkyl which is unsubstituted or substituted with OR3. When X is
N then a is 2. In the latter case one R is usually other than H.
Alternatively, two N-linked R groups are joined to form a carbocycle or O-
containing heterocycle, typically containing 3 to 5 carbon atoms in the ring.
When R is unsaturated, but not aryl, the site of unsaturation is not critical
and is in the Z or E configuration. The alkenyl chains of naturally
occurring unsaturated fatty acids would be suitable as R groups, for
example. R also includes cycloalkenyl or cycloalkynyl containing 1 or 2
unsaturated bonds, typically 1 unsaturated bond. When R is unsaturated,
usually it is alkenyl or alkynyl without aryl substitution.
If R is substituted with halo, cyano, azido, nitro or OR3, typically R will
contain 1 of these substituents. If substituted with 2 of these substituents,
they
are same or different. Generally, substituents found on R are OR3. An
exemplary R group containing an OR3 substituent is
-CH2C{CH20CH3)(CH3)2.
When R contains an aryl group, the aryl group generally is bonded
directly to X or is linked to X by methylene or ethylene. The aryl group
may contain -N= or -O- as a ring atom. In general, the aryl group contains
5 or 6 carbons. If substituted, the aryl moiety is substituted with halo or
OR3 in the ortho, meta or para positions, with R3 in this instance being
typically C1-C3. Aryl groups containing 5 carbons are typically 2-, 3- or 4-
pyridyl. In general, only one substituent group will be found on the aryl
moiety if it is substituted at all. Exemplary aromatic and nonaromatic
heterocyclic groups as used herein includes by way of example and not
limitation the heterocycles described in Paquette, Leo A.; "Principles of
Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968),
particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic
Compounds, A series of Monographs" (John Wiley & Sons, New York,
1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and "J. Am.
Chem. Soc.", 82:5566 (1960).
Examples of heterocycles include by way of example and not
limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized
tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
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imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl,
quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl,
pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-
1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl,
chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl,
isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-
indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,
carbazolyl, b-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl,
isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,
pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,
morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,
benzoxazolinyl, and isatinoyl.
By way of example and not limitation, carbon bonded heterocycles
are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or b
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 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, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4,
5, 6,
7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles
include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,
4-
pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-
pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 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 morpholine, and position 9 of a carbazole, or b-
carboline. Still more typically, nitrogen bonded heterocycles include 1-
aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-
piperidinyl.
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R includes the structure -C2-C6R5C2_C6 where each C2_C6 independently
is a 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl moiety, e.g.,
ethylene,
ethyl, propylene, propyl, isopropylene, isopropyl, cyclohexyl, etc., and R5 is
-O-
or -NR6- where R6 is linear, branched or cyclic alkyl having 1, 2, 3, 4, 5 or
6
carbon atoms.
Embodiments include compounds where R4 is -H or -CH3.
R includes the structure -C2_C12R9, where each C2-C12 independently is
a 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon linear, branched or cyclic alkyl
moiety,
and R9 is
S N o
N-morpholino ( ~--~ ) , N-piperidino, 2-pyridyl, 3-pyridyl or 4-pyridyl.
R also includes -C(CHZ(X)o_1R~)3, -CH[C(CH2(X)p_1R~)3]2 and -CH2(C(X)p_
1R~)3, where R~ is 1, 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl
or R~ is
5 or 6 carbon aryl. In these embodiments, one or two X are typically present,
usually 1, X is usually oxygen and R~ is typically methyl, ethyl, isopropyl,
propyl or butyl, usually methyl.
R usually is phenyl, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, i-butyl, t-
butyl, pentyl or 3-pentyl.
R1 is a substituent found in prior art phosphonomethoxy nucleotide
analogs. R1 typically is any of hydrogen, -CH3, -CH20H, -CH2F, -CH=CH2,
-CHZN3 or Rl and R8 are joined to form -CH2-. R1 is usually H or methyl. If
R1 and R8 are joined to form methylene, B typically is cytosin-1-yl.
R3 is C1-C12 alkyl, but typically is C1-C6 alkyl.
Compounds of structure (1) typically are those in which B is adenin-9-
yl, R1 is methyl or H, R8 is -CHR2-O-C(O)-OR and R, R2 and R3 are as set forth
above.
The compounds of this invention are optionally enriched or resolved
at the carbon atom chiral center linked to Rl in accordance with prior
findings
associating optimal antiviral activity with the configuration at this site.
Thus,
where R1 is methyl the compounds will be in (R) configuration at this center
and will be substantially free of the (S) enantiomer.
Other embodiments include structure (10) and (11) compounds where
R and each R2 are independently chosen and R2 is C1_C6 alkyl
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RZ O
B O ~ ~ R
O O N(
O~P
R1 2
(10)
R2
O
B ~~ O O N(R)2
O~P
2
R1 (11)
Exemplary embodiments include the compounds named in Table B.
Each compound in Table B is depicted as a compound having the formula (8)
Rz
B
o~P o 0 oR
Ri (8) 2
Compounds named in Table B are designated by numbers assigned to B, R, Rl
and R2 according to the following convention, B.R.R1.R2, using the numbered
structures depicted in Table A. Thus, the compound named 1.2.3.4 specifies
adenin-9-yl at B, -CH2CH3 at both R groups, -CH20H at Rl and -(CH2)2CH3 at
both R2 groups.
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TABLE A
Rl
1 adenin-9-yl 1 -CH3
2 guanin-9-yl 2 -H
3 2,6-diaminopurin-9-yl 3 -CH20H
4 2-aminopurin-9-yl 4 -CH2F
5 cytosin-1-yl 5 -CH=CH2
6 -CH2N3
R
R2
1 -CH3 1 -H
2 -C2H5 2 -CH3
3 -(CH2)2CH3 3 -C2H5
4 -CH(CH3)2 4 -(CH2)2CH3
5 -(CH2)3CH3 5 -CH(CH3)2
6 -CH2CH(CH3)2 6 -(CH2)3CH3
7 -CH(CH3)CH2CH3 7 -CH2CH(CH3)2
8 -C(CH3)3 8 -C(CH3)3
9 -(CH2)4CH3 9 -(CH2)4CH3
10 -CH(CH3)CH2CH2CH3 10
-(CH2)5CH3
11 -CH(CH2CH3)2
12 -C(CH3)2CH2CH3
13 -CH(CH3)CH(CH3}2
14 -CH2CH2CH(CH3)2
15 -CH2CH(CH3)CH2CH3
16 -CH2CH2CH2CH2CH2CH3
17 -CH(CH3)CH2CH2CH2CH3
18 -CH(CH2CH3)CH2CH2CH3
19 -C(CH3)2CH2CH2CH3
20 -CH(CH3)CH(CH3)CH2CH3
21 -CH(CH3)CH2CH(CH3)2
22 -C{CH3)(CH2CH3)2
23 -CH(CH2CH3)CH(CH3)2
24 -CH2C6H5
25 -C6H5
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 2.1.2.9 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 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 1.1.6.2
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 1.2.1.1
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.L10 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4
1.2.2.5 1.2.2.6 1.2.2.7 1.2.2.8
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CA 02261619 1999-O1-20
WO 98/04569 PCT/US97/13244
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CA 02261619 1999-O1-20
WO 98/04569 PCTIUS97/13244
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12
CA 02261619 1999-O1-20
WO 9$/04569 PCT/US97/13244
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1.25.6.6 1.25.6.7 1 1.25.6.1
0 2.1.1.1
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2.1.1.7 2.1.1.8 2.1.1.9 2.1.1.10 2.1.2.2 2.1.2.5
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2.2.3.5 2.2.3.6 2.2.3.7 2.2.3.9 2.2.4.3
2.2.3.10
2.2.4.4 2.2.4.5 2.2.4.6 2.2.4.7 2.2.5.12.2.5.2 2.2.5.4 2.2.5.5
2.2.4.8 2.2.4.9 2.2.4.1 0 2.2.5.3 2.2.5.6
2.2.5.7 2.2.5.8 2.2.5.9 2.2.5.10 2.2.6.42.2.6.5 2.2.6.7 2.2.6.8
2.2.6.1 2.2.6.2 2.2.6.3 2.2.6.6 2.2.6.9
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2.3.1.4 2.3.1.5 2.3.1.6 2.3.1.9 2.3.2.2
1 2.3.2.3 2.3.2.4 2.3.2.5 2.3.2.6 2.3.3.1 2.3.3.3 2.3.3.4
5 2.3.2.7 2.3.2.8 2.3.2.9 2.3.2.10 2.3.3.2 2.3.3.5
2.3.3.6 2.3.3.7 2.3.3.8 2.3.3.9 2.3.4.32.3.4.4 2.3.4.6 2.3.4.7
2.3.3.10 2.3.4.1 2.3.4.2 2.3.4.5 2.3.4.8
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2.3.5.3 2.3.5.4 2.3.5.5 2.3.5.8 0 2.3.6.1
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2.4.1.9 2.4.1.10 2.4.2.1 2.4.2.4 2.4.2.7
20 2.4.2.8 2.4.2.9 2.4.2.10 2.4.3.1 2.4.3.52.4.3.6 2.4.3.8 2.4.3.9
2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.7 2.4.3.10
2.4.4.1 2.4.4.2 2.4.4.3 2.4.4.4 2.4.4.8 2.4.5.1 2.4.5.2
2.4.4.5 2.4.4.6 2.4.4.7 2.4.4.9 2.4.5.3
2.4.4.1
0
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2.4.5.8 2.4.5.9 2.4.5.1 0 2.4.6.3 2.4.6.6
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2.5.1.1 0 2.5.2.1 2.5.2.2 2.5.2.32.5.2.72.5.2.8 2.5.2.10 2.5.3.1
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25 2.5.3.3 2.5.3.4 2.5.3.5 2.5.3.6 2.5.4.1 2.5.4.3 2.5.4.4
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2.5.4.1 0 2.5.5.1 2.5.5.2 2.5.5.5 2.5.5.8
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2.5.6.3 2.5.6.4 2.5.6.5 2.5.6.8 0 2.6.1.1
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2.6.5.5 2.6.5.6 2.6.5.7 2.6.5.9 2.6.6.3
2.6.5.10
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35 2.7.4.3 2.7.4.4 2.7.4.5 2.7.4.6 2.7.5.1 2.7.5.3 2.7.5.4
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0
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2.9.6.6 2.9.6.7 2.9.6.8 2.9.6.9 1.3 2.1
2.9.6.10 2.10.1.1 2.10.1.2 2.1 0.1.4
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2.10.2.2 2.10.2.3 2.10.2.6
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2.10.2.8
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2.10.3.3 2.10.3.4 2.10.3.7
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2.10.4.4 2.10.4.5 2.10.4.7
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2.10.6.6 2.10.6.7 2.11.1.2
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2.11.1.7 2.11.1.8 2.11.2.1
2.11.2.2
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2.11.2.4 2.11.2.5 2.11.2.6 2.11.2.7 2.11.3.1
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2.11.3.3
2.11.3.4
2.11.3.5 2.11.3.6 2.11.3.7 2.11.3.82.11.4.12.11.4.2
2.11.3.92.11.3.10 2.11.4.3
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2.11.4.5
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2.11.5.1 2.11.5.4
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2.11.5.7 2.11.5.8 2.11.5.92.11.5.102.11.6.32.11.6.4
2.11.6.1 2.11.6.2 2.11.6.5
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2.11.6.7
2.11.6.8 2.11.6.92.11.6.10 2.12.1.12.12.1.42.12.1.5
2.12.1.2 2.12.1.3 2.12.1.6
2.12.1.7
2.12.1.8
13
CA 02261619 1999-O1-20
WO 98104569 PCTIUS97113244
2.12.1.92.12.1.10
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2.12.2.10
2.12.3.22.12.3.32.12.3.42.12.3.52.12.3.62.12.3.72.12.3.82.12.3.92.12.3.10
2.12.3.1
2.12.4.12.12.4.22.12.4.32.12.4.42.12.4.52.12.4.62.12.4.72.12.4.8
2.12.5.1
2.12.4.92.12.4.10
2.12.5.22.12.5.32.12.5.42.12.5.52.12.5.62.12.5.72.12.5.82.12.5.92.12.5.10
2.12.6.12.12.6.2
2.12.6.32.12.6.42.12.6.52.12.6.62.12.6.72.12.6.82.12.6.92.12.6.10
2.13.1.12.13.1.22.13.1.3
2.13.1.42.13.1.52.13.1.62.13.1.72.13.1.82.13.1.92.13.1.10
2.13.2.12.13.2.22.13.2.32.13.2.4
2.13.2.52.13.2.62.13.2.72.13.2.82.13.2.92.13.2.10
2.13.3.12.13.3.22.13.3.32.13.3.42.13.3.5
2.13.3.62.13.3.72.13.3.82.13.3.92.13.3.10
2.13.4.12.13.4.22.13.4.32.13.4.42.13.4.52.13.4.6
2.13.4.72.13.4.82.13.4.92.13.4.10
2.13.5.12.13.5.22.13.5.32.13.5.42.13.5.52.13.5.62.13.5.7
2.13.5.82.13.5.92.13.5.10
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2.13.6.92.13.6.102.14.1.12.14.1.22.14.1.32.14.1.42.14.1.52.14.1.62.14.1.72.14.1
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2.14.2.1
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2.14.5.12.14.5.2
2.14.5.32.14.5.42.14.5.52.14.5.62.14.5.72.14.5.82.14.5.92.14.5.10
2.14.6.12.14.6.22.14.6.3
2.14.6.42.14.6.52.14.6.62.14.6.72.14.6.82.14.6.92.14.6.10
2.15.1.12.15.1.22.15.1.32.15.1.4
2.15.1.52.15.1.62.15.1.72.15.1.82.15.1.92.15.1.10
2.15.2.12.15.2.22.15.2.32.15.2.42.15.2.5
2.15.2.62.15.2.72.15.2.82.15.2.92.15.2.10
2.15.3.12.15.3.22.15.3.32.15.3.42.15.3.52.15.3.6
2.15.3.72.15.3.82.15.3.92.15.3.10
2.15.4.12.15.4.22.15.4.32.15.4.42.15.4.52.15.4.62.15.4.7
2.15.4.82.15.4.92.15.4.102.15.5.12.15.5.22.15.5.32.15.5.42.15.5.52.15.5.62.15.5
.72.15.5.8
2.15.5.92.15.5.102.15.6.12.15.6.22.15.6.32.15.6.42.15.6.52.15.6.62.15.6.72.15.6
.82.15.6.9
2.15.6.10 2.16.1.62.16.1.72.16.1.82.16.1.92.16.1.10
2.16.1.1
2.16.1.2
2.16.1.3
2.16.1.4
2.16.1.5
2.16.2.12.16.2.22.16.2.32.16.2.42.16.2.52.16.2.62.16.2.72.16.2.82.16.2.92.16.2.
10 2.16.3.1
2.16.3.22.16.3.32.16.3.42.16.3.52.16.3.62.16.3.72.16.3.82.16.3.9
2.26.4.12.16.42
2.16.3.10
2.16.4.32.16.4.42.16.4.52.16.4.62.16.4.72.16.4.82.16.4.92.16.4.10
2.16.5.12.16.5.22.16.5.3
2.16.5.42.16.5.52.16.5.62.16.5.72.16.5.82.16.5.92.16.5.10
2.16.6.12.16.6.22.16.6.32.16.6.4
2.16.6.52.16.6.62.16.6.72.16.6.82.16.6.92.16.6.102.17.1.12.17.1.22.17.1.32.17.1
.42.17.1.5
2.17.1.62.17.1.72.17.1.82.17.1.92.17.1.102.17.2.12.17.2.22.27.2.32.17.2.42.17.2
.52.17.2.6
2.17.2.72.17.2.82.17.2.92.17.2.102.17.3.12.17.3.22.17.3.32.17.3.42.17.3.52.17.3
.62.17.3.7
2.17.3.82.17.3.92.17.3.102.17.4.12.17.4.22.17.4.32.17.4.42.17.4.52.17.4.62.17.4
.72.17.4.8
2.17.4.92.17.4.102.17.5.12.17.5.22.17.5.32.17.5.42.17.5.52.17.5.62.17.5.72.17.5
.82.17.5.9
2.17.5.10 2.17.6.82.17.6.92.17.6.10
2.17.6.1
2.17.6.2
2.17.6.3
2.17.6.4
2.17.6.5
2.17.6.6
2.17.6.7
2.18.1.12.18.1.22.18.1.32.18.1.42.18.1.52.18.1.62.18.1.72.18.1.82.18.1.92.18.2.
10 2.18.2.1
2.18.2.22.18.2.32.18.2.42.18.2.52.18.2.62.18.2.72.18.2.82.18.2.92.18.2.10
2.18.3.12.18.3.2
2.18.3.32.18.3.42.18.3.52.18.3.62.18.3.72.18.3.82.18.3.92.18.3.102.18.4.12.18.4
.22.18.4.3
2.18.4.42.18.4.52.18.4.62.18.4.72.18.4.82.18.4.92.18.4.102.18.5.12.18.5.22.18.5
.32.18.5.4
2.18.5.52.18.5.62.18.5.72.18.5.82.18.5.92.18.5.102.18.6.12.18.6.22.18.6.32.18.6
.42.18.6.5
2.18.6.62.18.6.72.18.6.82.18.6.92.18.6.102.19.1.12.19.1.22.19.1.32.19.1.42.19.1
.52.19.1.6
2.19.1.72.19.1.82.19.1.92.19.1.102.19.2.12.19.2.22.19.2.32.19.2.42.19.2.52.19.2
.62.19.2.7
2.19.2.82.19.2.92.19.2.102.19.3.12.19.3.22.19.3.32.19.3.42.19.3.52.19.3.62.19.3
.72.19.3.8
2.19.3.92.19.3.102.19.4.12.19.4.22.19.4.32.19.4.42.19.4.52.19.4.62.19.4.72.19.4
.82.19.4.9
2.19.4.10 2.19.5.82.19.5.92.19.5.10
2.19.5.1
2.19.5.2
2.19.5.3
2.19.5.4
2.19.5.5
2.19.5.6
2.19.5.7
2.19.6.12.19.6.22.19.6.32.19.6.42.19.6.52.19.6.62.19.6.72.19.6.82.19.6.92.19.6.
10 2.20.1.1
2.20.1.22.20.1.32.20.1.42.20.1.52.20.1.62.20.1.72.20.1.82.20.1.9
2.20.2.12.20.2.2
2.20.L10
2.20.2.32.20.2.42.20.2.52.20.2.62.20.2.72.20.2.82.20.2.92.20.2.102.20.3.12.20.3
.22.20.3.3
2.20.3.42.20.3.52.20.3.62.20.3.72.20.3.82.20.3.92.20.3.102.20.4.12.20.4.22.20.4
.32.20.4.4
2.20.4.52.20.4.62.20.4.72.20.4.82.20.4.92.20.4.102.20.5.12.20.5.22.20.5.32.20.5
.42.20.5.5
2.20.5.62.20.5.72.20.5.82.20.5.92.20.5.102.20.6.12.20.6.22.20.6.32.20.6.42.20.6
.52.20.6.6
2.20.6.72.20.6.82.20.6.92.20.6.102.21.1.12.21.1.22.21.1.32.21.1.42.21.1.52.21.1
.62.21.1.7
2.21.1.82.21.1.92.21.1.10
2.21.2.22.21.2.32.21.2.42.21.2.52.21.2.62.21.2.72.21.2.8
2.21.2.1
2.21.2.92.21.2.10 2.21.3.2
2.21.3.42.21.3.52.21.3.62.21.3.72.21.3.82.21.3.9
2.21.3.1 2.21.3.3
2.21.3.10 2.21.4.1 2.21.4.92.21.4.10
2.21.4.2
2.21.4.3
2.21.4.4
2.21.4.5
2.21.4.6
2.21.4.7
2.21.4.8
2.21.5.12.21.5.22.21.5.32.21.5.42.21.5.52.21.5.62.21.5.72.21.5.82.21.5.92.21.5.
10 2.21.6.1
2.21.6.22.21.6.32.21.6.42.21.6.52.21.6.62.21.6.72.21.6.82.21.6.92.21.6.102.22.1
.12.22.1.2
2.22.1.32.22.1.42.22.1.52.22.1.62.22.1.72.22.1.82.22.1.92.22.1.102.22.2.12.22.2
.22.22.2.3
2.22.2.42.22.2.52.22.2.62.22.2.72.22.2.82.22.2.92.22.2.102.22.3.12.22.3.22.22.3
.32.22.3.4
2.22.3.52.22.3.62.22.3.72.22.3.82.22.3.92.22.3.102.22.4.12.22.4.22.22.4.32.22.4
.42.22.4.5
14
CA 02261619 1999-O1-20
WO 98/04569 PCTIUS97l13244
2.22.4.62.22.4.7 2.22.4.8 2.22.4.9 2.22.5.22.22.5.3
2.22.4.10 2.22.5.1 2.22.5.4
2.22.5.5
2.22.5.6
2.22.5.72.22.5.8 2.22.5.9 2.22.5.102.22.6.32.22.6.4 .5 2.22.6.6
2.22.6.1 2.22.6.2 2.22.6 2.22.6.7
2.22.6.82.22.6.9 2.22.6.10 2.23.1.12.23.1.42.23.1.5 .6 2.23.1.7
2.23.1.2 2.23.L3 2.23.1 2.23.1.8
2.23.1.92.23.1.10 2.23.2.1 2.23.2.22.23.2.52.23.2.6 .7 2.23.2.8
2.23.2.3 2.23.2.4 2.23.2 2.23.2.9
2.23.2.10 2.23.3.62.23.3.7
2.23.3.1 2.23.3.8
2.23.3.2 2.23.3.9
2.23.3.3 2.23.3.10
2.23.3.4
2.23.3.5
2.23.4.12.23.4.2 2.23.4.3 2.23.4.4 2.23.4.8 9 2.23.4.10
2.23.4.5 2.23.4.6 2.23.4.7 2.23.4. 2.23.5.1
2.23.5.22.23.5.3 2.23.5.4 2.23.5.5 2.23.5.9
2.23.5.6 2.23.5.7 2.23.5.8 2.23.5.1
0 2.23.6.2
2.23.6.2
2.23.6.32.23.6.4 2.23.6.5 2.23.6.6 .1 2.24.1.2
2.23.6.7 2.23.6.8 2.23.6.9 2.24.1.3
2.23.6.10 2.24.1
2.24.1.42.24.1.5 2.24.1.6 2.24.1.7 .24.1.102.24.2.1 .2 2.24.2.3
2.24.1.8 2.24.1.9 2 2.24.2 2.24.2.4
2.24.2.52.24.2.6 2.24.2.7 2.24.2.8 2.24.3.12.24.3.2 .3 2.24.3.4
2.24.2.9 2.24.2.10 2.24.3 2.24.3.5
2.24.3.62.24.3.7 2.24.3.8 2.24.3.9 2.24.4.22.24.4.3 .4 2.24.4.5
2.24.3.1 0 2.24.4.1 2.24.4 2.24.4.6
2.24.4.72.24.4.8 2.24.4.9 2.24.4.102.24.5.32.24.5.4 .5 2.24.5.6
2.24.5.1 2.24.5.2 2.24.5 2.24.5.7
2.24.5.82.24.5.9 2.24.5.1 0 2.24.6.12.24.6.42.24.6.5 .6 2.24.6.7
2.24.6.2 2.24.6.3 2.24.6 2.24.6.8
2.24.6.92.24.6.10 2.25.1.1 2.25.1.22.25.1.52.25.1.6 .7 2.25.1.8
2.25.1.3 2.25.1.4 2.25.1 2.25.1.9
2.25.1.10 2.25.2.62.25.2.7
2.25.2.1 2.25.2.8
2.25.2.2 2.25.2.9
2.25.2.3 2.25.2.10
2.252.4
2.25.2.5
2.25.3.12.25.3.2 2.25.3.3 2.25.3.4 2.25.3.8 9 2.25.3.1 0
2.25.3.5 2.25.3.6 2.25.3.7 2.25.3. 2.25.4.1
2.25.4.22.25.4.3 2.25.4.4 2.25.4.5 2.25.4.9
2.25.4.6 2.25.4.7 2.25.4.8 2.25.4.10
2.25.5.1
2.25.5.2
2.25.5.32.25.5.4 2.25.5.5 2.25.5.6 .1 2.25.6.2
2.25.5.7 2.25.5.8 2.25.5.9 2.25.6.3
2.25.5.10 2.25.6
2.25.6.42.25.6.5 2.25.6.6 2.25.6.7 3.1.1.1 3.1.1.3 3.1.1.4
2.25.6.8 2.25.6.9 2.25.6.10 3.1.1.2 3.1.1.5
3.1.1.63.1.1.7 3.1.1.8 3.1.1.9 3.1.2.33.1.2.4 3.1.2.6 3.1.2.7
3.1.1.10 3.1.2.1 3.1.2.2 3.1.2.5 3.1.2.8
3.1.2.9 3.1.3.63.1.3.7 3.1.3.9 3.1.3.1
3.1.2.10 3.1.3.8 0 3.1.4.1
3.1.3.1
3.1.3.2
3.1.3.3
3.1.3.4
3.1.3.5
3.1.4.23.1.4.3 3.1.4.4 3.1.4.5 3.1.4.9 3.1.5.2 3.1.5.3
3.1.4.6 3.1.4.7 3.1.4.8 3.L4.10 3.1.5.4
3.1.5.1
3.1.5.53.1.5.6 3.1.5.7 3.1.5.8 3.1.6.23.1.6.3 3.1.6.5 3.1.6.6
3.1.5.9 3.1.5.1 0 3.1.6.1 3.1.6.4 3.1.6.7
3.1.6.83.1.6.9 3.1.6.1 0 3.2.1.1 3.2.1.53.2.1.6 3.2.1.8 3.2.1.9
3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.7 3.2.1.1 0
3.2.2.13.2.2.2 3.2.2.3 3.2.2.4 3.2.2.83.2.2.9 3.2.3.1 3.2.3.2
3.2.2.5 3.2.2.6 3.2.2.7 3.2.2.1 3.2.3.3
0
3.2.3.43.2.3.5 3.2.3.6 3.2.3.7 3.2.4.13.2.4.2 3.2.4.4 3.2.4.5
3.2.3.8 3.2.3.9 3.2.3.1 3.2.4.3 3.2.4.6
0
3.2.4.73.2.4.8 3.2.4.9 3.2.4.10 3.2.5.43.2.5.5 3.2.5.7 3.2.5.8
3.2.5.1 3.2.5.2 3.2.5.3 3.2.5.6 3.2.5.9
3.2.5.103.2.6.1 3.2.6.2 3.2.6.3 3.2.6.8 3.2.6.10 3.3.1.1
3.2.6.4 3.2.6.5 3.2.6.6 3.2.6.9 3.3.1.2
3.2.6.7
3.3.1.33.3.1.4 3.3.1.5 3.3.1.6 3.3.2.1 3.3.2.3 3.3.2.4
3.3.1.7 3.3.1.8 3.3.1.9 3.3.2.2 3.3.2.5
3.3.1.10
3.3.2.63.3.2.7 3.3.2.8 3.3.2.9 3.3.3.33.3.3.4 3.3.3.6 3.3.3.7
3.3.2.1 0 3.3.3.1 3.3.3.2 3.3.3.5 3.3.3.8
3.3.3.9 3.3.4.63.3.4.7 3.3.4.9 3.3.4.1
3.3.3.10 3.3.4.8 0 3.3.5.1
3.3.4.1
3.3.4.2
3.3.4.3
3.3.4.4
3.3.4.5
3.3.5.23.3.5.3 3.3.5.4 3.3.5.5 3.3.5.9 3.3.6.2 3.3.6.3
3.3.5.6 3.3.5.7 3.3.5.8 3.3.5.10 3.3.6.4
3.3.6.1
3.3.6.53.3.6.6 3.3.6.7 3.3.6.8 3.4.1.23.4.1.3 3.4.1.5 3.4.1.6
3.3.6.9 3.3.6.10 3.4.1.1 3.4.1.4 3.4.1.7
3.4.1.83.4.1.9 3.4.1.1 0 3.4.2.1 3.4.2.53.4.2.6 3.4.2.8 3.4.2.9
3.4.2.2 3.4.2.3 3.4.2.4 3.4.2.7 3.4.2.1 0
3.4.3.13.4.3.2 3.4.3.3 3.4.3.4 3.4.3.83.4.3.9 3.4.4.1 3.4.4.2
3.4.3.5 3.4.3.6 3.4.3.7 3.4.3.1 3.4.4.3
0
3.4.4.43.4.4.5 3.4.4.6 3.4.4.7 3.4.5.13.4.5.2 3.4.5.4 3.4.5.5
3.4.4.8 3.4.4.9 3.4.4.1 3.4.5.3 3.4.5.6
0
3.4.5.73.4.5.8 3.4.5.9 3.4.5.10 3.4.6.43.4.6.5 3.4.6.7 3.4.6.8
3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.6 3.4.6.9
3.4.6.13.5.1.1 3.5.1.2 3.5.1.3 3.5.1.8 3.5.1.1 0 3.5.2.1
0 3.5.1.4 3.5.1.5 3.5.1.6 3.5.1.9 3.5.2.2
3.5.1.7
3.5.2.33.5.2.4 3.5.2.5 3.5.2.6 3.5.2.103.5.3.1 3.5.3.3 3.5.3.4
3.5.2.7 3.5.2.8 3.5.2.9 3.5.3.2 3.5.3.5
3.5.3.63.5.3.7 3.5.3.8 3.5.3.9 3.5.4.33.5.4.4 3.5.4.6 3.5.4.7
3.5.3.10 3.5.4.1 3.5.4.2 3.5.4.5 3.5.4.8
3.5.4.9 3.5.5.63.5.5.7 3.5.5.9 3.5.5.10
3.5.4.10 3.5.5.8 3.5.6.1
3.5.5.1
3.5.5.2
3.5.5.3
3.5.5.4
3.5.5.5
3.5.6.23.5.6.3 3.5.6.4 3.5.6.5 3.5.6.9 3.6.1.2 3.6.1.3
3.5.6.6 3.5.6.7 3.5.6.8 3.5.6.10 3.6.1.4
3.6.1.1
3.6.1.53.6.1.6 3.6.1.7 3.6.1.8 3.6.2.23.6.2.3 3.6.2.5 3.6.2.6
3.6.1.9 3.6.1.10 3.6.2.1 3.6.2.4 3.6.2.7
3.6.2.83.6.2.9 3.6.2.1 0 3.6.3.1 3.6.3.53.6.3.6 3.6.3.8 3.6.3.9
3.6.3.2 3.6.3.3 3.6.3.4 3.6.3.7 3.6.3.1 0
3.6.4.13.6.4.2 3.6.4.3 3.6.4.4 3.6.4.83.6.4.9 3.6.5.1 3.6.5.2
3.6.4.5 3.6.4.6 3.6.4.7 3.6.4.1 3.6.5.3
0
3.6.5.43.6.5.5 3.6.5.6 3.6.5.7 3.6.6.13.6.6.2 3.6.6.4 3.6.6.5
3.6.5.8 3.6.5.9 3.6.5.1 3.6.6.3 3.6.6.6
0
3.6.6.73.6.6.8 3.6.6.9 3.6.6.10 3.7.1.43.7.1.5 3.7.1.7 3.7.1.8
3.7.1.1 3.7.1.2 3.7.1.3 3.7.1.6 3.7.1.9
3.7.1.103.7.2.1 3.7.2.2 3.7.2.3 3.7.2.8 3.7.2.1 0 3.7.3.1
3.7.2.4 3.7.2.5 3.7.2.6 3.7.2.9 3.7.3.2
3.7.2.7
3.7.3.33.7.3.4 3.7.3.5 3.7.3.6 3.7.3.103.7.4.1 3.7.4.3 3.7.4.4
3.7.3.7 3.7.3.8 3.7.3.9 3.7.4.2 3.7.4.5
3.7.4.63.7.4.7 3.7.4.8 3.7.4.9 3.7.5.33.7.5.4 3.7.5.6 3.7.5.7
3.7.4.1 0 3.7.5.1 3.7.5.2 3.7.5.5 3.7.5.8
3.7.5.9 3.7.6.63.7.6.7 3.7.6.9 3.7.6.10
3.7.5.10 3.7.6.8 3.8.1.1
3.7.6.1
3.7.6.2
3.7.6.3
3.7.6.4
3.7.6.5
3.8.1.23.8.1.3 3.8.1.4 3.8.1.5 3.8.1.9 3.8.2.2 3.8.2.3
3.8.1.6 3.8.1.7 3.8.1.8 3.8.1.10 3.8.2.4
3.8.2.1
3.8.2.53.8.2.6 3.8.2.7 3.8.2.8 3.8.3.23.8.3.3 3.8.3.5 3.8.3.6
3.8.2.9 3.8.2.10 3.8.3.1 3.8.3.4 3.8.3.7
3.8.3.83.8.3.9 3.8.3.1 0 3.8.4.1 3.8.4.53.8.4.6 3.8.4.8 3.8.4.9
3.8.4.2 3.8.4.3 3.8.4.4 3.8.4.7 3.8.4.1 0
3.8.5.13.8.5.2 3.8.5.3 3.8.5.4 3.8.5.83.8.5.9 3.8.6.1 3.8.6.2
3.8.5.5 3.8.5.6 3.8.5.7 3.8.5.10 3.8.6.3
3.8.6.43.8.6.5 3.8.6.6 3.8.6.7 3.9.1.13.9.1.2 3.9.1.4 3.9.1.5
3.8.6.8 3.8.6.9 3.8.6.1 3.9.1.3 3.9.1.6
0
3.9.1.73.9.1.8 3.9.1.9 3.9.1.10 3.9.2.43.9.2.5 3.9.2.7 3.9.2.8
3.9.2.1 3.9.2.2 3.9.2.3 3.9.2.6 3.9.2.9
CA 02261619 1999-O1-20
WO 98/04569 PCTlUS97/13244
3.9.2.103.9.3.1 3.9.3.8
3.9.3.2 3.9.3.9
3.9.3.3 3.9.3.10
3.9.3.4 3.9.4.1
3.9.3.5 3.9.4.2
3.9.3.6
3.9.3.7
3.9.4.3.9.4.4 4.6 .7 3.9.4.93.9.4.103.9.5.19.5.2
3 3.9.4.5 3.9.4 3.9.4.8 3. 3.9.5.3
3.9. 3.9.5.4
3.9.5.5
3.9.5.6.9.5.7 5.93.9.5.10 3.9.6.33.9.6.49.6.5
3 3.9.5.8 3.9.6.1 3. 3.9.6.6
3.9. 3.9.6.2 3.9.6.7
3.9.6.8
3.9.6.93.9.6.10 10.1.110.1.210.1.3 10.1.510.1.6
3. 3. 3. 3.10.1.4 3. 3.10.1.7
3. 3.10.1.8
3.10.1.9
3.10.1.103.10.2.13.10.2.23.10.2.33.10.2.43.10.2.53.10.2.63.10.2.73.10.2.83.10.2
.93.10.2.10
3.10.3.13.10.3.23.10.3.33.10.3.43.10.3.5 3.10.3.73.10.3.8
3.10.4.1
3.10.3.6 3.10.3.93.10.3.10
3.20.4.23.10.4.33.10.4.43.10.4.53.10.4.6
3.10.4.83.10.4.93.10.4.103.10.5.13.10.5.2
3.10.4.7
3.10.5.33.10.5.43.10.5.53.10.5.63.10.5.7 3.10.5.93.10.5.10
3.10.6.13.10.6.23.10.6.3
3.10.5.8
3.10.6.43.10.6.53.10.6.63.10.6.73.10.6.8
3.11.1.13.11.1.23.11.1.33.11.1.4
3.10.6.93.10.6.10
3.11.1.53.11.1.63.11.1.73.11.1.83.11.1.93.11.1.10
3.11.2.13.11.2.23.11.2.33.11.2.43.11.2.5
3.11.2.63.11.2.73.11.2.83.11.2.93.11.2.10
3.11.3.13.11.3.23.11.3.33.11.3.43.11.3.53.11.3.6
3.11.3.73.11.3.83.11.3.93.11.3.10
3.11.4.13.11.4.23.11.4.33.11.4.43.11.4.53.11.4.63.11.4.7
3.11.4.83.11.4.93.11.4.10
3.11.5.13.11.5.23.11.5.33.11.5.43.11.5.53.11.5.63.11.5.73.11.5.8
3.11.5.93.11.5.10
3.11.6.13.11.6.23.11.6.33.11.6.43.11.6.53.11.6.63.11.6.73.11.6.83.11.6.9
3.11.6.103.12.1.13.12.1.23.12.1.33.12.1.43.12.1.53.12.1.63.12.1.73.12.1.83.12.1
.93.12.1.10
3.12.2.13.12.2.23.12.2.33.12.2.43.12.2.53.12.2.63.12.2.73.12.2.8
3.12.3.1
3.12.2.93.12.2.10
3.12.3.23.12.3.33.12.3.43.12.3.53.12.3.63.12.3.73.12.3.83.12.3.93.12.3.10
3.12.4.13.12.4.2
3.12.4.33.12.4.43.12.4.53.12.4.63.12.4.73.12.4.83.12.4.93.12.4.10
3.12.5.13.12.5.23.12.5.3
3.12.5.43.12.5.53.12.5.63.12.5.73.12.5.83.12.5.93.12.5.10
3.12.6.13.12.6.23.12.6.33.12.6.4
3.12.6.53.12.6.63.12.6.73.12.6.83.12.6.93.12.6.10
3.13.1.13.13.1.23.13.1.33.13.1.43.13.1.5
3.13.1.63.13.1.73.13.1.83.13.1.93.13.1.103.13.2.13.13.2.23.13.2.33.13.2.43.13.2
.53.13.2.6
3.13.2.73.13.2.83.13.2.93.13.2.103.13.3.13.13.3.23.13.3.33.13.3.43.13.3.53.13.3
.63.13.3.7
3.13.3.83.13.3.93.13.3.10
3.13.4.13.13.4.23.13.4.33.13.4.43.13.4.53.13.4.63.13.4.73.13.4.8
3.13.4.93.13.4.10
3.13.5.13.13.5.23.13.5.33.13.5.43.13.5.53.13.5.63.13.5.73.13.5.83.13.5.9
3.13.5.103.13.6.13.13.6.2
3.13.6.53.13.6.63.13.6.73.13.6.83.13.6.93.13.6.10
3.13.6.3
3.13.6.4
3.14.1.13.14.1.23.14.1.33.14.1.43.14.1.53.14.1.63.14.1.73.14.1.83.14.1.93.14.1.
10 3.14.2.1
3.14.2.23.14.2.33.14.2.43.14.2.53.14.2.63.14.2.73.14.2.83.14.2.93.14.2.10
3.14.3.13.14.3.2
3.14.3.33.14.3.43.14.3.53.14.3.63.14.3.73.14.3.83.14.3.93.14.3.10
3.14.4.13.14.4.23.14.4.3
3.14.4.43.14.4.53.14.4.63.14.4.73.14.4.83.14.4.93.14.4.10
3.14.5.13.14.5.23.14.5.33.14.5.4
3.14.5.53.14.5.63.14.5.73.14.5.83.14.5.93.14.5.10
3.14.6.13.14.6.23.14.6.33.14.6.43.14.6.5
3.14.6.63.14.6.73.14.6.83.14.6.93.14.6.103.15.1.13.15.1.23.15.1.33.15.1.43.15.1
.53.15.1.6
3.15.1.73.15.1.83.15.1.93.15.1.103.15.2.13.15.2.23.15.2.33.25.2.43.15.2.53.15.2
.63.15.2.7
3.15.2.83.15.2.93.15.2.103.15.3.13.15.3.23.15.3.33.15.3.43.15.3.53.15.3.63.15.3
.73.15.3.8
3.15.3.93.15.3.103.15.4.13.15.4.23.15.4.33.15.4.43.15.4.53.15.4.63.15.4.73.15.4
.83.15.4.9
3.15.4.10 3.15.5.5 3.15.5.83.15.5.93.15.5.10
3.15.5.1 3.15.5.6
3.15.5.2 3.15.5.7
3.15.5.3
3.15.5.4
3.15.6.13.15.6.23.15.6.33.15.6.43.15.6.53.15.6.63.15.6.73.15.6.83.15.6.93.15.6.
10 3.16.1.1
3.16.1.23.16.1.33.16.1.43.16.1.53.16.1.63.16.1.73.16.1.83.16.1.93.16.1.10
3.16.2.13.16.2.2
3.16.2.33.16.2.43.16.2.53.16.2.63.16.2.73.16.2.83.16.2.93.16.2.103.16.3.13.16.3
.23.16.3.3
3.16.3.43.16.3.53.16.3.63.16.3.73.16.3.83.16.3.93.16.3.103.16.4.13.16.4.23.16.4
.33.16.4.4
3.16.4.53.16.4.63.16.4.73.16.4.83.16.4.93.16.4.103.16.5.13.16.5.23.16.5.33.16.5
.43.16.5.5
3.16.5.63.16.5.73.16.5.83.16.5.93.16.5.103.16.6.13.16.6.23.16.6.33.16.6.43.16.6
.53.16.6.6
3.16.6.73.16.6.83.16.6.93.16.6.103.17.1.13.17.1.23.17.1.33.17.1.43.17.1.53.17.1
.63.17.1.7
3.17.1.83.17.1.93.17.1.10
3.17.2.23.17.2.33.17.2.43.17.2.53.17.2.63.17.2.73.17.2.8
3.17.2.1
3.17.2.93.17.2.103.17.3.13.17.3.2
3.17.3.43.17.3.53.17.3.63.17.3.73.17.3.83.17.3.9
3.17.3.3
3.17.3.10 3.17.4.8 3.17.4.10
3.17.4.1 3.17.4.9
3.17.4.2
3.17.4.3
3.17.4.4
3.17.4.5
3.17.4.6
3.17.4.7
3.17.5.13.17.5.23.17.5.33.17.5.43.17.5.53.17.5.63.17.5.73.17.5.83.17.5.93.17.5.
103.17.6.1
3.17.6.23.17.6.33.17.6.43.17.6.53.17.6.63.17.6.73.17.6.83.17.6.93.17.6.10
3.18.1.13.18.1.2
3.18.1.33.18.1.43.18.1.53.18.1.63.18.1.73.18.1.83.18.1.93.18.1.103.18.2.13.18.2
.23.18.2.3
3.18.2.43.18.2.53.18.2.63.18.2.73.18.2.83.18.2.93.18.2.103.18.3.13.18.3.23.18.3
.33.18.3.4
3.18.3.53.18.3.63.18.3.73.18.3.83.18.3.93.18.3.103.18.4.13.18.4.23.18.4.33.18.4
.43.18.4.5
3.18.4.63.18.4.73.18.4.83.18.4.93.18.4.103.18.5.13.18.5.23.18.5.33.18.5.43.18.5
.53.18.5.6
3.18.5.73.18.5.83.18.5.93.18.5.10 3.18.6.2
3.18.6.43.18.6.53.18.6.63.18.6.7
3.18.6.1 3.18.6.3
3.18.6.83.18.6.93.18.6.10 3.19.1.3
3.19.1.53.19.1.63.19.1.73.19.1.8
3.19.1.1 3.19.1.4
3.19.1.2
3.19.1.93.19.1.10 3.19.2.4 3.19.2.63.19.2.73.19.2.83.19.2.9
3.19.2.1 3.19.2.5
3.19.2.2
3.19.2.3
3.19.2.10 1 2 3.19.3.3
3.19.3. 3.19.3. 3.19.3.4
3.19.3.5
3.19.3.6
3.19.3.7
3.19.3.8
3.19.3.93.19.3.10
3.19.4.13.19.4.23.19.4.33.19.4.43.19.4.53.19.4.63.19.4.73.19.4.83.19.4.93.19.4.
103.19.5.1
3.19.5.23.19.5.33.19.5.43.19.5.53.19.5.63.19.5.73.19.5.83.19.5.93.19.5.103.19.6
.13.19.6.2
16
CA 02261619 1999-O1-20
WO 98/04569 PCT/US97113244
3.19.6.33.19.6.4 3.19.6.5 3.19.6.6 3.19.6.7 3.20.1.1 3.20.1.2
3.19.6.8 3.19.6.9 3.19.6.10 3.20.1.3
3.20.1.43.20.1.5 3.20.1.6 3.20.1.7 3.20.1.83.20.2.13.20.2.2 3.20.2.3
3.20.1.9 3.20.1.10 3.20.2.4
3.20.2.53.20.2.6 3.20.2.7 3.20.2.8 3.20.2.9320.3.23.20.3.3 3.20.3.4
3.20.2.10 3.20.3.1 3.20.3.5
3.20.3.63.20.3.7 3.20.3.8 3.20.3.9 3.20.3.103.20.4.33.20.4.4 3.20.4.5
3.20.4.1 3.20.4.2 3.20.4.6
3.20.4.73.20.4.8 3.20.4.9 3.20.4.10 3.20.5.13.20.5.43.20.5.5 3.20.5.6
3.20.5.2 3.20.5.3 3.20.5.7
3.20.5.83.20.5.9 3.20.5.10 3.20.6.1 3.20.6.23.20.6.53.20.6.6 3.20.6.7
3.20.6.3 3.20.6.4 3.20.6.8
3.20.6.93.20.6.10 3.21.1.1 3.21.1.2 3.21.1.33.21.1.63.21.1.7 3.21.1.8
3.21.1.4 3.21.1.5 3.21.1.9
3.21.1.10 3.21.2.7
3.21.2.1 3.21.2.8
3.21.2.2 3.21.2.93.21.2.10
3.21.2.3
3.21.2.4
3.21.2.5
3.21.2.6
3.21.3.13.21.3.2 3.21.3.3 3.21.3.4 3.21.3.53.21.3.83.21.3.9 3.21.3.10
3.21.3.6 3.21.3.7 3.2L4.1
3.21.4.23.21.4.3 3.21.4.4 3.21.4.5 3.21.4.63.21.4.93.21.4.10 3.21.5.1
3.21.4.7 3.21.4.8 3.21.5.2
3.21.5.33.21.5.4 3.21.5.5 3.21.5.6 3.21.5.7 3.21.6.1 3.21.62
3.21.5.8 3.21.5.93.21.5.10 3.21.6.3
3.21.6.43.21.6.5 3.21.6.6 3.21.6.7 3.21.6.83.22.1.13.22.1.2 3.22.1.3
3.21.6.9 3.21.6.10 3.22.1.4
3.22.1.53.22.1.6 3.22.1.7 3.22.1.8 3.22.1.93.22.2.23.22.2.3 3.22.2.4
3.22.1.10 3.22.2.1 3.22.2.5
3.22.2.63.22.2.7 3.22.2.8 3.22.2.9 3.22.2.103.22.3.33.22.3.4 3.22.3.5
3.22.3.1 3.22.3.2 3.22.3.6
3.22.3.73.22.3.8 3.22.3.9 3.22.3.10 3.22.4.13.22.4.43.22.4.5 3.22.4.6
3.22.4.2 3.22.4.3 3.22.4.7
3.22.4.83.22.4.9 3.22.4.10 3.22.5.1 3.22.5.23.22.5.53.22.5.6 3.22.5.7
3.22.5.3 3.22.5.4 3.22.5.8
3.22.5.93.22.5.10 3.22.6.1 3.22.6.2 3.22.6.33.22.6.63.22.6.7 3.22.6.8
3.22.6.4 3.22.6.5 3.22.6.9
3.22.6.10
3.23.1.1
3.23.1.2
3.23.1.3
3.23.1.4
3.23.1.5
3.23.1.6
3.23.1.7
3.23.1.8
3.23.1.9
3.23.1.10
3.23.2.13.23.2.2 3.23.2.3 3.23.2.4 3.23.2.53.23.2.83.23.2.9 3.23.2.10
3.23.2.6 3.23.2.7 3.23.3.1
3.23.3.23.23.3.3 3.23.3.4 3.23.3.5 3.23.3.63.23.3.93.23.3.10 3.23.4.1
3.23.3.7 3.23.3.8 3.23.4.2
3.23.4.33.23.4.4 3.23.4.5 3.23.4.6 3.23.4.73.23.4.103.23.5.1 3.23.5.2
3.23.4.8 3.23.4.9 3.23.5.3
3.23.5.43.23.5.5 3.23.5.6 3.23.5.7 3.23.5.83.23.6.13.23.6.2 3.23.6.3
3.23.5.9 3.23.5.10 3.23.6.4
3.23.6.53.23.6.6 3.23.6.7 3.23.6.8 3.23.6.93.24.1.23.24.1.3 3.24.1.4
3.23.6.10 3.24.1.1 3.24.1.5
3.24.1.63.24.1.7 3.24.1.8 3.24.1.9 3.24.1.103.24.2.33.24.2.4 3.24.2.5
3.24.2.1 3.24.2.2 3.24.2.6
3.24.2.73.24.2.8 3.24.2.9 3.24.2.10 3.24.3.13.24.3.43.24.3.5 3.24.3.6
3.24.3.2 3.24.3.3 3.24.3.7
3.24.3.83.24.3.9 3.24.3.10 3.24.4.1 3.24.4.23.24.4.53.24.4.6 3.24.4.7
3.24.4.3 3.24.4.4 3.24.4.8
3.24.4.93.24.4.10 3.24.5.1 3.24.5.2 3.24.5.33.24.5.63.24.5.7 3.24.5.8
3.24.5.4 3.24.5.5 3.24.5.9
3.24.5.10
3.24.6.1
3.24.6.2
3.24.6.3
3.24.6.4
3.24.6.5
3.24.6.6
3.24.6.7
3.24.6.8
3.24.6.9
3.24.6.10
3.25.1.13.25.1.2 3.25.1.3 3.25.1.4 3.25.1.53.25.1.83.25.1.9 3.25.1.10
3.25.1.6 3.25.1.7 3.25.2.1
3.25.2.23.25.2.3 3.25.2.4 3.25.2.5 3.25.2.63.25.2.93.25.2.10 3.25.3.1
3.25.2.7 3.25.2.8 3.25.3.2
3.25.3.33.25.3.4 3.25.3.5 3.25.3.6 3.25.3.73.25.3.10
3.25.3.8 3.25.3.9 3.25.4.1
3.25.4.2
3.25.4.3
3.25.4.43.25.4.5 3.25.4.6 3.25.4.7 3.25.4.83.25.5.13.25.5.2 3.25.5.3
3.25.4.9 3.25.4.10 3.25.5.4
3.25.5.53.25.5.6 3.25.5.7 3.25.5.8 3.25.5.93.25.6.2
3.25.5.10 3.25.6.1 3.25.6.3
3.25.6.4
3.25.6.5
3.25.6.63.25.6.73.25.6.83.25.6.93.25.6.104.1.1.14.1.1.24.1.1.34.L1.44.1.1.54.1.
1.64.1.1.7
4.1.1.84.1.1.94.1.1.10 4.1.2.1 4.1.2.2 4.1.2.64.1.2.7 4.1.2.8
4.1.2.3 4.1.2.4 4.1.2.5 4.1.2.94.1.2.10
4.1.3.14.1.3.2 4.1.3.3 4.1.3.4 4.1.3.5 4.1.3.9.1.3.10 4.1.4.1
4.1.3.6 4.1.3.7 4.1.3.8 4 4.1.4.2 4.1.4.3
4.1.4.44.1.4.5 4.1.4.6 4.1.4.7 4.1.4.8 4.1.5.24.1.5.3 4.1.5.4
4.1.4.9 4.1.4.10 4.1.5.1 4.1.5.5 4.1.5.6
4.1.5.74.1.5.8 4.1.5.9 4.1.5.10 4.1.6.1 4.1.6.54.1.6.6 4.1.6.7
4.1.6.2 4.1.6.3 4.1.6.4 4.1.6.8 4.1.6.9
4.1.6.104.2.1.1 4.2.1.2 4.2.1.3 4.2.1.4 4.2.1.84.2.1.9 4.2.1.10
4.2.1.5 4.2.1.6 4.2.1.7 4.2.2.1 4.2.2.2
4.2.2.34.2.2.4 4.2.2.5 4.2.2.6 4.2.2.7 4.2.3.14.2.3.2 4.2.3.3
4.2.2.8 4.2.2.9 4.2.2.10 4.2.3.4 4.2.3.5
4.2.3.64.2.3.7 4.2.3.8 4.2.3.94.2.3.10 4.2.4.44.2.4.5 4.2.4.6
4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.7 4.2.4.8
4.2.4.9 4.2.5.74.2.5.8 4.2.5.9
4.2.4.10 4.2.5.10 4.2.6.1
4.2.5.1
4.2.5.2
4.2.5.3
4.2.5.4
4.2.5.5
4.2.5.6
4.2.6.24.2.6.3 4.2.6.4 4.2.6.5 4.2.6.6 4.3.1.1 4.3.1.2
4.2.6.7 4.2.6.8 4.2.6.9 4.2.6.10 4.3.1.3 4.3.1.4
4.3.1.54.3.1.6 4.3.1.7 4.3.1.8 4.3.1.9 4.3.2.34.3.2.4 4.3.2.5
4.3.1.10 4.3.2.1 4.3.2.2 4.3.2.6 4.3.2.7
4.3.2.84.3.2.94.3.2.10 4.3.3.1 4.3.3.2 4.3.3.64.3.3.7 4.3.3.8
4.3.3.3 4.3.3.4 4.3.3.5 4.3.3.94.3.3.10
4.3.4.14.3.4.2 4.3.4.3 4.3.4.4 4.3.4.5 4.3.4.9
4.3.4.6 4.3.4.7 4.3.4.8 4.3.4.10
4.3.5.1
4.3.5.2
4.3.5.3
4.3.5.44.3.5.5 4.3.5.6 4.3.5.7 4.3.5.8 4.3.6.24.3.6.3 4.3.6.4
4.3.5.94.3.5.10 4.3.6.1 4.3.6.5 4.3.6.6
4.3.6.74.3.6.8 4.3.6.9 4.3.6.10 4.4.1.1 4.4.1.54.4.1.6 4.4.1.7
4.4.1.2 4.4.1.3 4.4.1.4 4.4.1.8 4.4.1.9
4.4.1.10 4.4.2.9 4.4.2.10
4.4.2.1 4.4.3.1 4.4.3.2
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
4.4.3.34.4.3.4 4.4.3.5 4.4.3.6 4.4.3.7 4.4.4.14.4.4.2 4.4.4.3
4.4.3.8 4.4.3.94.4.3.10 4.4.4.4 4.4.4.5
4.4.4.64.4.4.7 4.4.4.8 4.4.4.94.4.4.10 4.4.5.44.4.5.5 4.4.5.6
4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.7 4.4.5.8
4.4.5.9 4.4.6.74.4.6.8 4.4.6.9
4.4.5.10 4.4.6.10 4.5.1.1
4.4.6.1
4.4.6.2
4.4.6.3
4.4.6.4
4.4.6.5
4.4.6.6
4.5.1.24.5.1.3 4.5.1.4 4.5.1.5 4.5.1.6 4.5.1.104.5.2.1 4.5.2.2
4.5.1.7 4.5.1.8 4.5.1.9 4.5.2.3 4.5.2.4
4.5.2.54.5.2.6 4.5.2.7 4.5.2.8 4.5.2.9 4.5.3.34.5.3.4 4.5.3.5
4.5.2.10 4.5.3.1 4.5.3.2 4.5.3.6 4.5.3.7
4.5.3.84.5.3.9 4.5.3.10 4.5.4.1 4.5.4.2 4.5.4.64.5.4.7 4.5.4.8
4.5.4.3 4.5.4.4 4.5.4.5 4.5.4.9 4.5.4.10
4.5.5.14.5.5.2 4.5.5.3 4.5.5.4 4.5.5.5 4.5.5.9
4.5.5.6 4.5.5.7 4.5.5.8 4.5.5.10
4.5.6.1
4.5.6.2
4.5.6.3
4.5.6.44.5.6.5 4.5.6.6 4.5.6.7 4.5.6.8 4.6.1.24.6.1.3 4.6.L4
4.5.6.9 4.5.6.10 4.6.1.1 4.6.1.5 4.6.1.6
17
CA 02261619 1999-O1-20
WO 98104569 PCT/US97l13244
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 4.6.3.1 0 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 4.6.5.1 0 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 4.7.1.1 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 4.7.3.1 0 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 4.7.4.1 0 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 4.8.1.1 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 4.8.1.1 0 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 4.8.2.1 0 4.8.3.1 4.8.3.2 4.8.3.3 4.8.3.4 4.8.3.5
4.8.3.6 4.8.3.7 4.8.3.8 4.8.3.9
4.8.3.10 4.8.4.1 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 4.8.5.1 0 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 4.8.6.1 0 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 4.9.1.1 0 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
4.9.4.5 4.9.4.6 4.9.4.7 4.9.4.8 4.9.4.9 4.9.4.1 0 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
4.10.1.1 4.10.1.2 4.10.1.3 4.10.1.4 4.10.1.5 4.10.1.6 4.10.1.7 4.10.1.8
4.10.1.94.10.1.10 4.10.2.1
2~ 4.10.2.2 4.10.2.3 4.10.2.4 4.10.2.5 4.10.2.6 4.10.2.7 4.10.2.8
4.10.2.94.10.2.10 4.10.3.1 4.10.3.2
4.10.3.3 4.10.3.4 4.10.3.5 4.10.3.6 4.10.3.7 4.10.3.8 4.10.3.94.10.3.10
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 4.10.4.94.10.4.10 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 4.10.5.94.10.5.10 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 4.11.1.1 4.1L1.2 4.11.1.3
4.11.1.4 4.11.1.5 4.11.1.6
4.11.1.7 4.11.1.8 4.11.1.94.11.1.10 4.11.2.1 4.11.2.2 4.11.2.3 4.11.2.4
4.11.2.5 4.11.2.6 4.11.2.7
4.11.2.8 4.11.2.94.11.2.10 4.11.3.1 4.11.3.2 4.11.3.3 4.11.3.4 4.11.3.5
4.11.3.6 4.11.3.7 4.11.3.8
4.11.3.94.11.3.10 4.11.4.1 4.11.4.2 4.11.4.3 4.11.4.4 4.11.4.5 4.11.4.6
4.11.4.7 4.11.4.8 4.11.4.9
4.11.4.10 4.11.5.1 4.11.5.2 4.11.5.3 4.12.5.4 4.11.5.5 4.11.5.6 4.11.5.7
4.11.5.8 4.11.5.94.11.5.10
4.11.6.1 4.11.6.2 4.11.6.3 4.11.6.4 4.11.6.5 4.11.6.6 4.11.6.7 4.11.6.8
4.11.6.94.11.6.10 4.12.1.1
4.12.1.2 4.12.1.3 4.12.1.4 4.12.1.5 4.12.1.6 4.12.1.7 4.12.1.8
4.12.1.94.12.1.10 4.12.2.1 4.12.2.2
4.12.2.3 4.12.2.4 4.12.2.5 4.12.2.6 4.12.2.7 4.12.2.8 4.12.2.94.12.2.10
4.12.3.1 4.12.3.2 4.12.3.3
4.12.3.4 4.12.3.5 4.12.3.6 4.12.3.7 4.12.3.8 4.12.3.94.12.3.10 4.12.4.1
4.12.4.2 4.12.4.3 4.12.4.4
4.12.4.5 4.12.4.6 4.12.4.7 4.12.4.8 4.12.4.94.12.4.10 4.12.5.1 4.12.5.2
4.12.5.3 4.12.5.4 4.12.5.5
4.12.5.6 4.12.5.7 4.12.5.8 4.12.5.94.12.5.10 4.12.6.1 4.12.6.2 4.12.6.3
4.12.6.4 4.12.6.5 4.12.6.6
4.12.6.7 4.12.6.8 4.12.6.94.12.6.10 4.13.1.1 4.13.1.2 4.13.1.3 4.13.1.4
4.13.1.5 4.13.1.6 4.13.1.7
4.13.1.8 4.13.1.94.13.1.10 4.13.2.1 4.13.2.2 4.13.2.3 4.13.2.4 4.13.2.5
4.13.2.6 4.13.2.7 4.13.2.8
4.13.2.94.13.2.10 4.13.3.1 4.13.3.2 4.13.3.3 4.13.3.4 4.13.3.5 4.13.3.6
4.13.3.7 4.13.3.8 4.13.3.9
4.13.3.10 4.13.4.1 4.13.4.2 4.13.4.3 4.13.4.4 4.13.4.5 4.13.4.6 4.13.4.7
4.13.4.8 4.13.4.94.13.4.10
4.13.5.1 4.13.5.2 4.13.5.3 4.13.5.4 4.13.5.5 4.13.5.6 4.13.5.7 4.13.5.8
4.13.5.94.13.5.10 4.13.6.1
4.13.6.2 4.13.6.3 4.13.6.4 4.13.6.5 4.13.6.6 4.13.6.7 4.13.6.8
4.13.6.94.13.6.10 4.14.1.1 4.14.1.2
4.14.1.3 4.14.1.4 4.14.1.5 4.14.1.6 4.14.1.7 4.14.1.8 4.14.1.94.14.1.10
4.14.2.1 4.14.2.2 4.14.2.3
4.14.2.4 4.14.2.5 4.14.2.6 4.14.2.7 4.14.2.8 4.14.2.9 4.14.2.1 0 4.14.3.1 4.1
4.3.2 4.14.3.3 4.14.3.4
4.14.3.5 4.14.3.6 4.14.3.7 4.14.3.8 4.14.3.94.14.3.10 4.14.4.1 4.14.4.2
4.14.4.3 4.14.4.4 4.14.4.5
4.14.4.6 4.14.4.7 4.14.4.8 4.14.4.94.14.4.10 4.14.5.1 4.14.5.2 4.14.5.3
4.14.5.4 4.14.5.5 4.14.5.6
4.14.5.7 4.14.5.8 4.14.5.94.14.5.10 4.14.6.1 4.14.6.2 4.14.6.3 4.14.6.4
4.14.6.5 4.14.6.6 4.14.6.7
4.14.6.8 4.14.6.94.14.6.10 4.15.1.1 4.15.1.2 4.15.1.3 4.15.1.4 4.15.1.5
4.15.1.6 4.15.1.7 4.15.1.8
4.15.1.94.15.1.10 4.15.2.1 4.15.2.2 4.15.2.3 4.15.2.4 4.15.2.5 4.15.2.6
4.15.2.7 4.15.2.8 4.15.2.9
4.15.2.10 4.15.3.1 4.15.3.2 4.15.3.3 4.15.3.4 4.15.3.5 4.15.3.6 4.15.3.7
4.15.3.8 4.15.3.94.15.3.10
4.15.4.1 4.15.4.2 4.15.4.3 4.15.4.4 4.15.4.5 4.15.4.6 4.15.4.7 4.15.4.8
4.15.4.94.15.4.10 4.15.5.1
4.15.5.2 4.15.5.3 4.15.5.4 4.15.5.5 4.15.5.6 4.15.5.7 4.15.5.8
4.15.5.94.15.5.10 4.15.6.1 4.15.6.2
4.15.6.3 4.15.6.4 4.15.6.5 4.15.6.6 4.15.6.7 4.15.6.8 4.15.6.94.15.6.10
4.16.1.1 4.16.1.2 4.16.1.3
4.16.1.4 4.16.1.5 4.16.1.6 4.16.1.7 4.16.1.8 4.16.1.94.16.1.10 4.16.2.1
4.16.2.2 4.16.2.3 4.16.2.4
4.16.2.5 4.16.2.6 4.16.2.7 4.16.2.8 4.16.2.94.16.2.10 4.16.3.1 4.16.3.2
4.16.3.3 4.16.3.4 4.16.3.5
4.16.3.6 4.16.3.7 4.16.3.8 4.16.3.94.16.3.10 4.16.4.1 4.16.4.2 4.16.4.3
4.16.4.4 4.16.4.5 4.16.4.6
4.16.4.7 4.16.4.8 4.16.4.94.16.4.10 4.16.5.1 4.16.5.2 4.16.5.3 4.16.5.4
4.16.5.5 4.16.5.6 4.16.5.7
4.16.5.8 4.16.5.94.16.5.10 4.16.6.1 4.16.6.2 4.16.6.3 4.16.6.4 4.16.6.5
4.16.6.6 4.16.6.7 4.16.6.8
4.16.6.94.16.6.10 4.17.1.1 4.17.1.2 4.17.1.3 4.17.1.4 4.17.1.5 4.17.1.6
4.17.1.7 4.17.1.8 4.17.1.9
18
CA 02261619 1999-O1-20
WO 98104569 PCTIL1S97I13244
4.17.1.10
4.17.2.24.17.2.34.17.2.44.17.2.54.17.2.64.17.2.74.17.2.84.17.2.94.17.2.10
4.17.2.1
4.17.3.14.17.3.24.17.3.34.17.3.44.17.3.54.17.3.64.17.3.74.17.3.8
4.17.4.1
4.17.3.94.17.3.10
4.17.4.24.17.4.34.17.4.44.17.4.54.17.4.64.17.4.74.17.4.84.17.4.94.17.4.10
4.17.5.14.17.5.2
4.17.5.34.17.5.44.17.5.54.17.5.64.17.5.74.17.5.84.17.5.94.17.5.10
4.17.6.14.17.6.24.17.6.3
4.17.6.44.17.6.54.17.6.64.17.6.74.17.6.84.17.6.94.17.6.10
4.18.1.14.18.1.24.18.1.34.18.1.4
4.18.1.54.18.1.64.18.1.74.18.1.84.18.1.94.18.1.10
4.18.2.14.18.2.24.28.2.34.18.2.44.18.2.5
4.18.2.64.18.2.74.18.2.84.18.2.94.18.2.10
4.18.3.14.18.3.24.18.3.34.18.3.44.18.3.54.18.3.6
4.18.3.74.18.3.84.18.3.94.18.3.10
4.18.4.14.18.4.24.18.4.34.18.4.44.18.4.54.18.4.64.18.4.7
4.18.4.84.18.4.94.18.4.10
4.18.5.14.18.5.24.18.5.34.18.5.44.18.5.54.18.5.64.18.5.74.18.5.8
4.18.5.94.18.5.104.18.6.14.18.6.24.18.6.34.18.6.44.18.6.54.18.6.64.18.6.74.18.6
.84.18.6.9
4.18.6.10 4.19.1.24.19.1.3
4.19.1.54.19.1.64.19.1.74.19.1.84.19.1.94.19.1.10
4.19.1.1 4.19.1.4
4.19.2.14.19.2.24.19.2.34.19.2.44.19.2.54.19.2.64.19.2.74.19.2.84.19.2.94.19.2.
10 4.19.3.1
4.29.3.24.19.3.34.19.3.44.19.3.54.19.3.64.19.3.74.19.3.84.19.3.94.19.3.10
4.19.4.14.19.4.2
4.19.4.34.19.4.44.19.4.54.19.4.64.19.4.74.19.4.84.19.4.94.19.4.10
4.19.5.14.19.5.24.19.5.3
4.19.5.44.19.5.54.19.5.64.19.5.74.19.5.84.19.5.94.19.5.10
4.19.6.14.19.6.24.19.6.34.19.6.4
4.19.6.54.19.6.64.19.6.74.19.6.84.19.6.9
4.20.1.14.20.1.24.20.1.34.20.1.44.20.1.5
4.19.6.10
4.20.1.64.20.1.74.20.1.84.20.1.94.20.1.104.20.2.14.20.2.24.20.2.34.20.2.44.20.2
.54.20.2.6
4.20.2.74.20.2.84.20.2.9
4.20.3.14.20.3.24.20.3.34.20.3.44.20.3.54.20.3.64.20.3.7
4.20.2.10
4.20.3.84.20.3.94.20.3.104.20.4.14.20.4.24.20.4.34.20.4.44.20.4.54.20.4.64.20.4
.74.20.4.8
4.20.4.94.20.4.104.20.5.14.20.5.24.20.5.34.20.5.44.20.5.54.20.5.64.20.5.74.20.5
.84.20.5.9
4.20.5.10 4.20.6.3
4.20.6.54.20.6.64.20.6.74.20.6.84.20.6.94.20.6.10
4.20.6.1 4.20.6.4
4.20.6.2
4.21.1.14.21.1.24.21.1.34.21.1.44.21.1.54.21.1.64.21.2.74.21.1.84.21.1.9
4.21.2.1
4.21.1.10
4.21.2.24.21.2.34.2L2.44.21.2.54.21.2.64.21.2.74.22.2.84.21.2.9
4.21.3.14.21.3.2
4.21.2.10
4.21.3.34.21.3.44.21.3.54.21.3.64.22.3.74.21.3.84.21.3.9
4.21.4.14.21.4.24.21.4.3
4.21.3.10
4.21.4.44.21.4.54.21.4.64.21.4.74.21.4.84.21.4.94.21.4.10
4.21.5.14.21.5.24.21.5.34.21.5.4
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CA 02261619 1999-O1-20
WO 98104569 PCTIUS97113244
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WO 98104569 PCT/US97/13244
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5.15.3.15.15.3.25.15.3.35.15.3.45.15.3.55.15.3.65.15.3.75.15.3.85.15.3.95.15.3.
10 5.15.4.1
5.15.4.25.15.4.35.15.4.45.15.4.55.15.4.65.15.4.75.15.4.85.15.4.95.15.4.10
5.15.5.15.15.5.2
5.15.5.35.15.5.45.15.5.55.15.5.65.15.5.75.15.5.85.15.5.95.15.5.10
5.15.6.15.15.6.25.15.6.3
5.15.6.45.15.6.55.15.6.65.15.6.75.15.6.85.15.6.95.15.6.10
5.16.1.15.16.1.25.16.1.35.16.1.4
5.16.1.55.16.1.65.16.1.75.16.1.85.16.1.95.16.1.10
5.16.2.15.16.2.25.16.2.35.16.2.45.16.2.5
5.16.2.65.16.2.75.16.2.85.16.2.95.16.2.10
5.16.3.15.16.3.25.16.3.35.16.3.45.16.3.55.16.3.6
5.16.3.75.16.3.85.16.3.95.16.3.10
5.16.4.15.16.4.25.16.4.35.16.4.45.16.4.55.16.4.65.16.4.7
5.16.4.85.16.4.95.16.4.10
5.16.5.15.16.5.25.16.5.35.16.5.45.16.5.55.16.5.65.16.5.75.16.5.8
5.16.5.95.16.5.105.16.6.15.16.6.25.16.6.35.16.6.45.16.6.55.16.6.65.16.6.75.16.6
.85.16.6.9
5.16.6.10
5.17.1.25.17.1.35.17.1.45.17.1.55.17.1.65.17.1.75.17.1.85.17.1.95.17.1.10
5.17.1.1
5.17.2.15.17.2.25.17.2.35.17.2.45.17.2.55.17.2.65.17.2.75.17.2.85.17.2.95.17.2.
10 5.17.3.1
5.17.3.25.17.3.35.17.3.45.17.3.55.17.3.65.17.3.75.17.3.85.17.3.95.17.3.10
5.17.4.15.17.4.2
5.17.4.35.17.4.45.17.4.55.17.4.65.17.4.75.17.4.85.17.4.95.17.4.10
5.17.5.15.17.5.25.17.5.3
5.17.5.45.17.5.55.17.5.65.17.5.75.17.5.85.17.5.95.17.5.10
5.17.6.15.17.6.25.17.6.35.17.6.4
5.17.6.55.17.6.65.17.6.75.17.6.85.17.6.95.17.6.10
5.18.1.15.18.1.25.18.1.35.18.1.45.18.1.5
5.18.1.65.18.1.75.18.1.85.18.1.95.18.1.10
5.18.2.15.18.2.25.18.2.35.18.2.45.18.2.55.18.2.6
5.18.2.75.18.2.85.18.2.95.18.2.10
5.18.3.15.18.3.25.18.3.35.18.3.45.18.3.55.18.3.65.18.3.7
5.18.3.85.18.3.95.18.3.105.18.4.15.18.4.25.18.4.35.18.4.45.18.4.55.18.4.65.18.4
.75.18.4.8
5.18.4.95.18.4.105.18.5.15.18.5.25.18.5.35.18.5.45.18.5.55.18.5.65.18.5.75.18.5
.85.18.5.9
5.18.5.10 5.18.6.25.18.6.35.18.6.45.18.6.55.18.6.6
5.18.6.85.18.6.95.18.6.10
5.18.6.1 5.18.6.7
5.19.1.15.19.1.25.19.1.35.19.1.45.19.1.55.19.1.65.19.1.75.19.1.85.19.1.95.19.1.
10 5.19.2.1
5.19.2.25.19.2.35.19.2.45.19.2.55.19.2.65.19.2.75.19.2.85.19.2.95.19.2.10
5.19.3.15.19.3.2
5.19.3.35.19.3.45.19.3.55.19.3.65.19.3.75.19.3.85.19.3.95.19.3.10
5.19.4.15.19.4.25.19.4.3
5.19.4.45.19.4.55.19.4.65.19.4.75.19.4.85.19.4.95.19.4.10
5.19.5.15.19.5.25.19.5.35.19.5.4
5.19.5.55.19.5.65.19.5.75.19.5.85.19.5.95.19.5.10
5.19.6.15.19.6.25.19.6.35.19.6.45.19.6.5
5.19.6.65.19.6.75.19.6.85.19.6.9
5.20.1.15.20.1.25.20.1.35.20.1.45.20.1.55.20.1.6
5.19.6.10
5.20.1.75.20.1.85.20.1.9
5.20.2.15.20.2.25.20.2.35.20.2.45.20.2.55.20.2.65.20.2.7
5.20.1.10
5.20.2.85.20.2.95.20.2.105.20.3.15.20.3.25.20.3.35.20.3.45.20.3.55.20.3.65.20.3
.75.20.3.8
5.20.3.95.20.3.105.20.4.15.20.4.25.20.4.35.20.4.45.20.4.55.20.4.65.20.4.75.20.4
.85.20.4.9
5.20.4.10 5.20.5.55.20.5.6 5.20.5.85.20.5.95.20.5.10
5.20.5.1 5.20.5.7
5.20.5.2
5.20.5.3
5.20.5.4
5.20.6.15.20.6.25.20.6.35.20.6.45.20.6.55.20.6.65.20.6.75.20.6.85.20.6.9
5.21.1.1
5.20.6.10
5.21.1.25.21.1.35.21.1.45.21.1.55.21.1.65.21.1.75.21.1.85.21.1.95.21.1.10
5.21.2.15.21.2.2
5.21.2.35.21.2.45.21.2.55.21.2.65.21.2.75.21.2.85.21.2.95.21.2.105.21.3.15.21.3
.25.21.3.3
5.21.3.45.21.3.55.21.3.65.21.3.75.21.3.85.21.3.95.21.3.10
5.21.4.15.21.4.25.21.4.35.21.4.4
5.21.4.55.21.4.65.21.4.75.21.4.85.21.4.95.21.4.105.21.5.15.21.5.25.21.5.35.21.5
.45.21.5.5
5.21.5.65.21.5.75.21.5.85.21.5.95.21.5.105.21.6.15.21.6.25.21.6.35.21.6.45.21.6
.55.21.6.6
5.21.6.75.21.6.85.21.6.95.21.6.105.22.1.15.22.1.25.22.1.35.22.1.45.22.1.55.22.1
.65.22.1.7
5.22.1.85.22.1.95.22.1.105.22.2.15.22.2.25.22.2.35.22.2.45.22.2.55.22.2.65.22.2
.75.22.2.8
5.22.2.95.22.2.105.22.3.15.22.3.25.22.3.35.22.3.45.22.3.55.22.3.65.22.3.75.22.3
.85.22.3.9
5.22.3.10 5.22.4.6 5.22.4.85.22.4.95.22.4.10
5.22.4.1 5.22.4.7
5.22.4.2
5.22.4.3
5.22.4.4
5.22.4.5
5.22.5.15.22.5.25.22.5.35.22.5.45.22.5.55.22.5.65.22.5.75.22.5.85.22.5.9
5.22.6.1
5.22.5.10
5.22.6.25.22.6.35.22.6.45.22.6.55.22.6.65.22.6.75.22.6.85.22.6.9
5.23.1.15.23.1.2
5.22.6.10
5.23.1.35.23.1.45.23.1.55.23.1.65.23.1.75.23.1.85.23.1.95.23.1.105.23.2.15.23.2
.25.23.2.3
5.23.2.45.23.2.55.23.2.65.23.2.75.23.2.85.23.2.95.23.2.105.23.3.15.23.3.25.23.3
.35.23.3.4
5.23.3.55.23.3.65.23.3.75.23.3.85.23.3.95.23.3.105.23.4.15.23.4.25.23.4.35.23.4
.45.23.4.5
5.23.4.65.23.4.75.23.4.85.23.4.95.23.4.105.23.5.15.23.5.25.23.5.35.23.5.45.23.5
.55.23.5.6
5.23.5.75.23.5.85.23.5.95.23.5.105.23.6.15.23.6.25.23.6.35.23.6.45.23.6.55.23.6
.65.23.6.7
5.23.6.85.23.6.95.23.6.105.24.1.15.24.1.25.24.1.35.24.1.45.24.1.55.24.1.65.24.1
.75.24.1.8
5.24.1.95.24.1.105.24.2.15.24.2.25.24.2.35.24.2.45.24.2.55.24.2.65.24.2.75.24.2
.85.24.2.9
5.24.2.10 5.24.3.1 5.24.3.95.24.3.10
5.24.3.2
5.24.3.3
5.24.3.4
5.24.3.5
5.24.3.6
5.24.3.7
5.24.3.8
5.24.4.15.24.4.25.24.4.35.24.4.45.24.4.55.24.4.65.24.4.75.24.4.85.24.4.9
5.24.5.1
5.24.4.10
5.24.5.25.24.5.35.24.5.45.24.5.55.24.5.65.24.5.75.24.5.85.24.5.9
5.24.6.15.24.6.2
5.24.5.10
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5.24.6.3 5.24.6.4 5.24.6.5 5.24.6.6 5.24.6.7 5.24.6.8 5.24.6.9 5.24.6.10
5.25.1.1 5.25.1.2 5.25.1.3
5.25.1.4 5.25.1.5 5.25.1.6 5.25.1.7 5.25.1.8 5.25.1.9 5.25. L 10 5.25.2.1
5.25.2.2 5.25.2.3 5.25.2.4
5.25.2.5 5.25.2.6 5.25.2.7 5.25.2.8 5.25.2.9 5.25.2.10 5.25.3.1 5.25.3.2
5.25.3.3 5.25.3.4 5.25.3.5
5.25.3.6 5.25.3.7 5.25.3.8 5.25.3.9 5.25.3.10 5.25.4.1 5.25.4.2 5.25.4.3
5.25.4.4 5.25.4.5 5.25.4.6
5.25.4.7 5.25.4.8 5.25.4.9 5.25.4.10 5.25.5.1 5.25.5.2 5.25.5.3 5.25.5.4
5.25.5.5 5.25.5.6 5.25.5.7
5.25.5.8 5.25.5.9 5.25.5.10 5.25.6.1 5.25.6.2 5.25.6.3 5.25.6.4 5.25.6.5
5.25.6.6 5.25.6.7 5.25.6.8
5.25.6.9 5.25.6.10
Exemplary embodiments include the following numbered groups of
compounds.
1 Each compound named in Table B having only one carbonate moiety
and a hydroxyl group linked to the phosphorus atom in place of the second
carbonate moiety, i.e., B-CH2-CHRl-O-CH2-P(O)(OH}-O-CHR2-O-C(O)-OR.
Thus, the group 1 compound named 1.4.1.1 in Table B has the structure:
adenin-9-yl-CH2-CH{CH3)-O-CH2-P{O)(OH)-O-CH2-O-C(O)-OCH(CH3)2.
2 Compounds named in Table B having only one carbonate moiety
and having only the Rl moiety, #3 (-CH20H), which is modified such that R8
of formula (1) compounds is joined with Rl to form -CH2-. Thus, the group 2
compound named 1.4.3.1 in Table B has the structure:
adenin-9-yl-CH2-CH(CH2-0)-O-CH2-P(O)(O-0)-O-CH2-O-C{O)-OCH(CH3)2,
where the symbols 0 indicate a covalent bond that links the oxygen and
carbon atoms. together.
3 Compounds named in Table B and compounds named by compound
groups 1 and 2 where each purine base listed in Table A is the 3-deaza analog,
e.g., 3-deazaadenin-9-yl. Thus, the group 3 compound defined in Table A and
named 1.4.1.1 in Table B has the structure:
3-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(-O-CH2-O-C(O)-OCH(CH3)2)2.
The group 3 compound defined in Table A and named 1.4.1.1 in compound
group 1 has the structure:
3-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(OH)-O-CH2-O-C(O}-OCH(CH3)2.
4 Compounds named in Table B and compounds named by compound
groups 1 and 2 where each purine base listed in Table A is the 1-deaza analog,
e.g., 1-deazaadenin-9-yl. Thus, the group 4 compound defined in Table A and
named 1.4.1.1 in Table B has the structure:
1-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O}(-O-CH2-O-C(O)-OCH(CH3)2)2.
The group 3 compound defined in Table A and named 1.4.1.1 in compound
group 1 has the structure:
1-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(OH}-O-CH2-O-C{O)-OCH{CH3)2.
5 Compounds named in Table B and compounds named by compound
groups 1 and 2 where each purine base listed in Table A is the 8-aza analog,
e.g., 8-azaadenin-9-yl.
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6 Compounds named in Table B and compounds named by compound
groups 1-5 where R moieties 1-25 listed in Table A are replaced with the
following groups:
1 -cyclopropyl (cyclopropyl replaces -CH3, which is R moiety 1 in Table A)
2 -CH2-cyclopropyl
3 -(CH2)2-cyclopropyl
4 -(CH2)3-cyclopropyl
5 -(CH2)4-cyclopropyl
6 -cyclobutyl
7 -CH2-cyclobutyl
8 -(CH2)2-cyclobutyl
9 -(CH2)3-cyclobutyl
10 -(CHZ)4-cyclobutyl
11 -cyclopentyl
22 -CH2-cyclopentyl
13 -(CHZ)2-cyclopentyl
14 -{CH2)3-cyclopentyl
15 -{CH2)4-cyclopentyl
16 -cyclohexyl
17 -CH2-cyclohexyl
18 -(CHZ}2-cyclohexyl
19 -(CH2)3-cyclohexyl
20 -(CH2)4-cyclohexyl
21 -CH(CH3)CH2-cyclopropyl
22 -CH(CH3)CH2-cyclobutyl
23 -CH(CH3)CH2-cyclopentyl
24 -CH(CH3)CH2-cyclohexyl
25 -(CH2)~4-cyclooctyl.
Thus, the group 6 compound defined in Table A and named 1.16.1.1 in Table
B has the structure:
adenin-9-yl-CHZ-CH(CH3)-O-CH2-P(O)(-O-CH2-O-C(O)-O-cyclohexyl)2. The
group 6 compound defined in Table A and named 1.16.1.1 in compound
group 1 has the structure:
adenin-9-yl-CHZ-CH(CH3)-O-CH2-P(O)(OH)-O-CH2-O-C(O)-O-cyclohexyl. The
group 6 compound defined in Table A and named 1.16.1.1 in compound
group 3 has the structure:
3-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(-O-CH2-O-C(O)-O-cyclohexyl)2.
7 Compounds named in Table B and compounds named by compound
groups 1-5 where R moieties 1-25 listed in Table A are replaced with the
following groups:
1 7 carbon alkyl* 4 10 carbon alkyl 7 -(CH2)2C6H5
2 8 carbon alkyl 5 11 carbon alkyl 8 -(CH2)3C6H5
3 9 carbon alkyl 6 12 carbon alkyl 9 -(CHZ)4C6H5
10 -C(CH3)2CH(CH3)2
11 -CH(CH3)C(CH3)3
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12 -{CH2)2CH(C2H5)CH2CH3
13 -(CH2)2CH(C2H5)(CH2)2CH3
14 -(CH2)2CH(C2H5)(CH2)3CH3
15 -(CH2)3CH(C2H5)CH3
16 -(CH2)3CH(C2H5)CHZCH3
17 -(CH2}3CH(C2H5)(CH2)2CH3
18 -CH2CH(C2H~)CH2CH3
19 -CHZCH(C2H5)(CHZ)2CH3
20 -CH2CH(C2H5)(CH2)3CH3
21 -(CH2)2CH(C3H~)CH2CH3
22 -(CH2)ZCH(C3H~)(CHZ)2CH3
23 -(CH2)2CH(C3H7){CH2}3CH3
24 -CH2CH=CH2
25 -CH=CHCH3.
* Alkyl groups are linear, branched, cyclic or monounsaturated (-C=C-).
8 Compounds named in Table B and compounds named by compound
groups 1-5 where R moieties 1-25 listed in Table A are replaced with the
following groups:
1 -(CH2)20CH3 14 -(CH2)50(CH2}2CH3
2 -(CH2)30CH3 15 -(CH2)6O(CH2)2CH3
3 -(CH2)40CH3 16 -(CH2)20CH(CH3)2
4 -(CH2)50CH3 17 -(CH2)3OCH(CH3)2
5 -{CH2)60CH3 18 -(CHZ}40CH(CH3)2
6 -(CH2)2~H2CH3 19 -(CH2)5~H{CH3)2
7 -(CH2)30CH2CH3 20 -(CH2)60CH(CH3)2
8 -(CH2)40(CH2)2CH3 21 -(CH2)20(CH2)3CH3
9 -(CH2)5O(CH2)2CH3 22 -(CH2)ZOCH2CH(CH3)2
10 -(CHZ)60(CH2)ZCH3 23 -(CH2)ZOC(CH3)3
11 -(CH2)z0(CH2)2CH3 24 -(CH2)20C5H11
12 -(CH2)30(CH2)2CH3 25 -(CH2)20C6H13.
13 -(CHZ)40{CH2)2CH3
9 Compounds named in Table B and compounds named by compound
groups 1-5 where R moieties 1-25 listed in Table A are replaced with the
following groups:
1 -CH(CH3)CHZOCH3
2 -CH(CH3)(CH2)?OCH3
3 -CH(CH3)(CH2)30CH3
4 -CH(CH3)(CH2)40CH3
5 -CH(CH3)CHZOCH2CH3
6 -CH(CH3)(CH2)20CH2CH3
7 -CH(CH3)(CH2)30CH2CH3
8 -CH(CH3)(CHZ)40CH2CH3
9 -CH(CH3}CHZO(CH2)2CH3
10 -CH(CH3){CH2)ZO(CH2)2CH3
11 -CH(CH3)(CH2)30(CH2)ZCH3
12 -CH(CH3)(CH2)40(CH2)2CH3
13 -CH(CH3)CHZOCH(CH3)2
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14 -CH(CH3){CH2)20CH(CH3)2
15 -CH(CH3)(CH2)30CH(CH3)2
16 -CH(CH3){CH2)40CH(CH3)2
17 -CH(CH3)CHZOC4H9
18 -CH(CH3)(CH2)2OC4H9
19 -CH(CH3)(CHZ)30C4H9
20 -CH(CH3)(CH2)40C4H9
21 -CH(CH3)CH20CSH11
22 -CH(CH3)(CH2)20C5H11
-CH{CH3)(CH2)30C5H11
23
24 -CH(CH3)(CH2)40C5H11
25 -CH(CH3)CH20C6H13~
10 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
1 -CH(CH3)(CH2}20C6H1s
2 -CH(CH3)(CH2)30C6H13
3 -CH(CH3)(CH2)40C6H1s
4 -CH2CH(CH3)OCH3
5 -(CH2)2CH(CH3)OCH3
6 -(CH2)3CH(CH3)OCH3
7 -(CH2)4CH(CH3)OCH3
8 -CHZCH(CH3)OCH2CH3
9 -(CH2)2CH(CH3)OCH2CH3
10 -(CH2)3CH(CH3)OCH2CH3
11 -{CHZ)4CH(CH3)OCH2CH3
12 -CH2CH(CH3)OCH2CH3
13 -(CH2)2CH(CH3)O(CH2)2CH3
14 -(CH2)3CH(CH3)O(CHZ)3CH3
15 -(CH2)4CH(CH3)O(CHZ)4CH3
16 -CHZCH(CH3)OCH(CH3)2
17 -(CHZ)2CH(CH3)OCH(CH3)2
18 -(CH2)3CH(CH3)OCH(CH3)2
19 -(CH2)4CH(CH3)OCH(CH3)2
20 -CH2CH(CH3)OC4H9
21 -(CHZ)2CH(CH3)OC4H9
22 -(CH2)3CH(CH3)OC4H9
23 -(CHz)4CH(CH3)OC4H9
24 -CH2CH(CH3)OC5H11
25 -(CH2)2CH(CH3)OC5H11
11 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
1 -(CHZ)3CH(CH3)OCSHl
2 -(CH2)4CH(CH3)OC5H11
3 -CH2CH(CH3)OC6Hls
4 -{CH2)2CH(CH3)OC6H13
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-(CH2)3CH{CH3)C~C6H13
6 -(CH2)4CH(CH3)C~C6HI3
7 -{CH2)20CH{CH3)CZHS
8 -(CH2)20CH(CH3){CH2)2CH3
5 9 -(CH2)ZC~CH(CH3)CH(CH3)2
-(CH2)2~H(CH3)(CH2)3CH3
11 -(CH2)2C~CH(CH3)C(CH3)3
12 -(CH2)20CH(CH3)CH(CH3)CH2CH3
13 -{CH2)20CH(CH3)CH2CH(CH3)2
10 14 -(CHZ}gC~CH(CH3)C2H5
-(CH2)3C~CH(CH3){CH2)2CH3
16 -(CH2)3C~CH(CH3)CH{CH3)2
17 -(CHZ)3~H{CH3)(CH2)3CH3
18 -(CHZ)30CH(CH3)C(CH3)3
15 19 -(CH2)30CH(CH3)CH{CH3)CH2CH3
-(CH2)30CH(CH3)CH2CH(CH3)2
21 -(CHz)40CH(CH3)C2H5
22 -{CH2)40CH{CH3){CHZ)2CH3
23 -(CH2)40CH(CH3)CH(CH3)2
20 24 -(CHZ)40CH(CH3){CH2)3CH3
-(CH2)4C~CH(CH3)C(CH3)3
12 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
25 1 -{CH2)2O(CH2)3CH3
2 -{CH2)2~{CH2)4CH3
3 -(CH2)2~{CH2)5CH3
4 -(CH2)3~(CH2)3CH3
5 -(CH2)30(CH2)4CH3
6 -(CH2)3O(CH2)5CH3
7 -(CH2)2~6H5
8 -(CH2)20C6H5
9 -(CH2)2C~6H5
10 -CH{C2H5)CH20CH3
11 -CH(CZHS)CH2UC2H5
12 -CH(C2H5)CH20(CH2)?CH3
13 -CH(C2H5)CH2C~CH2(CH3)2
14 -CH{C2H5)CH20{CH2)3CH3
15 -CH(C2H5)CH20CH(CH3)CZHS
16 -CH(CZHS)CHZOCH2CH(CH3)2
17 -CH(C2H5)CH20C(CH3)3
28 -CH(C2H5)CH2O(CH2)4CH3
19 -CH(CZHS)CH20(CH2)2CH(CH3)2
20 -CH(C2H5)CH2O(CH2)5CH3
21 -CH(C2H5)CH2O(CH2)3CH(CH3)2
22 -CH2CH(C2H5)C~CH3
23 -CH2CH{C2H5)OCZHS
24 -CH2CH(C2H5)OC3H~
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25 -CH2CH(C2H5)OC4H9.
13 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
1 -(CH2)20-cyclopropyl
2 -(CH2)20-cyclobutyl
3 -(CH2)20-cyclopentyl
4 -(CH2)20-cyclohexyl
5 -(CH2)20CH2-cyclopropyl
6 -(CH2)20CH2-cyclobutyl
7 -(CH2)ZOCH2-cyclopentyl
8 -(CHZ)20CH2-cyclohexyl
9 -(CH2)20-(CH2)2cyclopropyl
10 -(CHZ)?O-(CH2)2cyclobutyl
11 -(CH2)20-(CH2)2cyclopentyl
12 -(CH2)20-(CHZ)2cyclohexyl
13 -(CHZ)30-cyclopropyl
14 -(CHZ)~O-cyclobutyl
15 -(CHZ)30-cyclopentyl
16 -(CH2)30-cyclohexyl
17 -(CHZ)30CH2-cyclopropyl
18 -(CH2)30CH2-cyclobutyl
19 -(CH2)30CH2-cyclopentyl
20 -(CH2)30CH2-cyclohexyl
21 -CH(CH3)CH20-cyclopropyl
22 -CH(CH3)CH20-cyclobutyl
23 -CH(CH3)CH20-cyclopentyl
24 -CH(CH3)CH20-cyclohexyl
25 -CH(CH3)CH20CH2-cyclohexyl.
14 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
1 -C(CHZOCH3)3
2 -C(C2H5)2(CH20CH3)
3 -CH(CZHS)(CHZOCH3)
4 -CHZ(CH?OCH3)
5 -C(CH3)2(CH20CH3)
6 -CH(CH~)(CH20CH3)
7 -C(CH20CZH5)3
8 -C(C2H5)2(CH2OC2H5)
9 -CH(C2H5)(CHZOCZHS)
10 -CH(C4H9)(CH20CH3)
11 -CH2C(CHZOCH3)s
12 -CHZC(C?H5)2(CH20CH3)
13 -CH2CH(C2H5)(CH20CH3)
14 -CH(CH20CH3)2
15 -CH2C(CH20CH3)3
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16 -CH2CH(CH20CH3)2
17 -C(CH20C2H5)3
18 -CH(CH2OC2H5)2
19 -CH2C(CH20C2H5)3
20 -CHZCH(CH20C2H5)2
21 -C(CZHS)2(CH2OC3H7)
22 -CH(C3H~)(CH20CH3)
23 -C(C3H~)2(CH20CH3)
24 -CH(CgH~)(CH20C2H5)
25 -C(C3H~)2(CH2OC2H5)
The following groups of compounds A-J.
A Compounds named in groups 8-14 where the oxygen atom (-O-) in
the R moiety is replaced with -NH-.
15 B Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with -N(CH3)-.
C Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with -N(C2H5)-.
D Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with -N(CH2CHZCH3)-.
E Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with -N(CH(CHg)2-.
F Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with n-butyl substituted nitrogen (-N(CH2)3CH3)-).
G Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with i-butyl substituted nitrogen.
H Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with t-butyl substituted nitrogen.
I Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with linear, branched or cyclic 5 carbon alkyl substituted
nitrogen.
J Compounds named in groups 8-14 where the oxygen atom in the R
moiety is replaced with linear, branched or cyclic 6 carbon alkyl substituted
nitrogen.
Thus, the group 15B compound defined in Table A and named 1.1.1.1 in
compound group 8 has the structure:
adenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(-O-CH2-O-C(O)-O-(CH2)2N(CH~)2)?.
The group 15B compound defined in Table A and named 1.1.1.1 in compound
group 1, as named under group 8, has the structure:
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adenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(OH}-O-CH2-O-C{O}-O-(CH2)2N(CH3)2.
The group 15B compound defined in Table A and named 1.26.1.1 in
compound group 3, as named under group 8, has the structure:
3-deazaadenin-9-yl-CH2-CH(CH3)-O-CHZ-P(O}{-O-CHz-O-C(O}-O-
(CH2)2N(CH3)2)2.
16 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
1 -(CH2)2R9
2 -(CH2)3R9
3 -(CH2)4R9
4 -(CH2)5R9
5 -(CH2)6R9
6 -(CH2)7R9
7 -(CHZ)8R9
8 -CH(CH3)CH2R9
9 -CH(CH3)(CH2)2R9
10 -CH(CH3)(CH2)3R9
11 -(CHZ)ZR9
12 -(CH2)3R9
13 -(CH2)4R9
14 -(CH2)5R9
15 -{CH2)6R9
16 -(CH2)~R9
17 -(CH2)8R9
18 -CH(CH3)CH2R9
19 -CH(CH3)(CH2)2R9
20 -CH(CH3)(CH2)3R9
21 -(CH2)ZR9
22 -(CH2)3R9
23 -(CHz)4Ra
24 -(CHz)5R9
25 -(CHZ)6R9
In moieties 1-10, R9 is N-morpholino, in moieties 11-20, R9 is 2-pyridyl and
in
moieties 21-25, R9 is 3-pyridyl.
17 Compounds named in Table B and compounds named by
compound groups 1-5 where R moieties 1-25 listed in Table A are replaced
with the following groups:
1 -(CHZ)2R9
2 -(CH2)3R9
3 -(CH2)4R9
4 -(CH2)5R9
5 -(CH2)6R9
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6 -(CHz)zCH(CH3)R9
7 -(CHz)3CH(CH3)R9
8 -{CHz)4CH(CH3)R9
9 -{CHz)zR9
9 -{CHz)3R9
11 -(CHz)4R9
12 -(CHz)5R9
13 -(CHz}6R9
14 -(CHz}6CH3
15 -(CHz)~CH3
16 -{CHz)8CH3
17 -(CHz)9CH3
18 -(CHz)loCHs
19 -{CHz)11CH3
20 -{CHz)4CH(CH3)2
21 -(CHz)5CH{CH3)z
22 -(CHz)6CH(CH3)z
23 -(CHz)~CH(CH3)z
24 -(CHz)gCH(CH3)2
25 -(CHz)9CH(CH3)z.
In moieties 1-5, R9 is 4-pyridyl, in moieties 6-9 R9 is N-morpholino and in
moieties 9-13, R9 is N-piperidyl.
18 The following groups of compounds A-J.
A Compounds named in Table B and compounds named by groups 1-
17 where compound (8) is replaced with compound (9}
Rz
O R
B ~~ O O OR
O~P
2
Rl (9)
where one Rz is as specified in Table A and the other Rz is -CH3.
B Compounds named in Table B and compounds named by
compound groups 1-17 where compound (8) is replaced with compound {9)
where one Rz is as specified in Table A and the other Rz is -CH2CH3.
C Compounds named in Table B and compounds named by
compound groups 1-17 where compound (8) is replaced with compound (9)
where one R2 is as specified in Table A and the other R2 is -{CHz)zCH3.
D Compounds named in Table B and compounds named by
compound groups 1-17 where compound (8) is replaced with compound (9)
where one R2 is as specified in Table A and the other R2 is -CH(CH3)2.
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E Compounds named in Table B and compounds named by compound
groups 1-17 where compound (8) is replaced with compound (9) where one R2
is as specified in Table A and the other R2 is -{CH2)3CH3.
F Compounds named in Table B and compounds named by compound
groups 1-17 where compound (8} is replaced with compound (9} where one RZ
is as specified in Table A and the other R2 is -(CH2)4CH3.
G Compounds named in Table B and compounds named by
compound groups 1-17 where compound (8) is replaced with compound (9)
where one R2 is as specified in Table A and the other R2 is -CH2CH{CH3)2.
H Compounds named in Table B and compounds named by
compound groups 1-17 where compound (8) is replaced with compound (9)
where one R2 is as specified in Table A and the other R2 is -C{CH3)3.
I Compounds named in Table B and compounds named by compound
groups 1-17 where compound (8) is replaced with compound (9) where one RZ
is as specified in Table A and the other R2 is -C5H11
J Compounds named in Table B and compounds named by compound
groups 1-17 where compound (8) is replaced with compound (9) where one RZ
is as specified in Table A and the other R2 is -C6H13~
Thus, the group 18A compound defined in Table A and named 1.4.2.3 in
Table B has the structure:
adenin-9-yl-CH2-CH2-O-CH(CH3)-P(O){-O-C(C2H5)(CH3)-O-C(O)-O-CH(CH3)2)2.
The group 18A compound defined in Table A and named 1.4.1.1 in
compound group 1 has the structure:
adenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(OH)-O-CH(CH3)-O-C(O)-O-CH(CH3)2.
The group 18A compound defined in Table A and named 1.1.1.1 in
compound group 3, as named under compound group 8, has the structure:
3-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(-O-CH(CH3)-O-C(O)-O-
(CH2)2~H3)2~
19 Compounds named in Table B and compounds named by
compound groups 1-28 where compound (8) and compound (9) are replaced
with compound (10) and {11) respectively
R2 R2
RZ O
O O N(R)2 B ~ p"O"N R
pip O
2
Ri (10) RI (11)
where both R moieties are the same. Thus, the group 19 compound defined
in Table A and named 1.4.1.1 in Table B has the structure:
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adenin-9-yl-CH2-CH(CH3)-O-CH(CH3)-P(O}(-O-CH2-O-C(O)-N-CH(CH3)2)2.
The group 19 compound defined in Table A and named 1.4.1.1 in compound
group 1 has the structure:
adenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(OH)-O-CH2-O-C(O)-N-CH(CH3)2. The
group 19 compound defined in Table A and named 1.1.1.1 in compound
group 3, as named under compound group 8, has the structure:
3-deazaadenin-9-yl-CH2-CH(CH3)-O-CH2-P(O)(-O-CH2-O-C(O)-N-
(CH2)20CH3}2~
The compounds of this invention are, to varying degrees, chemically
stable. It is preferable that the compounds be chemically stable in order to
ensure an adequate shelf-life and proper biodistribution upon oral
administration. In general, embodiments are selected that have a t 1/2 at pH
7.4 of greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours and preferably
in
addition possess a t 1/2 at pH 2.0 of greater than 1, 10 or 100 hours. For
example, the t-butyl carbonate found in Table 1 has a t 1 /2 that is less
stable
than these parameters and therefor is not preferred. In addition, the optimal
compounds of this invention should have bioavailability in beagle dogs {as
set forth in more detail below) that exceeds about 20%, preferably, about 30%.
SXnthetic Methods
The carbamates and carbonates of this invention are prepared from the
diacids of the phosphonomethoxy nucleotide analogs and the synthon
LCH(R2)OC(O}X(R)a. L is a leaving group such as Cl, although it will be
appreciated that any of the conventional leaving groups used in organic
chemistry in nucleophilic substitution reactions can be successfully employed
in place of chloro. In particular, leaving groups include halides, such as Cl,
Br
and I, and sulfonic acid esters such as methane, benzene or toluene sulfonic
acid esters. The synthon is prepared by reacting LCH(R2)OC(O)L with HOR for
preparation of the carbonate synthon or HNR2 for the preparation of the
carbamate synthon. The synthon is then reacted with the nucleotide analog
of choice, typically PMPA, to form the desired carbamate or carbonate adducts.
The carbamates are prepared by reacting the synthon with the nucleotide
analog under typical conditions of nucleophilic attack, for example in
Et3N/DMF at room temperature. The carbonates are formed by reacting the
appropriate synthon with the nucleotide analog in the presence of an organic
base, typically an amine base. In addition, masked leaving groups such as
thioethers, which may be activated by, for example, oxidation, and coupled
directly to the phosphonic acid moiety may be used. Intermediates may be
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WO 98104569 PCTIUS97113244
made with other leaving groups in this way, for example diphenylphosphinic
acids, and others known in the chemistry of formacetals and glycosylation.
O R
R..~ II
p + Q~O~CI ~ R~N O Q
R3 O
R3
O
I I
~OvP O H
R1
O R O
O~P O~O~~R
Ri ,O
R3
2
Compounds where X=N and R=OR3 may be prepared by alkylation
with the appropriate haloalkyl, O-alkyl carbamate. N, O-
dialkylhydroxylamines are known in the literature, and may be prepared by
alkylation of hydroxylamine, or by reductive amination of aldehydes or
ketones with alkyl hydroxylamines. The dialkylhydroxylamines may be
acylated with the appropriately substituted haloalkyl chloroformate under
conditions analagous to those used to prepare the unsubstituted chloromethyl
carbamates. Phosphonates may then be alkylated with the haloalkyl, O-alkyl
carbamates to give the prodrugs under conditions used for the carbonates and
carbamates. Leaving groups other than chloride may of course be used
throughout.
In a typical method, the carbonate compounds of this invention are
prepared by reacting L-CHR2-O-C(O)-OR with (4) to yield a compound of
formula (1).
(4)
O ~, OH Cl-CHR'--O-C{O)-OR
OR4 organic
R1 base
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R2
{I) O
,O O OR
O~P\O O OR
R1
R2 O
The reaction typically proceeds in two concurrent steps in which the
monoester forms first, and then the diester as the reaction proceeds longer.
In
this situation monoester is not typically isolated as an intermediate.
In order to make a diester that contains different carbonate or
carbamate functionalities the monoester intermediate is recovered from the
early reaction and the reaction is then completed with for example a second
L-CHR2-O-C{O)-OR reagent, thereby resulting in substitution with a second
ester different from the first.
One optionally conducts the carbonate synthesis reactions using at least
about 1.0 and typically 2 equivalents of L-CHR2-O-C(O)-OR. The reaction is
conducted in the presence of an organic base in an organic solvent at a
reaction temperature of about 4-100° for about 4-72 hours. Exemplary
suitable
organic bases include triethylamine or Hunig's base. Exemplary suitable
organic solvents include DMF, DMPU, or NMP.
The monoester or diester products are purified by standard methods
including flash column chromatography or salting out. Suitable salts for
purification and/or formulation will final product include the sulfuric acid,
phosphoric acid, lactic acid, fumaric or citric acid salts or complexes of the
diester or monoester compounds of structures (1) or (1a).
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Utilities
The compounds of this invention are useful in the treatment or
prophylaxis of one or more viral infections in man or animals, including
infections caused by DNA viruses, RNA viruses, herpesviruses (CMV, HSV 1,
HSV 2, VZV, and the like), retroviruses, hepadnaviruses, (e.g. HBV),
papillomavirus, hantavirus, adenoviruses and HIV. Other infections to be
treated with the compounds herein include MSV, RSV, SIV, FIV, MuLV, and
other retroviral infections of rodents and other animals. The prior art
describes the antiviral specificity of the nucleotide analogs, and the
parental
drug specificity is shared by the compounds of this invention. Dosages, viral
targets, and suitable administration routes to best attack the site of
infection
are well known in the art for the parental drugs. Determination of proper
doses is a straightforward matter for the clinician, taking into account the
molecular weight of the compounds of this invention and, when
adminstering them orally, their bioavailability in animals or as deduced in
clinical trials with humans. Oral dosages of the compounds of this invention
in humans for antiviral therapy will range about from 0.5 to 60 mg/Kg/day,
usually about from 1 to 30 mg/Kg/day and typically about from 1.5 to 10
mg/Kg/day.
The compounds of this invention also are useful as intermediates in
the preparation of detectable labels for oligonucleotide probes. The
compounds are hydrolyzed to yield the diacid, diphosphorylated and
incorporated into an oligonucleotide by conventional enzymatic or chemical
means. The incorporated base from the compound of the invention will be
capable of participating in base pairing and thus will not interfere
substantially with the binding of the oligonucleotide to its complementary
sequence (E. De Clercq Rev. Med. Virol. 3_:85-96 1993). However, if it does
interfere with binding of the oligonucleotide containing the analog to the
complementary sequence, the compound of the invention optionally is
incorporated into the oligonucleotide as the 3' terminal base, an innocuous
position and a conventional site for oligonucleotide labeling. The aglycon
donated by the nucleotide analog that is incorporated into the oligonucleotide
is detected by any means, such as NMR or by binding to antibodies specific for
the nucleotide analog.
Pharmaceutical Formulations
Compounds of the invention and their pharmaceutically, i.e.
physiologically, acceptable salts (hereafter collectively referred to as the
active
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ingredients), are administered by any route appropriate to the condition to be
treated, suitable routes including oral, rectal, nasal, topical (including
ocular,
buccal and sublingual), vaginal and parenteral (including subcutaneous,
intramuscular, intravenous, intradermal, intrathecal and epidural).
Generally, the compounds of this invention are administered orally, but if an
embodiment is not sufficiently orally bioavailable it can be administered by
any of the other routes noted above.
Y~lhile it is possible for the active ingredients to be administered as pure
compounds it is preferable to present them as pharmaceutical formulations.
The formulations of the present invention comprise at least one active
ingredient, as above defined, together with one or more acceptable carriers
and optionally other therapeutic ingredients. The carriers) must be
"acceptable" in the sense of being compatible with the other ingredients of
the
formulation and not deleterious to the patient.
The formulations include those suitable for topical or systemic
administration, including oral, rectal, nasal, buccal, sublingual, vaginal or
parenteral (including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural) administration. The formulations are
in unit dosage form and are prepared by any of the methods well known in
the art of pharmacy. Such methods include the step of bringing into
association the active ingredient with the carrier which constitutes one or
more accessory ingredients. In general the formulations are prepared by
uniformly and intimately bringing into association the active ingredient with
liquid carriers or finely divided solid carriers or both, and then, if
necessary,
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 active ingredient; 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 active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one
or more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient 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
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optionally be coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredient therein.
For infections of the eye or other external tissues, e.g. mouth and skin,
the formulations are preferably applied as a topical ointment or cream
containing the active ingredient{s) in an amount of, for example, 0.01 to 10%
w/w (including active ingredients) in a range between 0.1% and 5% in
increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to
3% w/w and most preferably 0.5 to 2% w/w. When formulated in an
ointment, the active ingredients may be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredients may be
formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for
example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two
or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures
thereof. The topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through the skin
or other affected areas. Examples of such dermal penetration enhancers
include dimethyl sulphoxide and related analogs.
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 lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the emulsifiers) with or
without stabilizers) make up the emulsifying wax, and the wax together with
the oil and fat make up the emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation
of the present invention include Tween~ 60, Span~ 80, cetostearyl alcohol,
benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl
sulfate.
The choice of suitable oils or fats for the formulation is based on
achieving the desired cosmetic properties. Thus the cream should preferably
be a non-greasy, non-staining and washable product with suitable consistency
to avoid leakage from tubes or other containers. Straight or branched chain,
mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate,
propylene
37
CA 02261619 2005-03-23
glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate,
isopropyl
palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain
esters known as Crodamoh'CAP may be used, the last three being preferred
esters. These may be used alone or in combination depending on the
properties required. Alternatively, high melting point lipids such as white
soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include
eye drops wherein the active ingredient is dissolved or suspended in a
suitable carrier, especially an aqueous solvent for the active ingredient. The
active ingredient is suitably present in such formulations in a concentration
of 0.01 to 20%, in some embodiments 0.I to IO%, and in others about 1.0%
Formulations suitable for topical administration in the mouth include
lozenges comprising the active ingredient in a flavored basis, usually sucrose
and acacia or tragacanth; pastilles comprising the active ingredient in an
inert
basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes
comprising the active ingredient, iri a suitable liquid carrier.
Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa butter or a
salicylate.
Formulations suitable for nasal cir inhalational administration
wherein the carrier is a solid include a powder having a particle size for
example in the range 1 to 500 microns (including particle sizes in a range
between 20 and 500 microns in increments of 5 microns such as 30 microns, 35
microns, etc). Suitable formulations wherein the carrier is a liquid, for
administration as for example a nasal spray or as nasal drops, include aqueous
or oily solutions of the active ingredient. Formulations suitable for aerosol
administration may be prepared according to conventional methods and may
be delivered with other therapeutic agents. Inhalational 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 active ingredient such carriers as are known in
the art to be appropriate.
Formulations suitable for parenteral administration are sterile and
*trademark 38
CA 02261619 2005-03-23
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 ana
thickening agents. The formulations may be presented in unit-dose or multi-
dose containers, for example sealed ampoules and vials with elastomeric
stoppers, and may be stored in a freeze-dried (lyophilized) condition
requiring
only the addition of the sterile liquid carrier, for example water for
injections,
immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and tablets of the
kind previously described. Preferred unit dosage formulations are those
containing a daily dose or unit daily sub-dose, as recited above, or an
appropriate fraction thereof, of an active ingredient.
In addition to the ingredients particularly mentioned above the
formulations of this invention may include other agents conventional in the
art having regard to the type of formulation in question, for example those
suitable for oral administration may include flavoring agents.
The present invention further provides veterinary compositions
comprising at least one active ingredient as above defined together with a
veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of
administering the composition to cats, dogs, horses, rabbits and other animals
and may be solid, liquid or gaseous materials which are otherwise inert or .
acceptable in the veterinary art and are compatible with the active
ingredient.
~ese veterinary compositions may be administered orally, parenterally or by
any other desired route.
Compounds of the invention can be used to provide controlled release
pharmaceutical formulations containing a matrix or absorbent material and
as active ingredient one or more compounds of the invention in which the
release of the active ingredient can be controlled and regulated to allow less
frequent dosing or to improve the pharmacokinetic or toxicity profile of the
compound. Controlled release formulations adapted for oral administration
in which discrete units comprising one or more compounds of the invention
can be prepared according to conventional methods.
The following examples further illustrate the invention but are not to
be construed as Limiting the invention.
39
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EXAMPLES
Example 1
PMPA Synthesis
O Pd/C,H2, EtOH O
OH OH (Et0)zC(O)
NaOEt/EtOH O O
CH20H .I'~~CH3 2
(S)-glycidol 'CH3
adenine,
DMF, NaOH 4a
1) (CH20)"/Et3N/toluene
(CzHsO)2P(O)H 2) P-TsCI
(CZH50)2 P(O)CHZOTs NH2
N
NHS N N
N ~ N ~OH
~N N O CHs
~O~P~OOH
CHs (CH3)3SiBr
CH3CN
6 1) H20,100 °C 5 DMF
4b ~ BuOLi
2) 10 °C NH2
3) acetone rinse
~N N O
NHS ~O P\ OCHZCH3
N' N ~ H O ~ OCH2CH3
2 CHs
N N O
~O~P:~H
CH3
40
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WO 98/04569 PCT/US97/13244
PMPA ~ H20
1) (CH3)2CHOC(O)OCHZCI,
1-methyl-2-pyrrolidinone
Et3N
2} fumaric acid
iPrOH
C02H
NH2
N ~ I NO HO?C
N N p CH3
~O~P
O O O CH3
CH3 2
Process Summary
PMPA is prepared as follows: (S)-Glycidol is reduced to (R)-1,2-
propanediol by catalytic hydrogenation, which is then reacted with diethyl
carbonate to afford (R)-1,2-propylene carbonate. The carbonate is reacted with
adenine and catalytic amounts of a base such as sodium hydroxide to give (R)-
9-[2-(diethylphosphonomethoxy)propyl]adenine which, without isolation, is
reacted with lithium alkoxide {alkyl containing 1, 2, 3, 4, 5 or 6 carbon
atoms,
e.g., n-hexoxide, n-pentoxide, n-butoxide, i-butoxide, t-butoxide, n-
propoxide,
i-propoxide, ethoxide, methoxide) and diethyl p-toluenesulfonyl-
oxymethylphosphonate (prepared by reacting diethyl phosphite and
paraformaldehyde, and tosylating the product in situ). The resulting (R)-9-[2-
diethylphosphonomethoxypropyl]adenine is deesterified with
bromotrimethylsilane to give crude PMPA, which is then purified by
precipitation from water with pH adjustment. The product is further purified
by recrystallization with water to afford PMPA monohydrate.
The process uses a small amount of a base such as NaOH at step 1,
which increases the reaction rate about 10-fold compared to the same reaction
lacking the base. Step 1 also uses hydrogen gas instead of using a reagent
such
as HC02NH4 to generate hydrogen in situ. The process uses lithium alkoxide
at step 4b, which is mildly exothermic on addition to the reaction mixture.
The use of a highly reactive base such as NaH, results in an exothermic
41
CA 02261619 1999-O1-20
WO 98/04569 PCT/U597113244
reaction that generates hydrogen gas in a reaction is difficult to control.
The
use of NaH thus requires more labor and care to use than lithium alkoxide.
Lithium alkoxide bases also give a product that has an improved by-product
profile compared to that obtained using NaH, e.g., lower amounts of starting
material or overalkylated products usually result from the use of lithium
alkoxide.
The scale of the following method is proportionately reduced or
increased if desired. The scheme and process steps depict synthesis of {R)-
PMPA. One can practice the method using chirally impure starting materials
such as (R,S}-glycidol to obtain a chiral mixture of intermediates or of the
final product.
One can increase or decrease the scale of the process steps described
below if desired. The scheme and process steps depict synthesis of (R)-PMPA
and (R}-bis(POC)PMPA. One can practice the method using chirally impure
starting materials such as (R,S}-glycidol to obtain a chiral mixture of
intermediates, e.g., a chiral mixture of 1,2-propylene carbonate, PMPA or
bis(POC)PMPA.
Step 1 (R)-12-Proranediol: (S)-Glycidol {1.0 kg, 13.5 moles) is added to
a reactor containing (i) an inert, e.g., nitrogen, atmosphere and {ii) a
stirred
suspension of 5% palladium on activated carbon (50'% wet) catalyst (100 g) in
denatured ethyl alcohol containing 2 mole% sodium hydroxide (7.85 kg EtOH
and 54 g of 16.7% NaOH solution). The contents of the inerted reactor
containing catalyst and the ethanol solution is usually cooled to about
0°C
(usually about -5 to 5°C) before the (S)-glycidol is added. Hydrogen
gas at no
more than 20 psi is then introduced to the inerted reaction vessel containing
reactants at a temperature of no more than 25°C. The mixture is
agitated for
approximately 4-5 hours, until hydrogen consumption stops. Reaction
completion is monitored by TLC (trace or no (S)-glycidol remaining}. The
mixture is then filtered e.g., diatomaceous earth (about 150 g), to remove
solids and the filtrate is concentrated in vacuo at no more than 50°C,
until
volatile collection stops or is very slow, to obtain an oil containing the
crude
product. The crude product is used directly in the next step. Title compound
yield is about 100%.
Step 2 (R)-12-Prop,Xlene carbonate: Diethyl carbonate (1.78 kg, 15.1
moles) and sodium ethoxide in denatured ethyl alcohol (210 g of 21% w/w
sodium ethoxide in ethanol) are added to (R)-1,2-propanediol (1.0 kg
42
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WO 98/04569 PCT/US97113244
theoretical based on the quantity of (S)-glycidol used in step 1 above), and
the
solution is heated to 80 to 150°C to distill off the ethanol. If
necessary to
achieve reaction completion, additional diethyl carbonate (0.16 kg) is added
to
the reaction mixture, followed by distillation to remove ethanol. Reaction
completion is monitored by TLC showing a trace or no detectable (R)-1,2-
propanediol. The residue is fractionally distilled at 120°C and 10-17
mm Hg,
to yield the title compound as a colorless liquid. The product purity is
typically 96% or greater purity by GC analysis.
Step 3 Diethyl ~-toluenesulfon~rloxyrneth~rl~hos~honate: In a reactor
containing an inert atmosphere, e.g., nitrogen, a mixture of diethyl phosphite
(0.80 kg), paraformaldehyde (0.22 kg), and triethylamine (0.06 kg) in toluene
(0.11 kg) is heated at 87°C for about 2 hours, then refluxed for about
1 hour,
until the reaction is complete as monitored by TLC showing a trace or no
detectable diethyl phosphite. During the reaction, the inert atmosphere is
maintained. Toluene is necessary to moderate the reaction, which may
otherwise explode. Reaction completion is optionally confirmed by 1H NMR
(diethyl phosphite peak at 8 8.4-8.6 ppm no longer detected). The solution is
cooled to about 1°C (typically about -2 to 4°C) and p-
toluenesulfonyl chloride
(1.0 kg) is added and then triethylamine (0.82 kg) at about 5°C is
slowly added
(exothermic addition) while maintaining the temperature at no more than
about 10°C (typically 0 to 10°C). The resulting mixture is
warmed to 22°C and
stirred for at least about 5 hours (typically about 4.5 to 6.0 hours), until
the
reaction is complete as shown by TLC (trace or no p-toluenesulfonyl chloride
detectable) and optionally confirmed by 1H NMR (p-toluenesulfonyl chloride
doublet at 8 7.9 ppm no longer detected). The solids are removed by filtration
and washed with toluene (0.34 kg). The combined washings and filtrate are
washed either twice with water (1.15 kg per wash), or optionally with a
sequence of water (1.15 kg), 5% aqueous sodium carbonate (3.38 kg), and then
twice with water (1.15 kg). After each wash, the reactor contents are briefly
agitated, allowed to settle and the lower aqueous layer is then discarded. If
the
reaction results in an emulsion, brine (0.23 kg of water containing 0.08 kg
NaCI) may be added to the first organic/water mixture, followed by agitating
the reactor contents, allowing the solids to settle, discarding the lower
aqueous layer, adding 1.15 kg water, agitating, allowing solids to settle and
again discarding the lower aqueous layer. The organic phase is distilled in
vacuo at no more than 50°C (to LOD at 110°C of no more than 10%
and water
43
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WO 98/04569 PCT/US97/13244
content, by KF titration, no more than 0.3%), affording a yield of about 60-
70%
of the title compound as an oil of about 85-95% purity, exclusive of toluene.
Step 4. (R1-9-f2-(Dieth;1~ nhosphonometho x )nropylladenine: In a reactor
containing an inert atmosphere, e.g., nitrogen, a mixture of adenine (1.0 kg),
sodium hydroxide (11.8 g), (R)-1,2-propylene carbonate (0.83 kg), and N,N-
dimethylforrnamide (6.5 kg) is heated to about 130°C (typically about
125-
138°C) for about 18-30 hours until the reaction is complete as
optionally
monitored by area normalized HPLC showing no more than about 0.5%
adenine remaining. The resulting mixture is cooled to about 25°C,
typically
about 20-30°C, and contains the stage I intermediate, (R)-9-(2-
hydroxypropyl)adenine, which may precipitate out at this point. After
cooling, lithium t-butoxide (3.62 kg), 2.0 M in tetrahydrofuran is added to
the
stage I intermediate, to produce the lithium salt of (R)-9-(2-
hydroxypropyl)adenine in a mildly exothermic addition. The slurry is treated
with diethyl p-toluenesulfonyloxymethylphosphonate (1.19 kg) and the
mixture is heated to a temperature of about 32°C, typically about 30-
45°C, and
is stirred for at least about 2 hours (typically about 2-3 hours) during which
time the mixture becomes homogeneous. More diethyl p-
toluenesulfonyloxymethylphosphonate {1.43 kg) is added and the mixture is
stirred at a temperature of about 32°C (typically about 30-45°C)
for at least
about 2 hours (typically about 2-3 hours}. Additional lithium t-butoxide (0.66
kg}, 2.0 M in tetrahydrofuran and diethyl p-
toluenesulfonyloxymethylphosphonate (0.48 kg} are added twice more, each
time followed by stirring the mixture, which is at a temperature of about
32°C
for at least about 2 hours. Reaction completion is optionally monitored by
area normalized HPLC showing no more than about 10% of stage I
intermediate remaining. If the reaction is incomplete, additional lithium t-
butoxide (0.33 kg), 2.0 M in tetrahydrofuran and diethyl p-
toluenesulfonyloxymethylphosphonate (0.24 kg) are added and the reaction
mixture is maintained at a temperature of about 32°C for at least about
2
hours to achieve reaction completion. The mixture is then cooled to about
25°C {typically about 20-40°C} and glacial acetic acid (0.5 kg)
is then added. The
resulting mixture is concentrated in vacuo at a final maximum mixture
temperature of about 80°C under about 29 in Hg vacuum. The residue is
cooled to about 50°C (typically about 40-60°C} and water (1.8
kg) is added and
the reaction is rinsed forward with additional water (1.8 kg). The solution is
continuously extracted with dichloromethane (about 35 kg) for 12-48 hours
44
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WO 98104569 PCTIUS97/13244
with periodic additions of glacial acetic acid (0.2 kg) to the aqueous phase
after
about 5 hours and after about 10 hours of continuous extraction time.
Extraction completion is optionally confirmed by area normalized HPLC as
shown by no more than about 7% of (R)-9-[2-
(diethylphosphonomethoxy)propyl]adenine remaining in the aqueous phase.
The combined dichloromethane extracts are concentrated initially at
atmospheric pressure then in vacuo at an extract temperature of no more
than about 80°C to give the title compound as a viscous orange oil. The
title
compound yield is about 40-45% by weight normalized HPLC and its purity is
typically 60-65% by area normalized HPLC. The actual weight of the title
compound after concentration is approximately 1.6 times the theoretical
weight (or 3.8 times the expected yield). The additional observed weight is
attributed to impurities and/or solvents remaining after the continuous
extraction and concentration.
Step 5. (R)-9-f2-(Phosphonomethox~propylladenine,, crude:
Bromotrimethylsilane (1.56 kg) is added to a reactor containing a mixture of
crude (R)-9-[2-(diethylphosphonomethoxy)propylJadenine (1.0 kg calculated
based on adenine input from step 4 above) and acetonitrile (0.9 kg) with
cooling to maintain a temperature no higher than about 50°C. The Iines
are
rinsed forward with acetonitrile (0.3 kg) and the mixture is refluxed at about
60-75°C for about 2-4 hours with moderate agitation to avoid splashing
the
reactor contents. Reaction completion is monitored by area normalized HPLC
showing no more than about 3% total of monoethyl PMPA and diethyl PMPA
remaining. If the reaction is incomplete, additional bromotrimethylsilane
(0.04 kg) is charged into the reactor and the reaction is refluxed for at
least
about 1 hour with moderate agitation. The volatiles are removed by
distillation at no higher than about 70°C initially at atmospheric
pressure and
then in vacuo (about 24-27 in Hg) at no higher than about 70°C. The
reactor is
then cooled to about 20°C (typically about 15-25°C) and water
(1.9 kg) is added
(exothermic addition) to the residue with the temperature maintained at no
higher than about 50°C. The mixture is cooled to 20°C and washed
with
dichloromethane (1.7 kg) by agitating for about 30 minutes. The isolated
aqueous phase is then filtered through a 1 ~m cartridge filter, diluted with
water (3.2 kg), heated to about 40°C (typically about 35-50°C)
and adjusted to
pH about 1.1 (typically about 0.9-1.3) with aqueous sodium hydroxide (about
0.15 kg NaOH as a 50% solution) while the temperature is maintained at
about 45°C. PMPA seed crystals are added to the mixture and the pH is
CA 02261619 1999-O1-20
WO 98/04569 PCTIL1S97113244
adjusted to about 2.8 (typically about 2.6-3.0) with a 50% aqueous sodium
hydroxide solution (about 0.15 kg NaOH required) while the temperature is
maintained at about 45°C (typically about 35-50° C). The
solution is cooled to
about 22°C (typically about 15-25°C) over about 3-20 hours with
slow to
moderate agitation that avoids splashing the contents, during which time the
product should precipitate, beginning at about 35°C. The pH of the
slurry is
adjusted to about 3.2 (typically about 3.1-3.3), usually using 50% aqueous
sodium hydroxide or concentrated hydrochloric acid, if necessary. The slurry
is cooled to approximately 5°C, typically about 0-10°C, and
slowly agitated for
at least about 3 hours in that temperature range. The solids are collected by
filtration, washed sequentially with cold water (0.35 kg) and acetone (0.3 kg)
giving crude PMPA as a damp solid typically of about 97% purity. The
product is heated to about 50°C and dried in vacuo to a water content
of less
than 10%. The quantity of diethyl PMPA is calculated from the quantity of
adenine used in the preceding step of the synthesis (assuming 100% yield) and
not from the net weight of the crude diethyl PMPA, which may contain other
compounds.
Step 6. (R)-9-f2-(Phosphonomethox, )vropylladenine pure: A
suspension of the crude PMPA (1.00 kg corrected for water content) (Step 5
product) in water is heated to about 100°C {typically about 95-
I10°C) with
moderate to high agitation until all solids dissolve, and the resulting
solution
is clarified by filtration while hot, rinsing forward using additional hot
water
(1 kg, about 95-110°C). The filtrate is heated to 100°C prior to
cooling, first to
about 30°C (typically about 20-25°C} over about 3-5 hours with
slow agitation,
then cooling is continued to about 10°C (typically about 5-
15°C). After
holding at about 10°C for at least about 3 hours, the solids are
collected by
filtration and washed sequentially with cold water (1.5 kg, about 0-
10°C) and
then acetone (1 kg}. The wet cake is dried in vactco at about 50 °C
(typically
about 40-60°C) to a water content of about 5.9% (typically about 3.9-
7.9%),
affording pure PMPA monohydrate. The product purity is typically 98% or
greater by both area normalized and weight normalized HPLC. If the
chemical purity is unsatisfactory, the product may be repurified by a repeat
of
this step.
Optional recrvstallization: 0.75 g of PMPA (preparation A) was
recrystallized from H20 (11.3 mL, 15:1 wt. ratio) by heating the suspension to
95-100°C. Upon cooling to room temperature, the crystallized PMPA was
46
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WO 98/04569 PCT/C1S97113244
chilled in a freezer. After 3 h the crystals were filtered on a coarse frit
fit with
TyvekT"', the filter cake rinsed with ice-cold H20 and acetone, and air dried
to
constant weight to give a fluffy white solid (Preparation B). Recovery was
0.64 g (85.3%}. HPLC showed 98.5-98.9% pure PMPA. No 14.7 min impurity
was observed. Recrystallized liquors (1039-91-23) showed 71.4% pure PMPA
with a major impurity at 4.8 min (26.9%), possibly solvent. 14.7 min impurity
= 0.05%.
Preparation B PMPA was recrystallized again from 9.6 mL (15:1 wt.
ratio) H20 heated to 95-100°C. Upon cooling to room temperature, the
crystallized PMPA was chilled in a freezer overnight. The PMPA was filtered
through a coarse frit fit with TyvekTM and the filter cake was rinsed with ice-
cold H20 and acetone, then sucked dry to constant weight to afford a fluffy,
white solid (Preparation C). Recovery was 0.52 g (81.3%). HPLC (JH52807,
JH52810) showed 99.3-99.5% pure PMPA. The largest impurity at 19 min =
0.22%. Recrystallized liquors showed 64.9% pure PMPA with 0.01% 14.7 min
impurity and 0.09% 19 min impurity.
Preparation C PMPA (0.50 g) was recrystallized from approximately 7.5
mL boiling H20 (15:1 wt. ratio). Upon cooling to room temperature, the
PMPA was filtered on a coarse frit fit with TyvekT~''. The filter cake was
rinsed
with ice-cold H20 and acetone then sucked to dryness to afford a fluffy white
solid (Preparation D). The filtrate was also concentrated to afford a white
solid
(Preparation E).
Recovery: Filter cake: 0.41 g (82%), Filtrate: 0.08 g = 0.49 g combined (98%).
HPLC analysis showed the filtrate (Preparation E) was 99.9% pure. PMPA
prepared in this fashion is used to manufacture the compounds of this
invention.
Step 7. Bis(POC)PMPA fumarate: In a reactor with an inert
atmosphere, e.g., nitrogen, a mixture of 1-methyl-2-pyrrolidinone (4.12 kg),
PMPA monohydrate (1.00 kg), triethylamine (0.996 kg), are agitated for about
15-45 min., typically about 30 min, and then chloromethyl-2-propyl carbonate
(2.50 kg) is added and the mixture is heated to about 55-65°C,
typically about
60°C and agitated without splashing the contents for about 3-6 hours,
typically
about 4 hours, until the reaction is complete, as optionally indicated by HPLC
(no more than 15% mono(POC)PMPA present). The mixture is diluted with
isopropyl acetate (10.72 kg), cooled to about 15-30°C, typically about
25°C, as
rapidly as possible, and while holding the reactor contents at a of about 15-
30°C, typically at about 25°C, the mixture is agitated for about
20-60 minutes,
47
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WO 98/04569 PCTILTS97/13244
typically about 30 minutes. The solids are removed by filtration and washed
with isopropyl acetate (4.44 kg). The combined organic phases at about 15-
30°C, typically about 25°C, are extracted twice with water (3.28
kg) using
moderate agitation for about 1-10 min. to avoid forming an emulsion
followed by allowing the phases to separate. The combined aqueous phases
are back-extracted twice with isopropyl acetate {3.56 kg) (about 15-
30°C,
typically about 25°C). All organic phases are combined and washed with
water
(2.20 kg) {about 15-30°C, typically about 25°C) using moderate
agitation for
about 1-10 min. to avoid forming an emulsion, then the combined organic
phases, which are at about 25-43°C, but at no more than 45°C,
are concentrated
in vacuo (about 26.5-28" Hg) to approximately 30% of the original volume
(about 10-12 L/kg PMPA monohydrate). After a polishing filtration using an
in-Iine 1 ~,m filter, the concentration of the organic phase is resumed at
about
20-38°C, but no higher than 40°C under a vacuum (about 28" Hg)
until a pale
yellow oil remains. The oil is dissolved in a warmed solution (about 45-
55°
C, typically about 50°C) of fumaric acid {0.38 kg) in 2-propanol (6.24
kg) with
vigorous agitation until solids dissolve, about 0.5-2.0 hours. The warm
solution is then optionally filtered using an in-line 1 ~.m filter while
minimizing cooling of the solution. The filtrate at about 34-50°C,
typically at
about 40°C, is agitated using the minimum agitation needed to obtain a
homogenous solution. The resulting solution is cooled to about 30-33°C,
typically about 32°C, over about 30 minutes using minimal agitation,
optionally seeded with a small quantity of bis(POC}PMPA fumarate (about 100
mg), and cooled to about 12-18°C, typically about 15°C, over
about 1-2 hours,
typically over about 1 hour. Seed crystals may not be needed if crystal
formation begins before seed crystals are added. Crystals may form over a
range of about 12-33°C as the solution is cooled. Crystallization will
occur at
lower temperatures if the solution is further chilled, e.g., to about -
10° to
about 11°C. Agitation is discontinued when crystal formation begins.
The
mixture is allowed to stand at about 15°C for at /east about 12 hours,
typically
about 12-30 hours. The resulting slurry is filtered {Tyvek) and the filter
cake is
washed with a premixed solution of isopropyl acetate (0.70 kg) in butyl ether
(2.44 kg) (1: 4 v/v). The filter cake, which is at no more than 40°C,
is dried in
vacuo for about 1 to 3 days and the dried product is optionally milled
(Fitzmill
M5A fitted with a 0.050" screen), affording bis(POC)PMPA fumarate as white,
fine, powder-like crystals of about 97.0 to 99.5% purity.
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WO 98104569 PCTIUS97/13244
Example 2
Preparation of Alkyl Chloromethylcarbonates
O O
Pyridine
ROH + CIO~C1 Et2p RO~O~ I
C
0°-RT
85-95%
A solution of the alcohol (73 mmol) and chloromethyl chloroformate
(Fluka, 6.23 mL, 70 mmol) in diethyl ether was cooled to 0°C under
argon.
Pyridine (5.7 mL, 70 mmol) was added dropwise with stirring over 10
minutes. The solution was stirred at 0°C for one hour, then allowed to
warm
to room temperature and stirred for three additional hours. The ether
solution was filtered, washed with 1 M HCI, dried over MgS04, filtered, and
concentrated on a rotary evaporator. Brief application of 0.1 torr vacuum
gave the alkyl chloromethyl carbonates in 85-95% yields. Ethyl chloromethyl
carbonate is somewhat volatile, and cannot be left on the rotovap too long, or
the yield suffers {87-35%).
Example 3
Preparation of the Bis-ethyl Oxymethyl Carbonate of PMPA
NHz
z
O D~ - , N
N ~ + ~ ~ DMF ~ ~ O O
~O~P-OH RO O Cl RT, 24 hr, ~p~p,O~O~OR
_ OH 18% (small)
R = ethyl 40°. 4 days, 20% _ O~O~OR
(large) O
R= Et. Anhydrous PMPA (5 g, 16 mmol) and DIEA (Hunig's base) (11.5
mL, 66 mmol) were placed in anhydrous DMF (50 mL). The chloromethyl
carbonate (49 mmol) was then added and the suspension heated to 50°C
under
argon with rapid mechanical stirring. After 1 hr the reaction was clear and
the temperature was lowered to 35°C and the reaction stirred for 48 hr.
The
DMF was removed on a rotary evaporator, and the reaction partitioned
between CH2C12 and water. The CH2C12 layer was dried over magnesium
sulfate, filtered, and concentrated on a rotary evaporator. The residue was
taken up in methylene chloride and applied to a silica gel column (150 g
Si02). It was eluted with 500 mL each 0,3,6,9,12,15,18% (v/v) isopropanol in
49
CA 02261619 1999-O1-20
WO 98104569 PCTlUS97/13244
methylene chloride, and then with 2000 mL 21%. Appropriate fractions were
pooled and evaporated to give the desired product.
Example 4
Preparation of the Bis-n-butyl Oxymethyl Carbonate of PMPA
O O
II Pyridine
wOH+ Q~O~~ Et O ~O~O~Q
2
0°-RT
85%
NH2 DIEA
~ DMF
N
~ ~ RT-50
N
O 3d
~O 20%
~P-OH
OH
NH,
I
~N~J o 0
~o~P_o~o~o~
_ o~ ~
o'~
0
Butyl chloromethyl carbonate. A solution of butyl alcohol (50 mmol) and
chloromethyl chloroformate (4.5 mL, 50 mmol) in diethyl ether (200 mL) was
cooled to 0°C under argon. Pyridine (5.7 mL, 50 mmol) was added
dropwise
with stirring over 5 min. The solution was stirred at 0°C for 15 min,
then
allowed to warm to room temperature and stirred for three additional hours.
The ether solution was filtered, washed with 1 M HC1, and then twice with
water, dried over MgS04, filtered, and concentrated on a rotary evaporator to
give butyl chloromethyl carbonate {7 g, 85%).
Dibutvl PMPA carbonate. Anhydrous PMPA (4 g, 13 mmol) and DIEA (10.5
mL, 60 mmol) were placed in anhydrous DMF (40 mL). Butyl chloromethyl
carbonate (40 mmol) was then added and the suspension stirred at room
temperature for 48 hr. The reaction was then heated to 50°C for l8hr.
The
DMF was removed on a rotary evaporator, and the reaction partitioned
between CH2C12 (250 mL) and water (250 mL). The CH2C12 layer was washed
CA 02261619 1999-O1-20
WO 98/04569 PCTIUS97/13244
once with saturated aqueous NaHC03, dried over magnesium sulfate,
filtered, and concentrated on a rotary evaporator. The residue was taken up in
methylene chloride and applied to a silica gel column (150 g Si02). It was
eluted with 1000 mL CH2C12, 500 mL each 0,3,6,9,12,15,18% {v/v) isopropanol
in methylene chloride, and then with 2000 mL 21% isopropanol in rnethylene
chloride. Appropriate fractions were pooled and evaporated to give the
desired product.
Example 5
Synthesis of Bis-n-propyl Oxyethyl Carbonate of PMPA
O Pyridine
OOH + CI~O~CI EtzO ~O O Cl
0°-RT
84'%
NHz
DIEA
N ~ N DMF
50°
N N O 24 hr
" 16%
O~ P, OH
OH
NHz -
0 0
N N ~ II
~O~P-O~O~O~/
- O~O~O~
~(O
Preparation of prop,rl-1-chloroethyl carbonate. A solution of propyl alcohol
(70 mmol) and 1-chloroethyl chloroformate (7.6m1, 70 mmol) in diethyl ether
(200 mL) was cooled to 0°C under argon. Pyridine (70 mmol) was added
dropwise with stirring over 5 min. The solution was stirred at 0°C for
15 min,
then allowed to warm to room temperature and stirred for 4.5 additional
hours. The ether solution was filtered, washed with 1 M HC1, and then twice
with water, dried over MgS04, filtered, and concentrated on a rotary
evaporator to give propyl-1-chloroethyl carbonate {9.8 g, 84%). Anhydrous
PMPA (0.3 g, 1 mmol) and DIEA (0.7 mL, 4 mmol) were placed in anhydrous
DMF (2 mL) under argon. Propyl-1-chloroethyl carbonate (3 mmol) was then
51
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WO 98/04569 PCT/US97/13244
added and the suspension stirred at 50°C for 20 hr. The DMF was removed
on
a rotary evaporator, and the reaction partitioned between CH2C12 and water.
The CH2C12 layer was dried over magnesium sulfate, filtered, and
concentrated on a rotary evaporator. The residue was taken up in methylene
chloride and applied to a silica gel column (25 g Si02). It was eluted with
100
mL CH2C12, 50 mL each 3,6,9,12,15,18% (v/v) isopropanol in methylene
chloride, and then with 200 mL 21% isopropanol in methylene chloride.
Appropriate fractions were pooled and evaporated to give the desired product.
Example C
Synthesis of Chloromethyl Isopropyl Carbonate
To a cold solution (approximately 10°C) of
chloromethylchloroformate
(65 mL) in diethyl ether (1.4L) was added isopropanol (56 mL) followed by a
dropwise addition of pyridine (60 mL}. After the addition the cold bath was
removed and the reaction mixture was stirred for 18 h. The reaction mixture
was poured into a separation funnel containing cold water (100 mL). The
ether layer was separated and washed with water {100 mL x 2) and then dried
over Na2S0~. Evaporation of the solvent furnished the chloromethyl
isopropyl carbonate (107 g, 95%). Chloromethyl isobutyl carbonate,
chloromethyl neopentyl carbonate, chloromethyl tert butyl carbonate and
chloromethyl 3-pentyl carbonate are synthesized in a similar manner.
Example 7
Synthesis of Bis Isopropyl Oxymethyl Carbonate of PMPA
To a stirred suspension of PMPA (7.26 g, 0.026 mmol) in DMF (100 mL)
at 50°C was added Et3N (10.8 mL, 0.0778 mmol). The reaction mixture
became
homogeneous and chloromethyl isopropyl carbonate (12.1 g, 0.0778 mol) was
added to the reaction mixture and stirring continued at 50°C (oil bath
temperature) for 20 h. The solvents were removed under reduced pressure
and the crude was chromatographed on a silica gel column. Elution with 10%
isopropanol in CHzCl2 removed all the non polar impurities. Further elution
with the same solvent mixture furnished the prodrug, 1.3 g (approximately
10%}.
Example 8
Synthesis of Bis Isopropyl Oxymethyl Carbonate of PMPA
52
CA 02261619 1999-O1-20
WO 98/04569 PCTILTS97/13244
To a stirred suspension of PMPA (1 g, 3.57 mmol) in DMF (5 mL) were
added Et3N (1.5 mL, 10.71 mmol) and chloromethyl isopropyl carbonate (1.67
g, 10.71 mmol}. The reaction mixture was then diluted with ethyl acetate (100
mL) and filtered. The filtrate was washed with water (2 x 50 mL) and finally
with brine (10 mL). The crude obtained after removal of the solvent was
dried under vacuum. The resulting oil was dissolved in isopropanol (7 mL)
and citric acid (260 mg) was added. The mixture was stirred for 16 h at room
temperature and then cooled to 0°C. The product was crystallized and
crystals
were filtered and dried. Mp 76-8I °C.
Example 9
Preparation of chloromethylcarbamates
O O
n DIEA ~ N~O~CI
cl O Ci DMAP
CH2C12 OJ
0°-RT
92%
O
N ~ DIEA N~O~Cl
C1 O Cl D
CH2C12
0°-RT
94%
O
O
NH ~ ~ DMA N~O~Cl
Cl O Cl
DMAP
CH2C12
0°-RT
95%
A solution of the amine (24 mmol), DIEA (30 mmol}, and DMAP (.5
mmol) in methylene chloride (5 mL} was added dropwise to a cold (0°C)
solution of chloromethyl chloroformate (25 mmol) in methylene chloride (45
mL) over 5 min. The solution was allowed to warm to room temperature
over 1.5 hr. The solution was diluted into ethyl acetate (100 mL}, and washed
with saturated sodium bicarbonate, 1 M HC1, and saturated sodium chloride.
It was then dried over magnesium sulfate, filtered, and evaporated to give the
desired chloromethyl carbamate.
53
CA 02261619 1999-O1-20
WO 98!04569 PCTIUS97/13244
Example 10
Synthesis of Bis Morpholino Oxymethyl Carbamate of PMPA
NHz ~ NHz
of
N ~ Q N Q
~O~P OH DMF ~O~P O~O~N
- OH DIEA - (
~O
RT
3 days
Anhydrous PMPA (0.3 g, 1 mmol} and DIEA (1 mL, 6 mmol) were
placed in anhydrous DMF (2 mL). Chloromethyl morpholino carbamate (3
mmol) was then added and the suspension stirred at room temperature for 3
days. The reaction was partitioned between CH2C12/isopropanol and 0.1 M
citrate buffer (pH 6). The CH2C12 layer was washed with water, dried over
magnesium sulfate, filtered, and concentrated on a rotary evaporator. The
residue was taken up in methylene chloride and applied to a silica gel column
(5 g Si02). It was eluted with 25 mL each 0,3,6,9,12,15,18% {v/v) isopropanol
in methylene chloride, and then with 100 mL 21% isopropanol in methylene
chloride. Appropriate fractions were pooled and evaporated to give the
desired product.
Example 11
Synthesis of Bis Piperidino Oxymethyl Carbamate of PMPA
NH, O NHS
N~O~Q N ~ I I ~
N I J ~ ~' o
~N N O N NJ
~O~P~pH DM~ ~O~P O~O~N
- OH DIEA
RT 2
Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (0.7 mL, 4 mmol) were
placed in anhydrous DMF (2 mL). Chloromethyl piperidino carbamate (3
mmol) was then added and the suspension stirred at room temperature for 3
days. More DIEA {4 mmol) and chloromethyl piperidino carbamate (100 ~.1)
were added, and the reaction stirred for 27 hr. The reaction was partitioned
between CH2Cl2/isopropanol and 0.1 M citrate buffer {pH 6). The CH2C12
54
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WO 98/04569 PCTIUS97/i3244
layer was dried over magnesium sulfate, filtered, and concentrated on a rotary
evaporator. The residue was taken up in methylene chloride and applied to a
silica gel column (5 g Si02). It was eluted with 25 mL each 0,3,b,9,12,15,18%
(v/v) isopropanol in methylene chloride, and then with 100 mL 21%
isopropanol in methylene chloride. Appropriate fractions were pooled and
evaporated to give the desired product.
Example 12
Other Carbamate Intermediates
To a solution of chloromethylchloroformate (4.16 mL) in CH2C12 (30
mL) were added tert butyl amine (4.9 mL) and proton sponge (10 g). The
reaction mixture was stirred for 18 h and then it was poured into a separation
funnel containing cold 0.5N HCl (100 mL). The CH2C12 layer was separated
and washed with water (100 mL x 2) and then dried over Na2S04.
Evaporation of the solvent furnished the chloromethyl tert butyl carbamate (8
g). Chloromethyl n-butyl carbamate (R =n-butyl) and chloromethyl dimethyl
carbamate (R = Me) were prepared in the same fashion.
Example 13
Other Oxymethyl Alkyl Carbamate Prodrugs of PMPA
To a stirred suspension of PMPA (4.51 g, 0.01b mmol) in DMF (50 mL)
was added Et3N (b.7 mL, 0.048 mmol). The reaction mixture became
homogeneous and chloromethyl tert butyl carbamate (8 g, 0.048 mol) was
added to the reaction mixture and stirring continued at room temperature for
3 days. The solvents were removed under reduced pressure and the crude
was chromatographed on a silica gel column. Elution with 10% isopropanol
in CH2C12 removed all the less polar impurities. Further elution with the
same solvent mixture furnished the prodrug (1.25g). The n-butyl and methyl
carbamates were prepared in the same fashion from the intermediates of the
preceding example.
Example 14
Chemical Stability of PMPA Carbonates
The solution stability of PMPA carbonates was studied at pH 7.4 at
37°C
in 10 mM buffer (NaH2P04 and Na2HP04) with the total ionic strength
CA 02261619 1999-O1-20
WO 98/04569 PCTIUS97/13244
adjusted to 0.15 M with KCI. The assays were performed by adding 200 ~L of a
PMPA carbonate stock solution (about 1 mg/mL in DMSO) to 10 mL of pre-
equilibrated buffer at 37°C. Samples were removed at specific times
points
and analyzed by HPLC. The chemical t 1 /2 is expressed in terms of the
number of hours required to hydrolyze 50% of the carbonate at the specified
pH.
Example 15
Oral Bioavailability of PMPA and PMPA Carbonates in Beagle Dogs
PMPA (9-[(R)-2-(phosphonomethoxy}propyl]adenine) and PMPA
carbonates were examined to determine the effect of dose on the
pharmacokinetics of PMPA in beagle dogs, in particular the bioavailability of
PMPA following oral administration to beagle dogs.
PMPA monohydrate was synthesized by Gilead Sciences.
Tetrabutylammonium hydrogen phosphate (TBAHP) was obtained from
Fluka (Ronkonkoma, NY). Acetonitrile was obtained from Baxter
(Muskegon, MI). Dibasic potassium phosphate, monobasic potassium
phosphate, and sodium acetate trihydrate were obtained from Mallinckrodt
(Paris, KY). Chloroacetaldehyde and trifluoroacetic acid (TFA) were from
Aldrich (Milwaukee, WI).
The intravenous formulations used as standards were isotonic aqueous
solutions containing 50 mg/mL PMPA. Compound was added to 10 mL of
WFI (water for injection from Abbott Laboratory) and 1N NaOH was added to
adjust the pH to 7.4. The solutions were diluted to 15 mL with WFI and
sterile filtered with a 0.2 ~tm filter. The PMPA dose was 10 mg/kg {0.2
mL/kg).
The intravenous formulation for a 1 mg/kg dose was prepared as
described above except only 75 mg of PMPA was added to WFI and the final
concentration was 5 mg/mL. The dose was 1 mg/kg (0.2 mL/kg). Oral
formulation of carbonates were prepared in 20-40% PEG 400/50 mM citric acid
and were adjusted to pH 2.2. Doses ranged from 6.2-10 mg eq of PMPA/kg and
are shown in Table 1.
Two groups of five adult male beagle dogs were used. The mean body
weight at the time of the first dose was 9.6 ~ 0.4 Kg (range 9.2-10.2). The
dogs
were fasted 12-18 hours prior to dosing and until 6 hours post-dose. For
pentagastrin pretreatment, dogs were given a single intramuscular injection
of pentagastrin (Peptavlon 0.25 mg/mL, Ayerst Laboratories, Inc.,
56
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WO 98/04569 PCTIUS97/I3244
Philadelphia, PA) at a dose of 6 ~tg/kg, 20 minutes prior to dosing. Water was
provided ad lib.
Each formulation was administered as a single dose to five male beagle
dogs. Individual vials of each formulation were provided for each animal.
The intravenous formulation was administrated via a cephalic vein. The
oral suspension was administered by gavage, followed by two 10 mL water
washes. At least one week washout period was allowed between
administrafions.
Blood samples (4.0 mL) were collected by direct jugular access from each
animal into heparinized tubes. Animals remained conscious throughout the
sample collection period. Blood was processed immediately for plasma by
centrifugation at 2000 rpm for 10 minutes. Plasma samples were frozen and
maintained at <_ -20°C until analyzed.
Urine samples were collected over 0-24 and 24-48 hours time periods.
Urine samples from 0-24 and 24-48 hours were divided into aliquots and
mixed based on the volume collected and analyzed to determine amount of
PMPA recovered from urine during 0-48 hours.
PMPA in Plasma and Urine was determined as follows. PMEA (9-(2-
phosphono-methoxyethyl)adenine; adefovir) was used as the internal
standard for both analyses. The total concentration of PMPA in dog plasma or
urine samples was determined by derivatizing PMPA and PMEA with
chloroacetaldehyde to yield a highly fluorescent Nl, N6-ethenoadenine
derivative as described (Russell, J. et al. (1991) Determination of 9-[(2-
Phosphonylmethoxy)-ethyl]Adenine in Rat Urine by High-Performance
Liquid Chromatography with Fluorescence Detection. j. Chrornatvgr.
(Netherlands), 572, 321-326.).
Sample Extraction for PMPA in plasma and urine was performed as
follows. Plasma (200 ~tL) and internal standard (20 ~L of 10 ~g/mL PMEA
providing a final PMEA concentration of 1 ~g/mL) were mixed with 400 ~L of
acetonitrile containing 0.1 % TFA to precipitate protein. Samples were then
evaporated to dryness under reduced pressure at room temperature (Savant
SpeedVac). Urine samples {20 ~.L) and internal standard (30 ~L of 10 ~.g/mL
PMEA providing a final PMEA concentration of 1.5 ~g/mL) were used directly
for derivatization without drying.
The samples were derivatized for analysis as follows. Dried plasma
samples or urine samples were reconstituted or mixed in 200 ~L
derivatization cocktail (0.34% chloroacetaldehyde in 100 mM sodium acetate,
pH 4.5), vortexed, and centrifuged for 10 minutes at 14,000 rpm in an
57
CA 02261619 1999-O1-20
WO 98/04569 PCT/L1S97/13244
Eppendorf Centrifuge 5402. Supernatant was then transferred to a clean screw
capped tube and incubated at 95'C for 40 minutes. Derivatized samples were
quenched on ice and evaporated to dryness under reduced pressure at room
temperature. Dried samples were reconstituted in 200 ~L Mobile Phase A (see
below), vortexed and centrifuged for 10 minutes at 14,000 rpm in an
Eppendorf Centrifuge 5402. The supernatant was then transferred to
autoinjector vials for HPLC analysis.
The plasma and urine samples were analyzed by HPLC with
Fluorescence Detection as follows. The HPLC system comprised a Model
P4000 solvent delivery system with a Model AS3000 autoinjector and a Model
F2000 Fluorescence detector (Thermo Separation, San Jose, CA). The column
was a Zorbax RX-C18 (5 um, 150 x 4.6 mm) (MAC-MOD, Chadds Ford, NY)
equipped with a Brownlee RP-18 Newguard guard column (7 um, 15 x 3.2
mm) (Alltech, Deerfield, IL). The mobile phases used were: A, 2'% acetonitrile
in 25 mM potassium phosphate buffer with 5 mM TBAHP, pH 6.0; B, 65%
acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAHP, pH 6Ø
The flow rate was 1.5 mL/min and the column temperature was maintained
at 35°C by a column oven. The gradient profile was 100% A until 2.0
min,
then a linear gradient to 100% B by 13.0 minutes, returning immediately to
100% A. Detection was by fluorescence with excitation at 236 nm and
emission at 420 nm, and the injection volume was 50 ~L. Total cycle time
between injections was 25 min. Data was acquired and stored by a Peak Pro
data acquisition system (Beckman, Palo Alto, CA).
The pharmacokinetic parameters for intravenous and oral
formulations of PMPA and PMPA carbonates were assessed using non-
compartmental methods. Intravenous data were analyzed using PCNONLIN
Model 201 (5); oral data were analyzed using Model 200. Additional
pharmacokinetic parameters were calculated as follows:
CL = Dose/AUC (0-~) ; where CL is the total plasma clearance.
Vss = CL x MRT ; where Vss is the apparent volume of distribution at
steady state. MRT is the mean residence time.
The initial plasma concentration (Co) was determined by extrapolation of log
transformed data to zero time. Bioavailability was expressed as
Bioavailability (%) = AUC{0-( )~ ral or prodrug
AUC 0 ) intravenous x 100
58
CA 02261619 1999-O1-20
WO 98/04569 PCT/US97/13244
Urinary recovery was expressed as
Urinary Recovery (%) = amount (mg) of PMPA in urine (0-48 hr) x 100
amount (mg) of PMPA dosed
Oral bioavailability of t-Bu, 3-pentyl, isopropyl, Et carbonate parameters
were compared by unpaired t-tests (StatView~ Version 4.0, Software for the
Statistical Analysis. Abacus Concepts, Inc., Berkeley, CA). A P value of <_
0.05
was considered significant.
Biological tl /2: Dog liver was obtained fresh from Pharmakon USA
(Waverly, PA}. Liver homogenate was prepared following a standard
protocol. Dog liver was rinsed three times with ice-cold 50 mM
sodium/potassium phosphate buffer and homogenized with a Tekmar
Tissumizer homogenizer (VWR 33995-060). The homogenate was
centrifuged at 9000 g ( 11,000 rpm far Eppendorf Centrifuge 5402; Brinkmann
Instruments, Westbury, NY) at 4°C for 20 minutes. The supernatant
was
designated as the S9 fraction. The concentration of protein in the S9 fraction
was determined using a Bio-Rad Protein Assay Kit II, with bovine serum
albumin as standard. Esterase activity was determined using o-nitrophenyl
butyrate as substrate and activity was calculated based on the increase in
absorbance at 420 nm after a 1 min incubation. The homogenates were stored
as 1.0 mL aliquots at -70°C.
Intestinal Homogenate: Dog intestinal segments (jejunum/ileum) were
obtained fresh from Pharmakon USA (Waverly, PA) and intestinal
homogenate was prepared as described for liver. The intestinal homogenates
were stored as 1.0 mL aliquots at -70°C.
Human intestinal homogenate (S9) was obtained from Keystone Skin
Bank (Exton, PA) at concentration of 20 mg protein/mL.
Study Design: Enzymatic stability studies involving plasma and intestinal
homogenate were performed with 90% biological fluids.
Stability Measurement: One blank (drug free) incubation was performed for
each biological fluid. All biological fluid tubes {open) were preincubated
without PMPA prodrugs in a shaker bath at 37°C and 100 oscillation/min
for 5
minutes. PMPA prodrugs was added to the test incubations (final
concentration: 20 ~g/mL), mixed and maintained at 37°C and 100
oscillations/min. Samples {50 ~L) were withdrawn at 0, 30, and 60 minutes
59
CA 02261619 1999-O1-20
WO 98/04569 PCT/US97/13244
and the reaction was quenched with 100 ~L of 0.1% trifluoroacetic acid (TFA)
in acetonitrile. Quenched samples were centrifuged for 5 minutes at 14,000
rpm in an Eppendorf Centrifuge 5402, and the supernatant was used for
HPLC analysis.
Calculations: For each incubation, the observed rate constant for degradation
was calculated by plotting the log of the peak area of PMPA prodrugs versus
time of incubation (min). The slope was the observed rate constant (kobs)~
The half life was calculated according to the following equation:
0.693
tl /2 (min) _
kobs
If the observed rate constant for degradation was less than 0.01 miml, then
tl /2 was expressed as stable.
The results of the beagle study are shown below in Table 1.
CA 02261619 1999-O1-20
WO 98/04569 PCT/US97/13244
c
p p p
+i m cn cc cc
E- E-. F- ~.-
I I , I
v I I I , 1
I I 1 1
V O
6p
Q
I
'~ i I I
w L
o~G
L
y
N
I , i j
r~ I I I
I I
,
a o
G
n N ~ ~
c Q a o
O, 0
G ~G aD v cV Ov
tl +f ii + -f1
G N tr'~ O~ c~ O\
M
c~ N ~ ~ M
w.
M
C V V V V
y
0a
N ~ eC
~
W ~ ~ N l~ I~
O
V V V r.
Or a ~ .."" G
a
. ~ --. --. -~ ..., -
O r.
v w v ~
N '.
V v c~
v
C
U
I~ a O N t~ N
-, N M N cr1
Q
N
.. ,.., r..,
/1 /~
.
N
~
~
, Iw ~ T ~C ~D 00
_G
a a ~. g ._-. Q -
_ _
~' '~ ~ n ~ a C ~i ~i 2 a
cn ac.-. N N
. _ ~, x
=Q cca~ .. ~ a ._ ~ - ._
~
N :~ N ~ O ~ ~ :
C J ~ ~ ~ y ao
~
~
~-~" ~
~ ~, ~/ U , U ca,.
~, ~ ~
1
:~ ~ ~ ~ 1
..\ I
-
~ U ~ , .;; ~;, a ~' a C n '~ n
ca '~ ~
- ~ . = = c~
m
61
CA 02261619 1999-O1-20
WO 98/04569 PCTIUS97113244
>~ L
_
' > ~a o a a A
'~~ ~ z z
L
a..
.CO Z z O
V o
a
w o z z o
\ L
r
,.~, V
v
o N a a o
I z z
a o
a
o a ~ ~''
~ a a
a . ~, z z
Sri
cn
L
V
C > V ~ V
N ~ ~C
\ ~ ~O ~O ~C u~
.-. "
_ .~~ ~ N
.. 00
.r
_
w
:r
,Q, 'L
m a N ~ ~ ~M N
_
C
..
V
.- c~.a o
~ Z o ~
0
_ N
L ,~,
V r
U = ~ t~ ~ v~ o~
T
i
L
~. ~ ~ ~ ~ ~
v rm rr i
II X ~~ a II
J N n'J
~ ~ c.. ~ ~.. ~ = >, Q =
. . p ._ a
:~ ..
~ Z .-o y ~ ,~
'='~ i
a :~ ~~ w m ~ n ~,
c. ~ = '- n
U ~ ~ ~ ~ II
62
CA 02261619 1999-O1-20
WO 98104569 PCT/US97/13244
T
y ~.
a
z
a
z
yr n
'
U G
a +, a
~G ~ N Z
W C, ~
QC
r
C 4~
V
~/
> ~ ~ a
o ' z
Q
G
QO
M
ca..~ a
Z
00
v
_ ~ ~ c~
S ~ ~
.
E :.
N e0 _C~
W
GO ~ rn Ov _ep
'r c.
T
c ~ n~
J
G:W y O
.. ~
C
U d'
n
oa
O
N
V Z
v L
N
n ~ M
~
O
Lt7 Z ~ p
=
fJ7 ~ U
Z O
va n Za
"' ~'
2' p~
oa ~ ~ I I
_,~
p c~ p ~ ~ c ~..
~ x
'
tl 1
a ~ ~ ~ ~ x
63
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WO 98/04569 PCT/LTS97113244
Example 16
Antiviral Activity of PMPA and PMPA Carbonates in Tissue Culture
PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA
carbonates were examined to determine their activity against HIV-1. The
antiviral activity of the carbonates 5a, 5c-g against HIV-1{IIIB) was
determined
in MT-2 cells and the IC50 (50% inhibitory concentration) and CC50
(concentration to kill 50% of the cells) values were measured. The carbonate
prodrugs exhibited increased potency (about 2.5-500 fold) compared to PMPA
(Table 2). Although cytotoxicity of the prodrugs also increased, the
selectivity
indices were improved compared to PMPA. The increased activity can be
attributed to increased cellular uptake of the prodrugs followed by effective
intracellular conversion to PMPA, which undergoes subsequent
phosphorylation to the antivirally active diphosphate metabolite. The t-butyl
carbonate 5d exhibited only 2.5 fold increased activity over PMPA with
reduced selectivity possibly due to chemical instability. The antiviral
activity
data indicate good permeability of alkyl methyl carbonate prodrugs into cells,
possibly due to their increased lipophilicity. The partition coefficient
values
support this hypothesis, with all prodrugs being more iipophilic (loge = 0.6-
3.2) compared to PMPA {loge = -2.5).
NH2 NH2
N ~ N
O ~ ~ ~~ OII
N N I I,OH N N ~ O~ O~R
-'~~P~ OH ~ O~ P~ O~ O
~R
CH3 CH3 O
2 5
a. R = -OEt
c. R = -OBu'So
d. R = -OBut
e. R = -OPenne°
f. R = -OProlso
g. R = 3-Open
64
CA 02261619 1999-O1-20
WO 98104569 PCTIUS97/13244
10
Table 2. Antiretroviral activity of PMPA and PMPA prodrugs against HIV
1.
compoun IC50a CCSpb SIc
( M) ( M)
2 0.5 250 500
5a 0.002 40 20000
5c < 0.001 30 30000
5d 0.2 10 50
5e < 0.001 3 3000
5f 0.003 50 16600
5g < 0.001 40 40000
aICSp - 50% inhibitory concentration; bCC50 - Concentration to kill 50%
of the cells; cSI - Selectivity Index(CCSp/IC50); n.d - not determined; DMSO
used as control.
