U.S. patent application number 12/411951 was filed with the patent office on 2009-07-30 for novel bisamidate phosphonate prodrugs.
Invention is credited to Tao Jiang, Srinivas Rao Kasibhatla, K. Raja Reddy.
Application Number | 20090192121 12/411951 |
Document ID | / |
Family ID | 22625436 |
Filed Date | 2009-07-30 |
United States Patent
Application |
20090192121 |
Kind Code |
A1 |
Jiang; Tao ; et al. |
July 30, 2009 |
NOVEL BISAMIDATE PHOSPHONATE PRODRUGS
Abstract
Novel bisamidate phosphonate prodrugs of FBPase inhibitors of
the Formula IA: ##STR00001## and their use in the treatment of
diabetes and other conditions associated with elevated blood
glucose.
Inventors: |
Jiang; Tao; (San Diego,
CA) ; Kasibhatla; Srinivas Rao; (San Diego, CA)
; Reddy; K. Raja; (San Diego, CA) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK;A PROFESSIONAL ASSOCIATION
PO Box 142950
GAINESVILLE
FL
32614
US
|
Family ID: |
22625436 |
Appl. No.: |
12/411951 |
Filed: |
March 26, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10900718 |
Jul 28, 2004 |
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12411951 |
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09747182 |
Dec 22, 2000 |
6965033 |
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10900718 |
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60171862 |
Dec 22, 1999 |
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Current U.S.
Class: |
514/80 ;
548/113 |
Current CPC
Class: |
A61P 3/06 20180101; C07F
9/6561 20130101; C07F 9/4465 20130101; C07F 9/65515 20130101; A61P
3/10 20180101; A61P 5/48 20180101; A61P 43/00 20180101; A61P 9/10
20180101 |
Class at
Publication: |
514/80 ;
548/113 |
International
Class: |
A61K 31/675 20060101
A61K031/675; C07F 9/28 20060101 C07F009/28 |
Claims
1. A compound of formula IA ##STR00055## wherein compounds of
formula IA are converted in vivo or in vitro to M-PO.sub.3H.sub.2
which is an inhibitor of fructose-1,6-bisphosphatase and n is an
integer from 1 to 3; each R.sup.12 and R.sup.13 is independently
selected from the group consisting of H, lower alkyl, lower aryl,
lower aralkyl, all optionally substituted, or R.sup.12 and R.sup.13
together are connected via 2-6 atoms, optionally including 1-2
heteroatoms selected from the group consisting of O, N and S, to
form a cyclic group; each R.sup.14 is independently selected from
the group consisting of --OR.sup.17, --N(R.sup.17).sub.2,
--NHR.sup.17, --NR.sup.2OR.sup.19 and --SR.sup.17; R.sup.15 is
selected from the group consisting of --H, lower alkyl, lower aryl,
lower aralkyl, or together with R.sup.16 is connected via 2-6
atoms, optionally including 1 heteroatom selected from the group
consisting of O, N, and S; R.sup.16 is selected from the group
consisting of --(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14, --H,
lower alkyl, lower aryl, lower aralkyl, or together with R.sup.15
is connected via 2-6 atoms, optionally including 1 heteroatom
selected from the group consisting of O, N, and S; each R.sup.17 is
independently selected from the group consisting of lower alkyl,
lower aryl, and lower aralkyl, all optionally substituted, or
together R.sup.17 and R.sup.17 on N is connected via 2-6 atoms,
optionally including 1 heteroatom selected from the group
consisting of O, N, and S; R.sup.18 is independently selected from
the group consisting of H, lower alkyl, aryl, aralkyl, or together
with R.sup.12 is connected via 1-4 carbon atoms to form a cyclic
group; each R.sup.19 is independently selected from the group
consisting of --H, lower alkyl, lower aryl, lower alicyclic, lower
aralkyl, and COR.sup.3; M is ##STR00056## wherein: A.sup.3,
E.sup.3, and L.sup.3 are selected from the group consisting of
--NR.sup.8.sub.2, --NO.sub.2, --H, --OR.sup.7, --SR.sup.7,
--C(O)NR.sup.4.sub.2, halo, --COR.sup.11, --SO.sub.2R.sup.3,
guanidine, amidine, --NHSO.sub.2R.sup.3, --SO.sub.2NR.sup.4.sub.2,
--CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5
alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or
together A.sup.3 and L.sup.3 form a cyclic group, or together
L.sup.3 and E.sup.3 form a cyclic group, or together E.sup.3 and
J.sup.3 form a cyclic group including aryl, cyclic alkyl, and
heterocyclic; J.sup.3 is selected from the group consisting of
--NR.sup.8.sub.2, --NO.sub.2, --H, --OR.sup.7, --SR.sup.7,
--C(O)NR.sup.4.sub.2, halo, --C(O)R.sup.11, --CN, sulfonyl,
sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl,
haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and
aralkyl, or together with Y.sup.3 forms a cyclic group including
aryl, cyclic alkyl and heterocyclic alkyl; X.sup.3 is selected from
the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-,
-aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,
-alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-,
-alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-,
-alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and
-alkylaminocarbonylamino-, all optionally substituted; with the
proviso that X.sup.3 is not substituted with --COOR.sup.2,
--SO.sub.3H, or --PO.sub.3R.sup.2.sub.2; Y.sup.3 is selected from
the group consisting of --H, alkyl, alkenyl, alkynyl, aryl,
alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, --C(O)R.sup.3,
--S(O).sub.2R.sup.3, --C(O)--R.sup.11, --CONHR.sup.3,
--NR.sup.2.sub.2, and --OR.sup.3, all except H are optionally
substituted; R.sup.2 is selected from the group consisting of
R.sup.3 and --H; R.sup.3 is selected from the group consisting of
alkyl, aryl, alicyclic, and aralkyl; each R.sup.4 is independently
selected from the group consisting of --H, and alkyl, or together
R.sup.4 and R.sup.4 form a cyclic alkyl group; R.sup.7 is
independently selected from the group consisting of --H, lower
alkyl, lower alicyclic, lower aralkyl, lower aryl, and
--C(O)R.sup.10; R.sup.8 is independently selected from the group
consisting of --H, lower alkyl, lower aralkyl, lower aryl, lower
alicyclic, --C(O)R.sup.10, or together they form a bidentate alkyl;
each R.sup.9 is independently selected from the group consisting of
--H, -alkyl, aralkyl, and alicyclic, or together R.sup.9 and
R.sup.9 form a cyclic alkyl group; R.sup.10 is selected from the
group consisting of --H, lower alkyl, --NH.sub.2, lower aryl, and
lower perhaloalkyl; R.sup.11 is selected from the group consisting
of alkyl, aryl, --NR.sup.2.sub.2, and --OR.sup.2; and
pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein A.sup.3, L.sup.3, and E.sup.3
are independently selected from the group consisting of --H,
--NR.sup.8.sub.2, --NO.sub.2, hydroxy, halogen, --OR.sup.7,
alkylaminocarbonyl, --SR.sup.7, lower perhaloalkyl, and C1-C5
alkyl, or together E.sup.3 and J.sup.3 together form a cyclic
group; and wherein J.sup.3 is selected from the group consisting of
--H, halogen, lower alkyl, lower hydroxyalkyl, --NR.sup.8.sub.2,
lower R.sup.8.sub.2N-alkyl, lower haloalkyl, lower perhaloalkyl,
lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and
alicyclic; and wherein Y.sup.3 is selected from the group
consisting of alicyclic and lower alkyl; wherein X.sup.3 is
selected from the group consisting of -heteroaryl-,
-alkylcarbonylamino-, -alkylaminocarbonyl-, and
-alkoxycarbonyl-.
3. The compounds of claim 1, wherein n is 1; R.sup.12 and R.sup.13
are independently selected from the group consisting of --H, lower
alkyl, lower perhaloalkyl, and lower aryl, optionally substituted
with --OR.sup.19, --NR.sup.19.sub.2, --SR.sup.19,
--C(O)NR.sup.2R.sup.3, halo, --CO.sub.2R.sup.2, 3-indolyl,
4-imidazolyl, and guanidinyl, or R.sup.2 and R.sup.13 are connected
via 2-5 carbon atoms to form a cycloalkyl group; R.sup.14 is
selected from the group consisting of --OR.sup.17, --SR.sup.17, and
--NR.sup.2OR.sup.19 R.sup.15 is selected from the group consisting
of --H and C1-C6 alkyl; R.sup.16 is selected from the group
consisting of --H, C1-C6 alkyl, and
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.4; or together R.sup.15
and R.sup.16 are connected via 2-6 atoms, optionally including 1
heteroatom selected from the group consisting of N, O and S.
R.sup.17 is selected from the group consisting of C1-C7 alkyl,
phenyl, indolyl, sesimol, and benzyl, wherein said phenyl, indolyl,
sesimol, and benzyl may be optionally substituted with 1-3 groups
selected from the group of --CO.sub.2R.sup.2, --OR.sup.3,
--NHC(O)R.sup.3, halo and lower alkyl; and R.sup.18 is selected
from the group consisting of --H, C1-C6 alkyl, and benzyl.
4. The compound of claim 1, wherein A.sup.3 is selected from the
group consisting of --H, --NH.sub.2, --F, and --CH.sub.3; L.sup.3
is selected from the group consisting of --H, --F, --OCH.sub.3, Cl
and --CH.sub.3; E.sup.3 is selected from the group consisting of
--H, and --Cl; J.sup.3 is selected from the group consisting of
--H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl,
R.sup.8.sub.2N--C1-C5 alkyl, C1-C5 alicyclic, and C1-C5 alkyl;
X.sup.3 is selected from the group consisting of
--CH.sub.2OCH.sub.2--, -methyleneoxycarbonyl- and -furan-2,5-diyl-;
and Y.sup.3 is lower alkyl.
5. The compound of claim 4, where A.sup.3 is --NH.sub.2, L.sup.3 is
--F, E.sup.3 is --H, J.sup.3 is ethyl, Y.sup.3 is isobutyl, and
X.sup.3 is -furan-2,5-diyl-.
6. The compound of claim 4, where A.sup.3 is --NH.sub.2, L.sup.3 is
--F, E.sup.3 is --H, J.sup.3 is N,N-dimethylaminopropyl, Y.sup.3 is
isobutyl, and X.sup.3 is -furan-2,5-diyl-.
7. The compound of claim 5, wherein ##STR00057## is selected from
the group consisting of ##STR00058## wherein C* has S
stereochemistry.
8. The compounds of claim 6, wherein ##STR00059## is selected from
the group consisting of ##STR00060## wherein C* has S
stereochemistry.
9. A method of treating an animal for diabetes comprising
administering to said animal a therapeutically effective amount of
a compound of formula XI: ##STR00061## wherein: A.sup.3, E.sup.3,
and L.sup.3 are selected from the group consisting of
--NR.sup.8.sub.2, --NO.sub.2, --H, --OR.sup.7, --SR.sup.7,
--C(O)NR.sup.4.sub.2, halo, --COR.sup.11, --SO.sub.2R.sup.3,
guanidine, amidine, --NHSO.sub.2R.sup.3, --SO.sub.2NR.sup.4.sub.2,
--CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5
alkyl, C2-C5 alkenyl, C2-C5 alkynyl, and lower alicyclic, or
together A.sup.3 and L.sup.3 form a cyclic group, or together
L.sup.3 and E.sup.3 form a cyclic group, or together E.sup.3 and
J.sup.3 form a cyclic group including aryl, cyclic alkyl, and
heterocyclic; J.sup.3 is selected from the group consisting of
--NR.sup.8.sub.2, --NO.sub.2, --H, --OR.sup.7, --SR.sup.7,
--C(O)NR.sup.4.sub.2, halo, --C(O)R.sup.11, --CN, sulfonyl,
sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl,
haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and
aralkyl, or together with Y.sup.3 forms a cyclic group including
aryl, cyclic alkyl and heterocyclic alkyl; X.sup.3 is selected from
the group consisting of -alkyl(hydroxy)-, -alkyl-, -alkynyl-,
-aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,
-alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-,
-alkylcarbonylamino-, -alicyclic-, -aralkyl-, -alkylaryl-,
-alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino-, and
-alkylaminocarbonylamino-, all optionally substituted; with the
proviso that X.sup.3 is not substituted with --COOR.sup.2,
--SO.sub.3H, or --PO.sub.3R.sup.2.sub.2; Y.sup.3 is selected from
the group consisting of --H, alkyl, alkenyl, alkynyl, aryl,
alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, --C(O)R.sup.3,
--S(O).sub.2R.sup.3, --C(O)--R.sup.11, --CONHR.sup.3,
--NR.sup.2.sub.2, and --OR.sup.3, all except H are optionally
substituted; n is an integer from 1 to 3; R.sup.2 is selected from
the group consisting of R.sup.3 and --H; R.sup.3 is selected from
the group consisting of alkyl, aryl, alicyclic, and aralkyl; each
R.sup.4 is independently selected from the group consisting of --H,
and alkyl, or together R.sup.4 and R.sup.4 form a cyclic alkyl
group; R.sup.7 is independently selected from the group consisting
of --H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl,
and --C(O)R.sup.10; R.sup.8 is independently selected from the
group consisting of --H, lower alkyl, lower aralkyl, lower aryl,
lower alicyclic, --C(O)R.sup.10, or together they form a bidentate
alkyl; each R.sup.9 is independently selected from the group
consisting of --H.-alkyl, aralkyl, and alicyclic, or together
R.sup.9 and R.sup.9 form a cyclic alkyl group; R.sup.10 is selected
from the group consisting of --H, lower alkyl, --NH.sub.2, lower
aryl, and lower perhaloalkyl; R.sup.11 is selected from the group
consisting of alkyl, aryl, --NR.sup.2.sub.2, and --OR.sup.2; each
R.sup.12 and R.sup.13 is independently selected from the group
consisting of H, lower alkyl, lower aryl, lower aralkyl, all
optionally substituted, or R.sup.12 and R.sup.13 together are
connected via 2-6 atoms, optionally including 1-2 heteroatoms
selected from the group consisting of O, N and S, to form a cyclic
group; each R.sup.14 is independently selected from the group
consisting of --OR.sup.17, --N(R.sup.17).sub.2, --NHR.sup.17,
--NR.sup.2OR.sup.19 and --SR.sup.17; R.sup.15 is selected from the
group consisting of --H, lower alkyl, lower aryl, lower aralkyl, or
together with R.sup.16 is connected via 2-6 atoms, optionally
including 1 heteroatom selected from the group consisting of O, N,
and S; R.sup.16 is selected from the group consisting of
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14, --H lower alkyl, lower
aryl, lower aralkyl, or together with R.sup.15 is connected via 2-6
atoms, optionally including 1 heteroatom selected from the group
consisting of O, N, and S; each R.sup.17 is independently selected
from the group consisting of lower alkyl, lower aryl, and lower
aralkyl, all optionally substituted, or together R.sup.17 and
R.sup.17 on N is connected via 2-6 atoms, optionally including 1
heteroatom selected from the group consisting of O, N, and S;
R.sup.18 is independently selected from the group consisting of H,
lower alkyl, aryl, aralkyl, or together with R.sup.12 is connected
via 1-4 carbon atoms to form a cyclic group; each R.sup.19 is
independently selected from the group consisting of --H, lower
alkyl, lower aryl, lower alicyclic, lower aralkyl, and COR.sup.3;
and pharmaceutically acceptable salts thereof.
10. A method of lowering blood glucose levels in an animal in need
thereof, comprising administering to said animal a pharmaceutically
acceptable amount of a compound of claim 1.
11. A method of inhibiting gluconeogenesis in an animal in need
thereof comprising administering to said animal a pharmaceutically
effective amount of a compound of claim 1.
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 10/900,718, filed Jul. 28, 2004, which is a continuation of
U.S. application Ser. No. 09/747,182, filed Dec. 22, 2000, now U.S.
Pat. No. 6,965,033, which claims the benefit of priority to U.S.
Ser. No. 60/171,862 filed Dec. 22, 1999, which are each
incorporated by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention is directed towards novel prodrugs, to
their preparation, to their use for the oral delivery of
Fructose-1,6-bisphosphatase inhibitors (FBPase), and to their use
in the treatment of diabetes and other diseases where the
inhibition of gluconeogenesis, control of blood glucose levels,
reduction in glycogen storage, or reduction in insulin levels is
beneficial.
BACKGROUND OF THE INVENTION
[0003] Organic compounds that are charged at physiological pH
frequently exhibit limited oral bioavailability, cell penetration,
and tissue distribution (e.g. CNS). These properties are attributed
to the failure of ionic compounds to cross cell membranes by
passive diffusion. One strategy to circumvent this problem is to
prepare lipophilic prodrugs which are capable of crossing cell
membranes and subsequently undergoing a transformation to generate
the charged compound. The transformation could result from either
chemical instability or an enzyme-catalyzed reaction.
[0004] A large number of structurally-diverse prodrugs are
described for phosphonic acids. Freeman and Ross in Progress in
Medicinal Chemistry 34: 112-147 (1997). The most commonly used
prodrug class is the acyloxyalkyl ester, which was first used as a
prodrug strategy for carboxylic acids and then applied to
phosphates in 1983 by Farquhar et al. J. Pharm. Sci. 72: 324
(1983). Subsequently, the acyloxyalkyl ester was used to deliver
phosphonic acids across cell membranes and to enhance oral
bioavailability. A close valiant of the acyloxyalkyl ester
strategy, the alkoxycarbonyloxyalkyl ester, is also reported to
enhance oral bioavailability.
[0005] Much less success has been achieved with other classes of
phosphonate prodrugs. Aryl esters, especially phenyl esters, are
reported in a few cases to enhance oral bioavailability. DeLambert
et al., J. Med. Chem. 37: 498 (1994). Phenyl esters containing a
carboxylic ester ortho to the phosphate have also been described.
Khamnei and Torrence, J. Med. Chem. 39:4109-4115 (1996). Benzyl
esters are reported to generate the parent phosphonic acid. In some
cases using substituents at the ortho- or para-position can
accelerate the hydrolysis. Benzyl analogs with an acylated phenol
or an alkylated phenol can generate the phenolic compound through
the action of enzymes, e.g. esterases, oxidases, etc., which in
turn undergoes cleavage at the benzylic C--O bond to generate the
phosphoric acid and the quinone methide intermediate. Examples of
this class of prodrugs are described by Mitchell et al., J. Chem.
Soc. Perklin Trans. I 2345 (1992); Brook, et al. WO 91/19721. Still
other benzylic prodrugs have been described containing a carboxylic
ester-containing group attached to the benzylic methylene. Glazier
et al. WO 91/19721. Thio-containing prodrugs are reported to be
useful for the intracellular delivery of phosphonate drugs. These
proesters contain an ethylthio group in which the thiol group is
either esterified with an acyl group or combined with another thiol
group to form a disulfide. Desterification or reduction of the
disulfide generates the free thio intermediate which subsequently
breaks down to the phosphoric acid and episulfide. Puech et al.,
Antivircil Res., 22: 155-174 (1993); Benzaria, et al., J. Med.
Chem. 39: 4958 (1996). Cyclic phosphonate esters have also been
described as prodrugs of phosphorus-containing compounds.
[0006] Some phosphoramidates are also known prodrugs of
phosphonates, but they have shown poor oral bioavailability. In
some cases the phosphoramindates were very unstable under acidic
conditions which was reported as a potential explanation for their
poor oral bioavailability (J. Med. Chem., 37: 1857-1864 (1994)).
Similarly, poor oral bioavailability was reported for a bisamidate
of a PMEA analog (J. Med, Chem., 38: 1372-1379 (1995)). Another
PMEA prodrug consists of a mono glycine ester amidate and a phenyl
ester (WO 95/07920).
[0007] Although numerous phosphoric acid prodrug strategies are
reported to achieve high intracellular delivery of phosphoric
acids, few are known to result in good oral bioavailability. In
some cases, the prodrugs are unstable to the gastrointestinal tract
environment (low pH, esterase activity). In other cases the
prodrugs are too stable and are therefore poorly transformed in
vivo to the parent drug.
[0008] WO 98/39344, WO 98/39343, WO 98/139342, and WO 00/14095
describe compounds containing phosphoric acids and esters that
inhibit fructose-1,6-bisphosphatase.
[0009] The entire disclosures of the publication and references
referred to above and hereafter in this specification are
incorporated herein by reference and are not admitted to be prior
art.
SUMMARY OF THE INVENTION
[0010] The present invention is directed towards novel bisamidate
phosphonates that are potent FBPase inhibitors. In one aspect these
compounds possess superior oral bioavailability compared to the
corresponding phosphonic acids. In another aspect, the present
invention is directed to the in vitro and in vivo FBPase inhibitory
activity of these compounds. Another aspect of the present
invention is directed to the clinical use of these FBPase
inhibitors as a method of treatment or prevention of diseases
responsive to inhibition of gluconeogenesis and in diseases
responsive to lowered blood glucose levels.
[0011] In another aspect, the compounds are also useful in treating
or preventing excess glycogen storage diseases and diseases such as
cardiovascular diseases including atherosclerosis, myocardial
ischemic injury, and diseases such as metabolic disorders such as
hypercholesterolemia, hyperlipidemia which are exacerbated by
hyperinsulinema and hyperglycemia.
[0012] The invention also comprises the novel compounds and methods
of using them as specified below in formulae I, X, and XI. Also
included in the scope of the present invention are standard salts
and prodrugs of the compounds of formulae I, X, and XI.
##STR00002##
[0013] Since these compounds may have asymmetric centers, the
present invention is directed not only to racemic mixtures of these
compounds, but also to individual stereoisomers. The present
invention also includes pharmaceutically acceptable and/or useful
salts of the compounds of formulae I, X, and XI, including acid
addition salts. The present inventions also encompass standard
prodrugs of compounds of formulae I, X, and XI.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0014] In accordance with the present invention and as used herein,
the following terms are defined with the following meanings, unless
explicitly stated otherwise.
[0015] X, X'', X.sup.2 and X.sup.3 group nomenclature as used
herein in formulae I and XI describes the group attached to the
phosphonate and ends with the group attached to the heteroaromatic
ring. For example, when X is alkylamino, the following structure is
intended: [0016] (heteroaromatic
ring)-NR-alk-P(O)(NR.sup.15R.sup.16)(NR.sup.18--(CR.sup.12R.sup.13).sub.n-
--(C(O)--R.sup.14)
[0017] Likewise, A, B, C, D, E, A, B, C'', D'', E'', A.sup.2,
L.sup.2, E.sup.2, J.sup.2, A.sup.3, L.sup.3, E, and J.sup.3 groups
and other substituents of the heteroaromatic ring are described in
such a way that the term ends with the group attached to the
heteroaromatic ring. Generally, substituents are named such that
the term ends with the group at the point of attachment. A hyphen
before or after a term indicates a point of attachment. For
example, "-alkyl-" refers to divalent alkyl or alkylene.
[0018] The term "aryl" refers to aromatic groups which have 5-14
ring atoms and at least one ring having a conjugated pi electron
system and includes carbocyclic aryl, heterocyclic aryl and biaryl
groups, all of which may be optionally substituted. Suitable aryl
groups include phenyl and furan-2,5-diyl.
[0019] Carbocyclic aryl groups are groups wherein the ring atoms on
the aromatic ring are carbon atoms. Carbocyclic aryl groups include
monocyclic carbocyclic aryl groups and polycyclic or fused
compounds such as optionally substituted naphthyl groups.
[0020] Heterocyclic aryl or heteroaryl groups are groups having
from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the
remainder of the ring atoms being carbon atoms. Suitable
heteroatoms include oxygen, sulfur, nitrogen, and selenium.
Suitable heteroaryl groups include furanyl, thienyl, pyridyl,
pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl,
pyrazinyl, imidazolyl, and the like, all optionally
substituted.
[0021] The term "annulation" or "annulated" refers to the formation
of an additional cyclic moiety onto an existing aryl or heteroaryl
group. It is a form of optional substitution on an aryl or
heteroaryl group. The newly formed ring may be carbocyclic or
heterocyclic, saturated or unsaturated, and contains 2-9 new atoms
of which 0-3 may be heteroatoms taken from the group of N, O, and
S. The annulation may incorporate atoms from the X group as part of
the newly formed ring. For example, the phrase "together L.sup.2
and E.sup.2 form an annulated cyclic group", includes
##STR00003##
[0022] The term "biaryl" represents aryl groups containing more
than one aromatic ring including both fused ring systems and aryl
groups substituted with other aryl groups. Such groups may be
optionally substituted. Suitable biaryl groups include naphthyl and
biphenyl.
[0023] The term "alicyclic" means compounds which combine the
properties of aliphatic and cyclic compounds. Such cyclic compounds
include but are not limited to, aromatic, cycloalkyl and bridged
cycloalkyl compounds. The cyclic compound includes heterocycles.
Cyclohexenylethyl and cyclohexylethyl are suitable alicyclic
groups. Such groups may be optionally substituted.
[0024] The term "optionally substituted" or "substituted" includes
groups substituted by one to four substituents, independently
selected from lower alkyl, lower aryl, lower aralkyl, lower
alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy,
aralkoxy, heteroaryl, heterocyclic alkyl, heteroaryloxy,
heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, amidino,
halo, lower alkylthio, oxo, acylalkyl, carboxy esters, carboxyl,
-carboxamido, nitro, acyloxy, aminoalkyl, alkylaminoaryl,
alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino,
phosphono, sulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl,
hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,
aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower
perhaloalkyl, and arylalkyloxyalkyl. "Substituted aryl" and
"substituted heteroaryl" refer to aryl and heteroaryl groups
substituted with 1-2; 1-3; or 1-4 substituents. In one aspect,
suitable substituents of aryl groups include lower alkyl, lower
alkoxy, lower perhaloalkyl, halo, hydroxy, and amino. "Substituted"
when describing an R.sup.5 group does not include annulation.
[0025] The term "aralkyl" refers to an alkyl group substituted with
an aryl group. Suitable aralkyl groups include benzyl, picolyl, and
the like, and may be optionally substituted. The term "-aralkyl-"
refers to a divalent group -aryl-alkylene-. "Heteroarylalkyl"
refers to an alkylene group substituted with a heteroaryl
group.
[0026] The term "-alkylaryl-" refers to the group -alk-aryl- where
"alk" is an alkylene group. "Lower -alkylaryl-" refers to such
groups where alkylene is lower alkylene.
[0027] The term "lower" referred to herein in connection with
organic radicals or compounds respectively defines such as with up
to and including 10, or up to and including 6, or one to four
carbon atoms. Such groups may be straight chain, branched, or
cyclic.
[0028] The terms "arylamino" (a), and "aralkylamino" (b),
respectively, refer to the group --NRR' wherein respectively, (a) R
is aryl and R' is hydrogen, alkyl, aralkyl or aryl, and (b) R is
aralkyl and R' is hydrogen or aralkyl, aryl, alkyl.
[0029] The term "acyl" refers to --C(O)R where R is alkyl and
aryl.
[0030] The term "carboxy esters" refers to --C(O)OR where R is
alkyl, aryl, aralkyl, and alicyclic, all optionally
substituted.
[0031] The term "carboxyl" refers to --C(O)OH.
[0032] The term "oxo" refers to .dbd.O in an alkyl group.
[0033] The term "amino" refers to --NRR.sup.1 where R and R.sup.1
are independently selected from hydrogen, alkyl, aryl, aralkyl and
alicyclic, all except H are optionally substituted; and R and
R.sup.1 can form a cyclic ring system.
[0034] The term "carbonylamino" and "-carbonylamino-" refers to
RCONR-- and --CONR--, respectively, where each R is independently
hydrogen or alkyl.
[0035] The term "halogen" or "halo" refers to --F, --Cl, --Br and
--I.
[0036] The term "-oxyalkylamino-" refers to --O-alk-NR--, where
"alk" is an alkylene group and R is H or alkyl.
[0037] The term "-alkylaminoalkylcarboxy-" refers to the group
-alk-NR-alk-C(O)--O where "alk" is an alkylene group, and R is a H
or lower alkyl.
[0038] The term "-alkylaminocarbonyl-" refers to the group
-alk-NR--C(O)-- where "alk" is an alkylene group, and R is a H or
lower alkyl.
[0039] The term "-oxyalkyl-" refers to the group --O-alk- where
"alk" is an alkylene group.
[0040] The term "-alkylcarboxyalkyl-" refers to the group
-alk-C(O)--O-alk- where each alk is independently an alkylene
group.
[0041] The term "alkyl" refers to saturated aliphatic groups
including straight-chain, branched chain and cyclic groups. Alkyl
groups may be optionally substituted. Suitable alkyl groups include
methyl, isopropyl, and cyclopropyl.
[0042] The term "cyclic alkyl" or "cycloalkyl" refers to alkyl
groups that are cyclic groups of 3 to 6; or 3 to 10 atoms. Suitable
cyclic groups include norbornyl and cyclopropyl. Such groups may be
substituted.
[0043] The term "heterocyclic" and "heterocyclic alkyl" refer to
cyclic groups of 3 to 6; or 3 to 10 atoms, containing at least one
heteroatom. In one aspect, these groups contain 1 to 3 heteroatoms.
Suitable heteroatoms include oxygen, sulfur, and nitrogen.
Heterocyclic groups may be attached through a nitrogen or through a
carbon atom in the ring. Suitable heterocyclic groups include
pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl. Such groups
may be substituted.
[0044] The term "phosphono" refers to --PO.sub.3R.sub.2, where R is
selected from the group consisting of --H, alkyl, aryl, aralkyl,
and alicyclic.
[0045] The term "sulphonyl" or "sulfonyl" refers to --SO.sub.3R,
where R is H, alkyl, aryl, aralkyl, and alicyclic.
[0046] The term "alkenyl" refers to unsaturated groups which
contain at least one carbon-carbon double bond and includes
straight-chain, branched-chain and cyclic groups. Alkenyl groups
may be optionally substituted. Suitable alkenyl groups include
allyl. "1-alkenyl" refers to alkenyl groups where the double bond
is between the first and second carbon atom. If the 1-alkenyl group
is attached to another group, e.g. it is a W substituent attached
to the cyclic phosph(oramid)ate, it is attached at the first
carbon.
[0047] The term "alkynyl" refers to unsaturated groups which
contain at least one carbon-carbon triple bond and includes
straight-chain, branched-chain and cyclic groups. Alkynyl groups
may be optionally substituted. Suitable alkynyl groups include
ethynyl. "1-alkynyl" refers to alkynyl groups where the triple bond
is between the first and second carbon atom. If the 1-alkynyl group
is attached to another group, it is attached at the first
carbon.
[0048] The term "alkylene" refers to a divalent straight chain,
branched chain or cyclic saturated aliphatic group.
[0049] The term "-cycloalkylene-COOR.sup.3" refers to a divalent
cyclic alkyl group or heterocyclic group containing 4 to 6 atoms in
the ring, with 0-1 heteroatoms selected from O, N, and S. The
cyclic alkyl or heterocyclic group is substituted with
--COOR.sup.3.
[0050] The term "acyloxy" refers to the ester group --O--C(O)R,
where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or
alicyclic.
[0051] The term "aminoalkyl-" refers to the group NR.sub.2-alk-
wherein "alk" is an alkylene group and R is selected from H, alkyl,
aryl, aralkyl, and alicyclic.
[0052] The term "-alkyl(hydroxy)-" refers to an --OH off the alkyl
chain. When this term is an X group, the --OH is at the position a
to the phosphorus atom.
[0053] The term "alkylaminoalkyl-" refers to the group
alkyl-NR-alk- wherein each "alk" is an independently selected
alkylene, and R is H or lower alkyl. "Lower alkylaminoalkyl-"
refers to groups where each alkylene group is lower alkylene.
[0054] The term "arylaminoalkyl-" refers to the group aryl-NR-alk-
wherein "alk" is an alkylene group and R is H, alkyl, aryl,
aralkyl, and alicyclic. In "lower arylaminoalkyl-", the alkylene
group is lower alkylene.
[0055] The term "alkylaminoaryl-" refers to the group
alkyl-NR-aryl- wherein "aryl" is a divalent group and R is H,
alkyl, aralkyl, and alicyclic. In "lower alkylaminoaryl-", the
alkylene group is lower alkyl.
[0056] The term "alkyloxyaryl-" refers to an aryl group substituted
with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group
is lower alkyl.
[0057] The term "aryloxyalkyl-" refers to an alkyl group
substituted with an aryloxy group.
[0058] The term "aralkyloxyalkyl-" refers to the group
aryl-alk-O-alk- wherein "alk" is an alkylene group. "Lower
aralkyloxyalkyl-" refers to such groups where the alkylene groups
are lower alkylene.
[0059] The term "-alkoxy-" or "-alkyloxy-" refers to the group
-alk-O-- wherein "alk" is an alkylene group. The term "alkoxy-"
refers to the group alkyl-O--.
[0060] The term "-alkoxyalkyl-" or "-alkyloxyalkyl-" refer to the
group -alk-O-alk- wherein each "alk" is an independently selected
alkylene group. In "lower -alkoxyalkyl-", each alkylene is lower
alkylene.
[0061] The terms "alkylthio-" and "-alkylthio-" refer to the groups
alkyl-S--, and -alk-S--, respectively, wherein "alk" is alkylene
group.
[0062] The term "-alkylthioalkyl-" refers to the group -alk-S-alk-
wherein each "alk" is an independently selected alkylene group. In
"lower -alkylthioalkyl" each alkylene is lower alkylene.
[0063] The term "alkoxycarbonyloxy-" refers to
alkyl-O--C(O)--O--.
[0064] The term "aryloxycarbonyloxy-" refers to
aryl-O--C(O)--O--.
[0065] The term "alkylthiocarbonyloxy-" refers to
alkyl-S--C(O)--O--.
[0066] The term "-alkoxycarbonylamino-" refers to
-alk-O--C(O)--NR.sup.1--, where "alk" is alkylene and R.sup.1,
includes --H, alkyl, aryl, alicyclic, and aralkyl.
[0067] The term "-alkylaminocarbonylamino" refers to
-alk-NR.sup.1--C(O)--NR.sup.1--, where "alk" is alkylene and
R.sup.1 is independently selected from H, alkyl, aryl, aralkyl, and
alicyclic.
[0068] The terms "amido" or "carboxamido" refer to NR.sub.2--C(O)--
and RC(O)--NR.sup.1--, where R and R.sup.1 include H, alkyl, aryl,
aralkyl, and alicyclic. The term does not include urea,
--NR--C(O)--NR--.
[0069] The terms "carboxamidoalkylaryl" and "carboxamidoaryl"
refers to an aryl-alk-NR.sup.1--C(O)--, and ar-NR.sup.1--C(O)-alk-,
respectively, where "ar" is aryl, and "alk" is alkylene, R.sup.1
and R include H, alkyl, aryl, aralkyl, and alicyclic.
[0070] The term "-alkylcarboxamido-" or "-alkylcarbonylamino-"
refers to the group -alk-C(O)N(R)-- wherein "alk" is an alkylene
group and R is H or lower alkyl.
[0071] The term "-alkylaminocarbonyl-" refers to the group
-alk-NR--C(O)-- wherein "alk" is an alkylene group and R is H or
lower alkyl.
[0072] The term "aminocarboxamidoalkyl-" refers to the group
NR.sub.2--C(O)--N(R)-alk- wherein R is an alkyl group or H and
"alk" is an alkylene group. "Lower aminocarboxamidoalkyl-" refers
to such groups wherein "alk" is lower alkylene.
[0073] The term "thiocarbonate" refers to --O--C(S)--O-- either in
a chain or in a cyclic group.
[0074] The term "hydroxyalkyl" refers to an alkyl group substituted
with one --OH.
[0075] The term "haloalkyl" refers to an alkyl group substituted
with one halo, selected from the group I, Cl, Br, F.
[0076] The term "cyano" refers to --C.ident.N.
[0077] The term "nitro" refers to --NO.sub.2.
[0078] The term "acylalkyl" refers to an alkyl-C(O)-alk-, where
"alk" is alkylene.
[0079] The term "heteroarylalkyl" refers to an alkyl group
substituted with a heteroaryl group.
[0080] The term "-1,1-dihaloalkyl-" refers to an X group where the
1 position and therefore halogens are .alpha. to the phosphorus
atom.
[0081] The term "perhalo" refers to groups wherein every C--H bond
has been replaced with a C-halo bond on an aliphatic or aryl group.
Suitable perhaloalkyl groups include --CF.sub.3 and
--CFCl.sub.2.
[0082] The term "guanidino" refers to both --NR--C(NR)--NR.sub.2 as
well as --N.dbd.C(NR.sub.2).sub.2 where each R group is
independently selected from the group of --H, alkyl alkenyl,
alkynyl, aryl, and alicyclic, all except --H are optionally
substituted.
[0083] The term "bidentate" refers to an alkyl group that is
attached by its terminal ends to the same atom to form a cyclic
group. For example, propylene amine contains a bidentate propylene
group.
[0084] The term "naturally occurring amino acid" refers to alpha
amino acids containing at least one hydrogen at the alpha carbon
and when the alpha carbon is chiral, it has S absolute
configuration.
[0085] The term "amidino" refers to --C(NR)--NR.sub.2 where each R
group is independently selected from the group of --H, alkyl,
alkenyl, alkynyl, aryl, and alicyclic, all except --H are
optionally substituted.
[0086] The term "pharmaceutically acceptable salt" includes salts
of compounds of formula IA and its prodrugs derived from the
combination of a compound of this invention and an organic or
inorganic acid or base. Suitable acids include hydrochloric acid,
hydrobromic acid, acetic acid, trifluoroacetic acid,
methanesulfonic acid, p-toluenesulfonic acid and maleic acid.
[0087] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the "drug"
substance (a biologically active compound) as a result of
spontaneous chemical reaction(s), enzyme catalyzed chemical
reaction(s), and/or metabolic chemical reaction(s). Standard
prodrugs are formed using groups attached to functionality, e.g.
HO--, HS--, HOOC--, R.sub.2N--, associated with the FBPase
inhibitor, that cleave in vivo. Standard prodrugs include, but are
not limited to, carboxylate esters where the group is alkyl, aryl,
aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of
hydroxyl, thiol and amines where the group attached is an acyl
group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The
groups illustrated are exemplary, not exhaustive, and one skilled
in the art could prepare other known varieties of prodrugs. Such
prodrugs of the compounds of formulae I, X, and XI, fall within the
scope of the present invention. Prodrugs must undergo some form of
a chemical transformation to produce the compound that is
biologically active or is a precursor of the biologically active
compound. In some cases, the prodrug is biologically active usually
less than the drug itself, and serves to improve efficacy or safety
through improved oral bioavailability, pharmacodynamic half-life,
etc.
[0088] Phosphoramidate derivatives have been explored as phosphate
prodrugs (e.g. McGuigan et al., J. Med. Chem., 1999, 42: 393 and
references cited therein) and phosphonate prodrugs (Bischofberger,
et al., U.S. Pat. No. 5,798,340 and references cited therein) as
shown in Formulae G and H.
##STR00004##
[0089] Cyclic phosphoramidates have also been studied as
phosphonate prodrugs because of their speculated higher stability
compared to non-cyclic phosphoramidates (e.g. Starrett et al., J.
Med. Chem., 1994, 37:1857).
[0090] Another type of nucleotide prodrug was reported as the
combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron
et al., Nucleosides & Nucleotides, 1999, 18, 981) as shown in
Formula J.
##STR00005##
[0091] The term "enhancing" refers to increasing or improving a
specific property.
[0092] The term "enhanced oral bioavailability" refers to an
increase of at least 50% of the absorption of the dose of the
parent drug or prodrug (not of this invention) from the
gastrointestinal tract. In one aspect, this increase is at least
100%. Measurement of oral bioavailability usually refers to
measurements of the prodrug, drug, or drug metabolite in blood,
tissues, or urine following oral administration, compared to
measurements following systemic administration.
[0093] The term "parent drug" refers to any compound which delivers
the same biologically active compound. The parent drug form is
M-P(O)(OH).sub.2 and standard prodrugs, such as esters.
[0094] The term "drug metabolite" refers to any compound produced
in vivo or in vitro from the parent drug, which can include the
biologically active drug.
[0095] The term "pharmacodynamic half-life" refers to the time
after administration of the drug or prodrug to observe a diminution
of one half of the measured pharmacological response. In one
aspect, the half-life is enhanced when the half-life is increased
by at least 50%.
[0096] The term "biologically active drug or agent" refers to the
chemical entity that produces a biological effect. Thus, active
drugs or agents include compounds which as M-P(O)(OH).sub.2 are
biologically active.
[0097] The term "inhibitor of fructose-1,6-bisphosphatase" refers
to chemical entities M-PO.sub.3H.sub.2 that have an IC.sub.50 of
equal to or less than 50 .mu.M on human liver FBPase.
[0098] The term "therapeutically effective amount" refers to an
amount that has any beneficial effect in treating a disease or
condition.
Compounds
[0099] Suitable alkyl groups include groups having from 1 to about
20 carbon atoms. Suitable aryl groups include groups having from 1
to about 20 carbon atoms. Suitable aralkyl groups include groups
having from 2 to about 21 carbon atoms. Suitable acyloxy groups
include groups having from 1 to about 20 carbon atoms. Suitable
alkylene groups include groups having from 1 to about 20 carbon
atoms. Suitable alicyclic groups include groups having 3 to about
20 carbon atoms. Suitable heteroaryl groups include groups having
from 1 to about 20 carbon atoms and from 1 to 4 heteroatoms,
independently selected from nitrogen, oxygen, phosphorous, and
sulfur. Suitable heteroalicyclic groups include groups having from
2 to about twenty carbon atoms and from 1 to 5 heteroatoms,
independently selected from nitrogen, oxygen, phosphorous, and
sulfur.
[0100] One aspect of the invention is directed to the compound of
formula IA
##STR00006##
wherein compounds of formula IA are converted in vivo or in vitro
to M-PO.sub.3H.sub.2 which is an inhibitor of
fructose-1,6-bisphosphatase and
[0101] n is an integer from 1 to 3;
[0102] R.sup.2 is selected from the group of --H and --R.sup.3.
[0103] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0104] each R.sup.12 and R.sup.13 is independently selected from
the group consisting of H, lower alkyl, lower aryl, lower aralkyl,
all optionally substituted, or R.sup.12 and R.sup.13 together are
connected via 2-6 atoms, optionally including 1-2 heteroatoms
selected from the group consisting of O, N and S, to form a cyclic
group;
[0105] each R.sup.14 is independently selected from the group
consisting of --OR.sup.17, --N(R.sup.17).sub.2, --NHR.sup.17,
--NR.sup.2OR.sup.19 and --SR.sup.17;
[0106] R.sup.15 is selected from the group consisting of --H, lower
alkyl, lower aryl, lower aralkyl, or together with R.sup.16 is
connected via 2-6 atoms, optionally including 1 heteroatom selected
from the group consisting of O, N, and S;
[0107] R.sup.16 is selected from the group consisting of
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14, --H, lower alkyl,
lower aryl, lower aralkyl, or together with R.sup.15 is connected
via 2-6 atoms, optionally including 1 heteroatom selected from the
group consisting of O, N, and S;
[0108] each R.sup.17 is independently selected from the group
consisting of lower alkyl, lower aryl, and lower aralkyl, all
optionally substituted, or together R.sup.17 and R.sup.17 on N is
connected via 2-6 atoms, optionally including 1 heteroatom selected
from the group consisting of O, N, and S;
[0109] R.sup.18 is independently selected from the group consisting
of H, lower alkyl, aryl, aralkyl, or together with R.sup.12 is
connected via 1-4 carbon atoms to form a cyclic group;
[0110] each R.sup.19 is independently selected from the group
consisting of --H, lower alkyl, lower aryl, lower alicyclic, lower
aralkyl, and COR.sup.3;
[0111] and pharmaceutically acceptable salts thereof.
[0112] Such compounds converted to M-PO.sub.3H.sub.2 include
compounds that have an IC.sub.50 on isolated human liver FBPase
enzyme of less than or equal to 10 .mu.M. Alternatively, the
IC.sub.50 is less than or equal to 1 .mu.M. Such compounds may also
bind to the AMP site of FBPase.
[0113] In one aspect, M is R.sup.5--X--, wherein R.sup.5 is
selected from the group consisting of:
##STR00007##
wherein:
[0114] each G is independently selected from the group consisting
of C, N, O, S, and Se, and wherein only one G may be O, S, or Se,
and at most one G is N;
[0115] each G' is independently selected from the group consisting
of C and N and wherein no more than two G' groups are N;
[0116] A is selected from the group consisting of --H,
--NR.sup.4.sub.2, --CONR.sup.4.sub.2, --CO.sub.2R.sup.3, halo,
--S(O)R.sup.3, --SO.sub.2R.sup.3, alkyl, alkenyl, alkynyl,
perhaloalkyl, haloalkyl, aryl, --CH.sub.2OH,
--CH.sub.2NR.sup.4.sub.2, --CH.sub.2CN, --CN, --C(S)NH.sub.2,
--OR.sup.2, --SR.sup.2, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null;
[0117] each B and D are independently selected from the group
consisting of --H, alkyl, alkenyl, alkynyl, aryl, alicyclic,
aralkyl, alkoxyalkyl, --C(O)R.sup.11, --C(O)SR.sup.3,
--SO.sub.2R.sup.11, --S(O)R.sup.3, --CN, --NR.sup.9.sub.2,
--OR.sup.3, --SR.sup.3, perhaloalkyl, halo, --NO.sub.2, and null,
all except --H, --CN, perhaloalkyl, --NO.sub.2, and halo are
optionally substituted;
[0118] E is selected from the group consisting of --H, alkyl,
alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, --C(O)OR.sup.3,
--CONR.sup.4.sub.2, --CN, --NR.sup.9.sub.2, --NO.sub.2, --OR.sup.3,
--SR.sup.3, perhaloalkyl, halo, and null, all except --H, --CN,
perhaloalkyl, and halo are optionally substituted;
[0119] J is selected from the group consisting of --H and null;
[0120] X is an optionally substituted linking group that links
R.sup.5 to the phosphorus atom via 2-4 atoms, including 0-1
heteroatoms selected from N, O, and S, except that if X is urea or
carbamate there is 2 heteroatoms, measured by the shortest path
between R.sup.5 and the phosphorus atom, and wherein the atom
attached to the phosphorus is a carbon atom, and wherein X is
selected from the group consisting of -alkyl(hydroxy)-, -alkynyl-,
-heteroaryl-, -carbonylalkyl-, -1,1-dihaloalkyl-, -alkoxyalkyl-,
-alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-,
-alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-,
-alkoxycarbonylamino-, and -alkylaminocarbonylamino-, all
optionally substituted; with the proviso that X is not substituted
with --COOR.sup.2, --SO.sub.3H, or --PO.sub.3R.sup.2.sub.2;
[0121] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0122] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0123] each R.sup.4 is independently selected from the group
consisting of --H, and alkyl, or together R.sup.4 and R.sup.4 form
a cyclic alkyl group;
[0124] each R.sup.9 is independently selected from the group
consisting of --H, alkyl, aryl, aralkyl, and alicyclic, or together
R.sup.9 and R.sup.9 form a cyclic alkyl group;
[0125] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2;
[0126] and with the proviso that: [0127] 1) when G' is N, then the
respective A, B, D, or E is null; [0128] 2) at least one of A and
B, or A, B, D, and E is not selected from the group consisting of
--H or null; [0129] 3) when G is N, then the respective A or B is
not halogen or a group directly bonded to G via a heteroatom;
[0130] and pharmaceutically acceptable salts thereof.
[0131] In one aspect, the following additional provisos may apply:
[0132] 4) when R is a six-membered ring, then X is not any 2 atom
linker, an optionally substituted-alkyloxy-, or an optionally
substituted-alkylthio-; [0133] 5) when X is not .alpha.-heteroaryl-
group, then R is not substituted with two or more aryl groups.
[0134] In one aspect of the present invention, compounds of formula
IA have an IC.sub.50 of .ltoreq.50 .mu.M on glucose production in
isolated rat hepatocytes.
[0135] In one aspect, compounds of formula IA can be selected from
those compounds where M is attached to
##STR00008##
wherein R.sup.17 is selected from the group consisting of ethyl,
i-propyl, n-propyl and neopentyl and wherein C* has S
stereochemistry.
[0136] In thiazoles where A'' is --NH.sub.2, X is furan-2,5-diyl,
B'' is --S(CH.sub.2).sub.2CH.sub.3; or where A'' is --NH.sub.2, D
is furan-2,5-diyl, B'' is --CH.sub.2--CH(CH.sub.3).sub.2, then M
may be attached to
##STR00009##
wherein R.sup.17 is selected from the group consisting of ethyl,
i-propyl, n-propyl and neopentyl and wherein C* has S
stereochemistry.
[0137] In one aspect, the compounds of formula IA can be selected
from:
##STR00010##
[0138] Within such a group, compounds of formula IA may be
compounds of formulae II or IV:
##STR00011##
[0139] In one aspect, compounds are of Formula IA wherein M is
##STR00012##
wherein:
[0140] G'' is selected from the group consisting of --O-- and
--S--;
[0141] A.sup.2 is selected from the group consisting of --H,
--NR.sup.4.sub.2, --NHAc, --OR.sup.2, --SR.sup.2,
--C(O)NR.sup.4.sub.2, halo, --COR.sup.11, --CN, perhaloalkyl, C1-C6
alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
[0142] L.sup.2, E.sup.2, and J.sup.2 are selected from the group
consisting of --NR.sup.4.sub.2, --NHAc, --NO.sub.2, --H,
--OR.sup.2, --SR.sup.2, --C(O)NR.sup.4.sub.2, halo, --COR.sup.11,
--SO.sub.2R.sup.3, guanidinyl, amidinyl, aryl, aralkyl,
alkyloxyalkyl, --SCN, --NHSO.sub.2R.sup.3,
--SO.sub.2NR.sup.4.sub.2--CN, --S(O)R.sup.3, perhaloacyl,
perhaloalkyl, perhaloalkoxy, C1-C6 alkyl(OH), C1-C6 alkyl(SH),
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, and lower
alicyclic, or together L.sup.2 and E.sup.2 or E.sup.2 and J.sup.2
form an annulated cyclic group;
[0143] X.sup.2 is selected from the group consisting of
--CR.sup.2.sub.2--, --CF.sub.2--, --CR.sup.2.sub.2--O--,
--CR.sup.2.sub.2--S--, --C(O)--O--, --C(O)--S--, --C(S)--O--,
--CH.sub.2--C(O)--O-- and --CR.sup.2.sub.2--NR.sup.20--, and
wherein in the atom attached to the phosphorus is a carbon atom;
with the proviso that X.sup.2 is not substituted with
--COOR.sup.2--SO.sub.3H, or --PO.sub.3R.sup.2.sub.2;
[0144] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0145] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0146] each R.sup.4 is independently selected from the group
consisting of --H, and alkyl, or together R.sup.4 and R.sup.4 form
a cyclic alkyl group;
[0147] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2;
[0148] R.sup.20 is selected from the group consisting of lower
alkyl, --H, and --COR.sup.2; and
[0149] pharmaceutically acceptable salts thereof.
[0150] In one aspect, the bisphosphoramidate portion of the
compounds of the invention,
##STR00013##
may be selected from the group consisting of
##STR00014##
wherein R.sup.17 is selected from the group consisting of ethyl,
i-propyl, n-propyl, n-butyl and neopentyl. In another aspect, C*
has S stereochemistry.
[0151] Alternatively, such compounds may be of the formula:
##STR00015##
[0152] In one aspect of the invention, M is
##STR00016##
wherein:
[0153] A.sup.3, E.sup.3, and L.sup.3 are selected from the group
consisting of --NR.sup.8.sub.2, --NO.sub.2, --H, --OR.sup.7,
--SR.sup.7, --C(O)NR.sup.4.sub.2, halo, --COR.sup.11,
--SO.sub.2R.sup.3, guanidine, amidine, --NHSO.sub.2R.sup.3,
--SO.sub.2NR.sup.4.sub.2, --CN, sulfoxide, perhaloacyl,
perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5
alkynyl, and lower alicyclic, or together A.sup.3 and L.sup.3 form
a cyclic group, or together L.sup.3 and E.sup.3 form a cyclic
group, or together E.sup.3 and J.sup.3 form a cyclic group
including aryl, cyclic alkyl, and heterocyclic;
[0154] J.sup.3 is selected from the group consisting of
--NR.sup.8.sub.2, --NO.sub.2, --H, --OR.sup.7, --SR.sup.7,
--C(O)NR.sup.4.sub.2, halo, --C(O)R.sup.11, --CN, sulfonyl,
sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl,
haloalkyl, aminoalkyl, alkenyl, alkynyl; alicyclic, aryl, and
aralkyl, or together with Y.sup.3 forms a cyclic group including
aryl, cyclic alkyl and heterocyclic alkyl;
[0155] X.sup.3 is selected from the group consisting of
-alkyl(hydroxy)-, -alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-,
-1,1-dihaloalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-,
-alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-,
-alicyclic-, -aralkyl-, -alkylaryl-, -alkoxycarbonyl-,
-carbonyloxyalkyl-, -alkoxycarbonylamino-, and
-alkylaminocarbonylamino-, all optionally substituted; with the
proviso that X.sup.3 is not substituted with --COOR.sup.2,
--SO.sub.3H, or --PO.sub.3R.sup.2.sub.2;
[0156] Y.sup.3 is selected from the group consisting of --H, alkyl,
alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl,
alkoxyalkyl, --C(O)R.sup.3, --S(O).sub.2R.sup.3, --C(O)--R.sup.11,
--CONHR.sup.3, --NR.sup.2.sub.2, and --OR.sup.3, all except H are
optionally substituted;
[0157] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0158] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0159] each R.sup.4 is independently selected from the group
consisting of --H, and alkyl, or together R.sup.4 and R.sup.4 form
a cyclic alkyl group;
[0160] R.sup.7 is independently selected from the group consisting
of --H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl,
and --C(O)R.sup.10;
[0161] R.sup.8 is independently selected from the group consisting
of --H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic,
--C(O)R.sup.10, or together they form a bidentate alkyl;
[0162] each R.sup.9 is independently selected from the group
consisting of --H, -alkyl, aralkyl, and alicyclic, or together
R.sup.9 and R.sup.9 form a cyclic alkyl group;
[0163] R.sup.10 is selected from the group consisting of --H, lower
alkyl, --NH.sub.2, lower aryl, and lower perhaloalkyl;
[0164] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and
[0165] pharmaceutically acceptable salts thereof.
[0166] In one aspect, the following provisos may apply:
[0167] a) when X.sup.3 is alkyl or alkene, then A.sup.3 is
--N(R.sup.8.sub.2);
[0168] b) X.sup.3 is not alkylamine and alkylaminoalkyl substituted
with phosphonic esters and acids; and
[0169] c) A.sup.3, L.sup.3, E.sup.3, J.sup.3, and Y.sup.3 together
may only form 0-2 cyclic groups.
[0170] In the following table, the inventors contemplate any
combination of the following Markush groups and those described
above for the various variables.
TABLE-US-00001 TABLE A Table of Markush Groups by Variable Markush
Markush Markush Markush Group A Group B Group C Group D R.sup.2
R.sup.3 and --H --H, lower alkyl, --H, C1-C4 alkyl, lower aryl,
lower C2-C7 alicyclic, alicyclic and C4-C6 aryl, and lower aralkyl
C5-C7 aralkyl, wherein said alicyclic, aryl, aralkyl may be
optionally substituted with 1-2 heteroatoms R.sup.3 alkyl, aryl,
lower alkyl, C1-C4 alkyl, alicyclic, and lower aryl, lower C2-C7
alicyclic, aralkyl alicyclic and C4-C6 aryl, and lower aralkyl
C5-C7 aralkyl, wherein said alicyclic, aryl, aralkyl may be
optionally substituted with 1-2 heteroatoms R.sup.4 --H, and --H,
and C1-C4 alkyl, C1-C2 alkyl or R.sup.4 and R.sup.4 are connected
by 4-5 atoms to form a cyclic group R.sup.5 pyrrolyl, imidazolyl,
oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, pyrazolyl,
isoxazolyl, 1,2,3- oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5-
oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-
thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
1,3,5-triazinyl, 1,2,4-triazinyl, and 1,3- selenazolyl, all of
which contain at least one substituent pyrrolyl, imidazolyl,
isothiazolyl, 1,2,4- thiadiazolyl, pyrazolyl, isoxazolyl, 1,2,3-
oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-
oxadiazolyl, 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl,
1,2,4-triazinyl, and 1,3- selenazolyl, all of which contain at
least one substituent ##STR00017## ##STR00018## ##STR00019##
##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025## ##STR00026## thiazolyl, oxazolyl, and selenazolyl
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
R.sup.7 --H, lower alkyl, --H, C(O)R.sup.10, C1- lower alicyclic,
C4 alkyl, C2-C7 lower aralkyl, alicyclic, C4-C6 lower aryl, and
aryl, and C5-C7 C(O)R.sup.10 aralkyl, wherein said alicyclic, aryl,
aralkyl may be optionally substituted with 1-2 heteroatoms R.sup.8
--H, lower alkyl, H, C(O)R.sup.10, C1- lower alicyclic, C4 alkyl,
C2-C7 lower aralkyl, alicyclic, C4-C6 lower aryl, and aryl, and
C5-C7 C(O)R.sup.10; or aralkyl, wherein said alicyclic, aryl,
aralkyl may be optionally substituted with 1-2 heteroatoms; or
together R.sup.8 and together R.sup.8 and R.sup.8 form a R.sup.8
form a C2-C5 bidentate alkyl bidentate alkyl R.sup.9 --H, lower
alkyl, --H, C1-C4 alkyl, lower aralkyl, C5-C7 aralkyl, and lower
and C2-C7 alicyclic; or aliycylic, wherein said alicyclic, and
aralkyl may be optionally substituted with 1-2 heteroatoms; or
together R.sup.9 and together R.sup.9 and R.sup.9 form a cyclic
R.sup.9 form a C2-C6 alkyl group cyclic alkyl R.sup.10 --H,
--NH.sub.2, lower --H, --NH.sub.2, C1-C4 alkyl, lower aryl, alkyl,
C4-C6 and lower aryl, and C1-C4 perhaloalkyl perhaloalkyl, wherein
said aryl, may be optionally substituted with 1-2 heteroatoms
R.sup.11 --NR.sup.2.sub.2, --OR.sup.2, --NR.sup.2.sub.2,
--OR.sup.2, lower alkyl, and C1-C4 alkyl, and lower aryl C4-C6
aryl, wherein said aryl may be optionally substituted with 1-2
heteroatoms R.sup.12 --H, lower alkyl, --H, C1-C6 --H, --H,lower
--H, C1-C4 --H and lower alkyl, -lower C1-C4 alkyl, lower alkyl,
methyl, perhaloalkyl, alkoxyalkyl, alkyl, perhaloalkyl,
--CH.sub.2--O--C(CH.sub.3).sub.3, lower aralkyl, lower phenyl, and
lower phenyl, lower aryl, alkylthioalkyl, and aryl, and optionally
phenyl, and benzyl; optionally benzyl; or substituted with benzyl,
or or substituted --OR.sup.19, --NR.sup.19.sub.2, with --OR.sup.19,
methyl --SR.sup.19, --NR.sup.19.sub.2, --C(O)--NR.sup.2R.sup.3,
--SR.sup.19, halo, --CO.sub.2R.sup.2, --C(O)--NR.sub.2R.sup.3,
3-indolyl, halogen, 4-imidazolyl, or --CO.sub.2R.sup.2, H
guandinyl; or 3-indolyl, 4- imidazolyl, or guanidinyl; or together
R.sup.12 and R.sup.12 and R.sup.13 are R.sup.12 and R.sup.13 are
R.sup.12 and R.sup.12 and R.sup.13are connected via 2- connected
via 2-5 R.sup.13 are R.sup.13 are connected via 2- 5 carbon atoms
carbon atoms to form connectd connect- 5 carbon atoms to form a a
cycloalkyl group via 2 or 4 ed via 4 to form a cycloalkyl group
carbon carbon cycloalkyl group atoms to atoms to form a form
cyclopro- cyclo- pyl or pentyl cyclopent- group yl group R.sup.13
--H, lower alkyl, --H, C1-C6 alkyl, --H, --H, lower --H, Cl-C4 --H,
lower -lower C1-C4 alkyl, lower alkyl, methyl, perhaloalkyl,
alkoxyalkyl, alkyl, perhaloalkyl, --CH.sub.2--O--C(CH.sub.3).sub.3,
i-propyl, lower aralkyl, lower phenyl, and lower phenyl, and lower
aryl, alkylthioalkyl, and aryl, option- and benzyl, optionally
phenyl, and benzyl; ally substi- benzyl; or substituted with
benzyl, or or tuted with --OR.sup.19, --OR.sup.19,
--NR.sup.19.sub.2, NR.sup.19.sub.2SR.sup.19, --SR.sup.19,
C(O)NR.sup.2R.sup.3, --C(O)--NR.sup.2R.sup.3, halogen, halogen,
--CO.sub.2R.sup.2, 3- --CO.sub.2R.sup.2, indolyl, 4- 3-indolyl,
imidazolyl, 4-imidazolyl, or or guani- guandinyl; or dinyl; or
together and R.sup.12 and R.sup.12 and R.sup.13 are R.sup.12 and
R.sup.13 are R.sup.12 and R.sup.12 and R.sup.13 are connected via
2- connected via 2-5 R.sup.13 are R.sup.13 are connected via 2- 5
carbon atoms carbon atoms to form connected connect- 5 carbon atoms
to form a a cycloalkyl group via 2 or 4 ed via 4 to form a
cycloalkyl group carbon carbon cycloalkyl group atoms to atoms to
form a form cyclopropyl cyclo- or pentyl cyclo- group pentyl group
R.sup.14 --OR.sup.17, --SR.sup.17 and --OR.sup.17
--NR.sup.2OR.sup.19 R.sup.15 --H, lower alkyl, --H, and C1-C6 --H
and C1-C3 alkyl --H, methyl, ethyl, lower aryl, and alkyl, or and
propyl lower aralkyl, or together R.sup.15and together R.sup.15 and
--NR.sup.15R.sup.16 is a cyclic NR.sup.15R.sup.16 is R.sup.16 are
R.sup.16 are amine morpholinyl and connected via 2- connected via
2- pyrrolidinyl 6 atoms, 6 atoms optionally optionally including 1
including 1 heteroatom heteroatom selected from the selected from
the group consisting group consisting of O, N, and S of, O, N, and
S R.sup.16 --H, lower alkyl, --H, and C1-C6 --H and C1-C3 alkyl
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14 lower aryl, and alkyl,
or lower aralkyl, or together R.sup.15 and together R.sup.15 and
--NR.sup.15R.sup.16 is a cyclic NR.sup.15R.sup.16 is R.sup.16 are
R.sup.16 are amine morpholinyl and connected via 2- connected via
2- pyrrolidinyl 6 atoms 6 atoms, --H, C1-C6 alkyl and optionally
optionally --(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14 including 1
including 1 or heteroatom heteroatom selected from the selected
from the together R.sup.15 and R.sup.16 group consisting group
consisting are connected via 2-6 of O, N, and S of, O, N, and S
atoms, optionally including 1 heteroatom selected from the group
consisting of, 0, N, and S R.sup.17 C1-C7 alkyl, methyl, ethyl,
methyl, ethyl, ethyl, n-propyl, i- phenyl, indolyl, i-propyl
i-propyl, n-propyl, propyl, and neopentyl sesimol and n-propyl,
t-butyl, t-butyl, cyclopentyl, benzyl, wherein isobutyl neo-
neopentyl, phenyl and said phenyl, pentyl, cyclo- benzyl ethyl,
i-propyl, n- indolyl, sesimol pentyl and propyl, n-butyl, and and
benzyl may unsubstituted neopentyl be optionally benzyl substituted
with ethyl 1-3 groups selected from the group consisting of
--CO.sub.2R.sup.2, --OR.sup.3, halo, --NHC(O)R.sup.3, and lower
alkyl R.sup.18 --H, C1-C6 alkyl --H and C1-C6 --H and methyl --H
and benzyl alkyl R.sup.19 --H, --COR.sup.3, --H, --COR.sup.3, lower
alkyl, C1-C4 alkyl, C4- lower aryl, lower C6 aryl, C2-C7 alicyclic,
and alicyclic, and lower aralkyl C5-C7 aralkyl R.sup.20 --H,
--COR.sup.2, and --H, --COR.sup.2, and lower alkyl C1-C4 alkyl A
--H, --NR.sup.4.sub.2, --CONR.sup.4.sub.2, --CO.sub.2R.sup.3, halo,
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perhaloalkyl,
C1-C6 haloalkyl, aryl, --CH.sub.2OH, --CH.sub.2NR.sup.4.sub.2,
CH.sub.2CN, --CN, --C(S)NH.sub.2, --OR.sup.2, --SR.sup.2,
--N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc, and null B --H, alkyl,
alkenyl, alkynyl, aryl, heteroaryl. alicyclic, aralkyl,
alkoxyalkyl, --C(O)R.sup.11, --C(O)SR.sup.3, SO.sub.2R.sup.11,
--S(O)R.sup.3, --CN, --NR.sup.9.sub.2, --OR.sup.3, --SR.sup.3,
perhaloalkyl, halo, and null, all except --H, --CN, perhalo-alkyl,
and halo are optionally substituted D --H, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, alicyclic, aralkyl, alkoxyalkyl, --C(O)R.sup.11,
--C(O)SR.sup.3, SO.sub.2R.sup.11, --S(O)R.sup.3, --CN, --NR.sup.2,
--OR.sup.3, --SR.sup.3, perhaloalkyl, halo, and null, all except
--H, --CN, perhalo-alkyl, and halo are optionally substituted E
--H, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, aryl, C4-C6
alicyclic, alkoxyalkyl, --C(O)OR.sup.3, --CONR.sup.4.sub.2, --CN,
--NR.sup.9.sub.2, --OR.sup.3, --SR.sup.3, C1-C6
perhaloalkyl, halo, and null, all except --H, --CN, perhaloalkyl,
and halo are optionally substituted X -heteroaryl-, -heteroaryl-,
methylenoxycarbonyl furan-2,5-diyl -alkylcarbonyl- -alkylamino- and
furan-2,5-diyl amino-, -alkyl- carbonyl-, and aminocarbonyl-,
-alkoxy- and alkoxy- carbonyl-, all carbonyl- optionally sub-
stituted -heteroaryl-, -heteroaryl- and methylenoxycarbonyl
-alkoxyalkyl- -alkoxy- -alkylcarbonyl- carbonyl- amino-, -alkyl-
aminocarbonyl-, -alkoxyalkyl and -alkoxy- carbonyl- G' C, and N A''
--H, --NR.sup.4.sub.2, --NH.sub.2, --CONH.sub.2, --H, --NH.sub.2,
--Cl, --NH.sub.2 --CONR.sup.4.sub.2, halo, --Br, and
--CO.sub.2R.sup.3, halo, --CH.sub.3, --CF.sub.3, --CH.sub.3 C1-C6
alkyl, C2- --CH.sub.2-halo, --CN, C6 alkenyl, C2- --OCH.sub.3,
--SCH.sub.3, C6 alkynyl, C1- and --H C6 perhaloalkyl, C1-C6
haloalkyl, aryl, --CH.sub.2OH, --CH.sub.2NR.sup.4.sub.2,
--CH.sub.2CN, --CN, --C(S)NH.sub.2, --OR.sup.2, --SR.sup.2,
--N.sub.3, --NHC(S)NR.sup.4.sub.2, and --NHAc B'' --H, alkyl, --H,
--C(O)R.sup.11, --H, --C(O)OR.sup.3, --S(CH.sub.2).sub.2CH.sub.3
alkenyl, alkynyl, --C(O)SR.sup.3, alkyl, --C(O)SR.sup.3, C1-C6
aryl, heteroaryl, aryl, heteroaryl, alkyl, alicyclic, aryl, --SMe
alicyclic, aralkyl, alicyclic, halo, heteroaryl, and SR.sup.3
alkoxyalkyl, --CN, --SR.sup.3, OR.sup.3 --C(O)R.sup.11, and
--NR.sup.9.sub.2 --S(CH.sub.2).sub.2CH.sub.3, --CH(CH.sub.3).sub.2
--C(O)SR.sup.3, --CH.sub.2--CH(CH.sub.3).sub.2, --SO.sub.2R.sup.11,
--COOEt, --S(O)R.sup.3, --CN, --SMe, --CH(CH.sub.3).sub.2
--CH.sub.2--CH(CH.sub.3).sub.2 --NR.sup.9.sub.2, --OR.sup.3,
cyclopropyl and --COOEt --SR.sup.3, perhalo- n-propyl alkyl, and
halo, all except --H, --CN, perhalo- alkyl, and halo are optionally
substituted D'' --H, alkyl, --H, --C(O)R.sup.11, --H,
--C(O)OR.sup.3, lower --H alkenyl, alkynyl, --C(O)SR.sup.3, alkyl,
alkyl, alicyclic, and aryl, heteroaryl, aryl, heteroaryl, halo
alicyclic, aralkyl, alicyclic, halo, alkoxyalkyl, --NR.sup.9.sub.2,
and --SR.sup.3 --C(O)R.sup.11, --C(O)SR.sup.3, --SO.sub.2R.sup.11,
--CN, --S(O)R.sup.3, --NR.sup.9.sub.2, --OR.sup.3, --SR.sup.3,
perhaloalkyl, and halo, all except --H, --CN, per- haloalkyl, and
halo are optionally substituted E'' --H, C1-C6 alkyl, --H, C1-C6
alkyl, --H, C1--C6 alkyl, --H C2-C6 alkenyl, lower alicyclic, lower
alicyclic, halo, C2-C6 alkynyl, halo, --CN, --CN, --C(O)OR.sup.3,
and aryl, C4-C6 --C(O)OR.sup.3, --SR.sup.3, --SR.sup.3 alicyclic,
and --CONR.sup.4.sub.2 alkoxyalkyl, --C(O)OR.sup.3, H, --Br, and
--Cl --CONR.sup.4.sub.2, --CN, --NR.sup.9.sub.2, --OR.sup.3,
--SR.sup.3, C1-C6 perhaloalkyl, and halo, all except H, --CN,
perhalo- alkyl, and halo are optionally substituted G'' --S--
A.sup.2 --H, --NR.sup.4.sub.2, --CN, --H, --NR.sup.4.sub.2,
--NH.sub.2, --H, --NH.sub.2 --NHAc, halogen, halogen, and C1- --H,
--NH.sub.2, --OR.sup.3, perhalo- C5 alkyl, halo, and --Cl, alkyl,
C1-C5 alkyl --Br, --C(O)--NR.sup.4.sub.2, and C1-C6 --CH.sub.3
alkyl, C2-C6 alkenyl, C2-C6 alkynyl E.sup.2 --H, --NR.sup.4.sub.2,
--NO.sub.2, --H, --H, --NR.sup.4.sub.2, --H, H, lower --SCN,
--NHAc, --S--C.ident.N, --NR.sup.4.sub.2, --S--C.ident.N, --SCN,
alkyl, C1-C6 --CN, halogen, --S--C.ident.N, --CN, halo- halogen,
alkyl, --OR.sup.3, hydroxy, --C(O)OH, --C(O)OH, gen, --SCN, C1-C6
lower alkoxy- halogen, lower lower --CN, --OR.sup.3, alkoxy,
methylene, alkoxy, lower alkoxy, C1-C6 lower C1-C6 -alkyl(OH),
aryl, alkylthio, lower alkyl, alkyloxy- alkylthio, alkyloxy-
hydroxy, lower alkylthio, C1-C6 carbonyl, and --Br carbonyl,
alkyl(hydroxy), C1-C5 alkoxy, lower Me --CO(OH), --SR.sup.3, lower
alkoxy- alkyl, lower or alkyloxy, --SH, lower methylene, lower
alkyl(hydroxy), --CN, OMe perhaloalkyl, aryl, lower lower lower OEt
heteroaryl, lower heteroaryl, and aryl, and alkylthio, alicyclic
and C1- C1-C5 alkyl, or halogen, or or
--(O)--CH.sub.2--CH--CH--(CH.sub.3).sub.2 C6 alkyl, or together
L.sup.2 and together L.sup.2 and together L.sup.2 and E.sup.2
together E.sup.2 form an E.sup.2 form an form an annulated L.sup.2
and E.sup.2 annulated cyclic annulated cyclic cyclic group form a
group group containing an cyclic additional 4 carbon group atoms
including aryl, cyclic alkyl, hetero- aryl, or hetero- cyclic alkyl
J.sup.2 --H,--NR.sup.4.sub.2, --NO.sub.2, --H, --NR.sup.4.sub.2,
--H, halo, H, Cl, --H --NHAc, --S--C.ident.N, --S--C.ident.N, and
C1-C5 and --CN, halogen, --C(O)OH, alkyl --CH.sub.3 --OR.sup.3,
hydroxy, halogen, lower lower alkoxy- alkoxy, lower methylene,
alkylthio, -alkyl(OH), aryl, hydroxy, lower alkyloxy-
alkyl(hydroxy), carbonyl, lower alkoxy- --CO(OH), --SR.sup.3,
methylene, lower --SH, lower aryl, lower perhaloalkyl, heteroaryl,
and heteroaryl, lower C1-C5 alkyl alicyclic and C1- C6 alkyl
L.sup.2 --H, --NR.sup.4.sub.2, --NO.sub.2, --H, --NR.sup.4.sub.2,
--H, --NR.sup.4.sub.2, --H, --H, --CN, --H, --NHAc, --S--C.ident.N,
--S--C.ident.N, --S--C.ident.N, --CN, --SCN, methyl, --CN, halogen,
--C(O)OH, --CN, --SCN, lower ethyl, --OR.sup.3, hydroxy, halogen,
lower --C(O)OH, C1-C6 alkyl, propyl, lower alkoxy- alkoxy, lower
lower alkyl, alicyclic, --SCN and methylene, alkylthio, alkoxy,
halo- aryl, --Cl -alkyl(OH), aryl, hydroxy, lower lower gen,
halogen, alkyloxy- alkyl(hydroxy), alkylthio, and lower carbonyl,
lower alkoxy- C1-C5 lower alkyloxy, --CO(OH), --SR.sup.3,
methylene, lower alkyl, alkoxy, hydroxy, --SH, lower aryl, lower
lower or and perhaloalkyl, heteroaryl, and alkyl- alken-
heteroaryl, lower C1-C5 alkyl; or (hydroxy), ylene- alicyclic and
C1- lower aryl, OH, or C6 alkyl, or and halogen, or together
L.sup.2 and together L.sup.2 and together L.sup.2 and E.sup.2
together L.sup.2 E.sup.2 form an E.sup.2 form an form an annulated
and E.sup.2 form annulated cyclic annulated cyclic cyclic group a
cyclic group group containing an group additional 4 carbon
including atoms aryl, cyclic alkyl, heteroaryl, or hetero- cyclic
alkyl X.sup.2 --CR.sup.2.sub.2--, --CF.sub.2--, --CH.sub.2--O-- and
--CH.sub.2--O-- --CR.sup.2.sub.2--O--, --CH.sub.2--S--
--CR.sup.2.sub.2--S--, --C(O)--O--, --C(O)--S--, --C(S)--O--,
--CH.sub.2--C(O)--O-- and --CR.sup.2.sub.2--NR.sup.20-- A.sup.3
--H, --NR.sup.8.sub.2, --NO.sub.2, --H, --NH.sub.2, --F, --NH.sub.2
hydroxy, and --CH.sub.3 halogen, --OR.sup.7, alkylamino- earbonyl,
--SR.sup.7, lower perhalo- alkyl, and C1-C5 alkyl E --H,
--NR.sup.8.sub.2, --NO.sub.2, --H and --Cl --H hydroxy, halogen,
--OR.sup.7, alkylamino- earbonyl, --SR.sup.7, lower perhalo- alkyl,
and C1-C5 alkyl, or together E.sup.3 and J.sup.3 together form a
cyclic group J.sup.3 --H, halogen, --H, halo, C1-C5 -ethyl lower
alkyl, hydroxyalkyl, lower hydroxy- C1-C5 haloalkyl, alkyl,
--NR.sup.8.sub.2, R.sup.8.sub.2N-C1-C5 lower R.sup.8.sub.2N- alkyl,
C1-C5 -N,N-dimethylamino- alkyl, lower alicyclic, and propyl
haloalkyl, lower C1-C5 alkyl perhaloalkyl, lower alkenyl, lower
alkynyl, lower aryl, heterocyclic, and alicyclic or together
E.sup.3 and J.sup.3 together form a cyclic group L.sup.3 --H,
--NR.sup.8.sub.2,--NO.sub.2, --H, --F, --OCH.sub.3, --F hydroxy,
--Cl, and --CH.sub.3 halogen, --OR.sup.7.sub., alkylaminocar-
bonyl, --SR.sup.7, lower perhalo- alkyl, and C1-C5 alkyl Y.sup.3
alicyclic and lower alkyl -i-butyl lower alkyl X.sup.3
-heteroaryl-, --CH.sub.2OCH.sub.2-, -furan-2,5-diyl-
-alkylcarbonyl- -methyleneoxy- amino-, carbonyl- and -alkylamino-
-furan-2,5-diyl- carbonyl-, and -alkoxycarbonyl- n 1,2 1
[0171] Compounds of formula IA may have oral bioavailability of at
least 5% and some may have oral bioavailability of at least
10%.
[0172] The prodrugs of the present invention may have two isomeric
forms around the phosphorus. In one aspect, the compounds of the
invention are not chiral at the phosphorus. In another aspect,
there is no chiral center in the amino groups attached to the
phosphorus. The prodrugs of the present invention may have isomers
at the carbon substituted with R.sup.12 and R.sup.13. The invention
contemplates mixtures of isomers as well as individual
stereoisomers. For instance, when n is 1, and R.sup.12 is H, the
carbon attached to R.sup.12 and R.sup.13 can have R
stereochemistry. In another aspect, when n is 1 and R.sup.12 is
--H, the carbon attached to R.sup.12 and R.sup.13 can have S
stereochemistry.
[0173] The present invention includes compounds designated in Table
1 as defined in the following formulae: formula i, formula ii, and
formula iii.
##STR00032##
[0174] In the above formulae i, ii, and iii, R.sup.55 may be
substituted by A and B. The compounds of formulae i, ii, and iii
are listed in Table 1 by designated numbers assigned to R.sup.55,
A, B, Q.sup.1, and Q.sup.2 in the above formulae i, ii, and iii
according to the following convention:
[0175] Q.sup.1.Q.sup.2.R.sup.5.B.A. For each moiety, structures
assigned to a number shown in the following tables for R.sup.55, A,
B, Q.sup.1 and Q.sup.2.
[0176] Variable R.sup.55 is divided into two groups, each listing
four different structures.
[0177] Compounds named in Table 1 of formulae i, ii, and iii
wherein the R.sup.55 moieties are assigned the following
numbers:
[0178] Group 1:
TABLE-US-00002 1 2 3 4 R.sup.55 = ##STR00033## ##STR00034##
##STR00035## ##STR00036##
[0179] Group 2:
TABLE-US-00003 1 2 3 4 R.sup.55 = ##STR00037## ##STR00038##
##STR00039## ##STR00040##
[0180] Variable A moieties are assigned the following numbers:
TABLE-US-00004 1 2 3 4 A = NH.sub.2 H Me Cl
[0181] Variable B moieties are assigned the following numbers:
TABLE-US-00005 1 2 3 4 5 6 7 8 B = --SCH.sub.3 -iBu -cPr --S-nPr
--SEt -iPr -nPr --CH.sub.2cPr
[0182] Variables Q.sup.1 and Q.sup.2 are divided into three groups,
each listing eight different substituents.
[0183] Q.sup.1 and Q.sup.2 moieties are assigned the following
numbers:
Group 1:
Q.sup.1 and Q.sup.2
[0184] 1. --NH--CH.sub.2--C(O)R.sup.14 [0185] 2.
--NH--CH(CH.sub.3)--C(O)R.sup.14 [0186] 3.
--NH--C(CH.sub.3).sub.2--C(O)R.sup.14 [0187] 4.
--NH--C(CH.sub.3).sub.2CH.sub.2--C(O)R.sup.14 [0188] 5.
--NH--CH(CH(CH.sub.3).sub.2))--C(O)R.sup.14 [0189] 6.
--NH--CH(CH.sub.2(CH(CH.sub.3).sub.2)))--C(O)R.sup.14 [0190] 7.
--NH--CH(CH.sub.2CH.sub.2SCH.sub.3)--C(O)R.sup.14 [0191] 8.
--NH--CH(CH.sub.2SCH.sub.2Ph)--C(O)R.sup.14
Group 2:
Q.sup.1 and Q.sup.2
[0191] [0192] 1.--NH--CH.sub.2CH.sub.2--C(O)R.sup.14 [0193] 2.
--NH--CH(CH.sub.2CH.sub.2COR.sup.4)--C(O)R.sup.14 [0194] 3.
--NH--CH(CH.sub.2COR.sup.14)--C(O)R.sup.14 [0195] 4.
--NH--CH(CH.sub.2CONH.sub.2)--C(O)R.sup.14 [0196] 5.
--NH--CH(COR.sup.4)CH.sub.2--C(O)R.sup.14 [0197] 6.
--NH--CH(CH.sub.2OR.sup.21)--C(O)R.sup.14 [0198] 7.
--NH--CH(CH.sub.2CH.sub.2COR.sup.14)--C(O)R.sup.14 [0199] 8.
--NH--CH(CH.sub.2OH)--C(O)R.sup.14
Group 3:
Q.sup.1 and Q.sup.2
[0199] [0200] 1. --NH--CH(CH.sub.2--C.sub.6H.sub.5OH)--C(O)R.sup.14
[0201] 2. --NH--C(c-propyl)-C(O)R.sup.14 [0202] 3.
--NH--C(c-pentyl)-C(O)R.sup.14 [0203] 4.
--NH--C(c-hexyl)-C(O)R.sup.14 [0204] 5.
--NH--CH(CH.sub.2Ph)-C(O)R.sup.14 [0205] 6.
--N(CH.sub.3)--CH.sub.2--C(O)R.sup.4
[0205] ##STR00041## [0206] 8. --NR.sup.22R.sup.23 where R.sup.14 is
selected from the groups consisting of OMe, OEt, OBn, O-iPr,
O-neopentyl, O-tBu, O-nPr, OPh, --N(Me).sub.2,
oxyethylene-N-morpholino, SMe, SEt; R.sup.21 is methyl, ethyl,
benzyl, and propyl; R.sup.22 is H, Me, Et, Bn, Pr and Ph; and
R.sup.23 is Me, Et, Bn, Pr and Ph; or R.sup.22 and R.sup.23 is
morpholinyl and pyrrolidinyl.
[0207] Thus, the compound 3.3.1.2.1 in Group 1 corresponds to the
structure below for formula i:
##STR00042##
and when R.sup.14 is ethoxy the structure would be:
##STR00043##
[0208] The numbers designated in Table 1 also refer to
benzothiazole and benzoxazole compounds of formula X. These
compounds are shown in formulae iv and v.
##STR00044##
[0209] The compounds of formulae iv and formula v are listed in
Table 1 by designated numbers assigned to A, B, D, Q.sup.1, and
Q.sup.2 in the above formulae iv and v according to the following
convention: Q.sup.1.Q.sup.2.A.B.D. For each moiety, structures
assigned to a number shown in the following tables for A, B, D,
Q.sup.1 and Q.sup.2.
[0210] Variables Q.sup.1 and Q.sup.2 are divided into three groups,
each listing eight different substituents.
Group 1:
[0211] Q.sup.1 and Q.sup.2 moieties are assigned the following
numbers:
Q.sup.1 and Q.sup.2
[0212] 1. --NH--CH.sub.2--C(O)R.sup.14 [0213] 2.
--NH--CH(CH.sub.3)--C(O)R.sup.14 [0214] 3.
--NH--C(CH.sub.3).sub.2--C(O)R.sup.14 [0215] 4.
--NH--C(CH.sub.3).sub.2CH.sub.2--C(O)R.sup.14 [0216] 5.
--NH--CH(CH(CH.sub.3).sub.2))--C(O)R.sup.14 [0217] 6.
--NH--CH(CH.sub.2(CH(CH.sub.3).sub.2)))--C(O)R.sup.14 [0218] 7.
--NH--CH(CH.sub.2CH.sub.2SCH.sub.3)--C(O)R.sup.14 [0219] 8.
--NH--CH(CH.sub.2SCH.sub.2Ph)-C(O)R.sup.14
Group 2:
Q.sup.1 and Q.sup.2
[0219] [0220] 1. --NH--CH.sub.2CH.sub.2--C(O)R.sup.14 [0221] 2.
--NH--CH(CH.sub.2CH.sub.2COR.sup.14)--C(O)R.sup.14 [0222] 3.
--NH--CH(CH.sub.2COR.sup.14)--C(O)R.sup.14 [0223] 4.
--NH--CH(CH.sub.2CONH.sub.2)--C(O)R.sup.14 [0224] 5.
--NH--CH(COR.sup.14)CH.sub.2--C(O)R.sup.14 [0225] 6.
--NH--CH(CH.sub.2OR.sup.21)--C(O)R.sup.14 [0226] 7.
--NH--CH(CH.sub.2CH.sub.2COR.sup.14)--C(O)R.sup.14 [0227] 8.
--NH--CH(CH.sub.2OH)--C(O)R.sup.14
Group 3:
Q.sup.1 and Q.sup.2
[0227] [0228] 1. --NH--CH(CH.sub.2--C.sub.6H.sub.5OH)--C(O)R.sup.14
[0229] 2. --NH--C(c-propyl)-C(O)R.sup.14 [0230] 3.
--NH--C(c-pentyl)-C(O)R.sup.14 [0231] 4.
--NH--C(c-hexyl)-C(O)R.sup.14 [0232] 5.
--NH--CH(CH.sub.2Ph)-C(O)R.sup.14 [0233] 6.
--N(CH.sub.3)--CH.sub.2--C(O)R.sup.14
[0233] ##STR00045## [0234] 8. --NR.sup.22R.sup.23
[0235] Variable B is divided into three groups, each listing eight
different substituents.
Group 1:
[0236] B moieties are assigned the following numbers:
TABLE-US-00006 1 2 3 4 5 6 7 8 B = H Me Et nPr Br iPr SCN cPr
Group 2:
TABLE-US-00007 [0237] 1 2 3 4 5 6 7 8 B = CN F OMe OEt SMe SEt
2-furanyl C(O)OEt
Group 3:
TABLE-US-00008 [0238] 1 2 3 4 5 6 7 8 B = B&D are B&D are
B&D are B&D are B&D are B&D are B&D are B&D
are connected connected connected connected connected connected
connected connected to form to form to form to form to form to form
to form to form cyclohexyl phenyl furanyl furanyl cyclohexyl phenyl
furanyl furanyl ring ring ring (O ring (O ring ring ring (O ring (O
attached at attached at attached at attached at B) D) B) D)
[0239] Group 3 for Variable B can only be combined with Group 3
variable for D.
[0240] Variable D is divided into nine groups, each listing four
different substituents.
Group 1:
TABLE-US-00009 [0241] 1 2 3 4 D = H Me Et SCN
Group 2:
[0242] Variable D is replaced with the moieties assigned in the
following numbers:
TABLE-US-00010 1 2 3 4 D = SMe SEt CH.sub.2OMe OMe
Group 3:
TABLE-US-00011 [0243] 1 2 3 4 D = null null null null
Group 4:
TABLE-US-00012 [0244] 1 2 3 4 D = Pr O-Et O--Pr O-isopropyl
Group 5:
TABLE-US-00013 [0245] 1 2 3 4 D = O-Bu O-isobutyl O-cyclopropyl
O-pentyl
Group 6,
TABLE-US-00014 [0246] 1 2 3 4 D = O-neopentyl O-cyclopentyl
O-cyclohexyl O-benzyl
Group 7:
TABLE-US-00015 [0247] 1 2 3 4 D = S--Pr S-isopropyl S-Bu
S-isobutyl
Group 8:
TABLE-US-00016 [0248] 1 2 3 4 D = S-cyclopropyl S-pentyl
S-neopentyl S-cyclopentyl
Group 9:
TABLE-US-00017 [0249] 1 2 3 4 D = cyclohexyl S-benzyl
OCH.sub.2OCH.sub.3 OCH.sub.2SCH.sub.3
[0250] Compounds named in Table 1 of formulae iv and v wherein the
A moieties are assigned the following numbers:
TABLE-US-00018 1 2 3 4 A = NH.sub.2 H Me Cl
where R.sup.14 is selected from the groups consisting of OMe, OEt,
OBn, O-tBu, O-nPr, OPh, O-neopentyl, --N(Me).sub.2,
oxyethylene-N-morpholino, SMe, SEt; R.sup.21 is methyl, ethyl,
benzyl, and propyl; R.sup.22 is H, Me, Et, Bn, Pr, and Ph; and
R.sup.23 is Me, Et, Bn, Pr and Ph; or R.sup.22 and R.sup.23 is
morpholinyl and pyrrolidinyl.
[0251] Thus, the compound 2.2.1.7.4 from Group 1 for B, D, Q.sup.1
and Q.sup.2 corresponds to the structure below for formula iv
##STR00046##
and when R.sup.14 is ethoxy the structure would be
##STR00047##
[0252] Similarly, in group 3 for variable B, the compound 2.2.1.7.4
corresponds to the structure below for formula iv
##STR00048##
and when R.sup.14 is ethoxy the structure would be
##STR00049##
TABLE-US-00019 TABLE 1 1.1.1.1.1 1.1.1.1.2 1.1.1.1.3 1.1.1.1.4
1.1.1.2.1 1.1.1.2.2 1.1.1.2.3 1.1.1.2.4 1.1.1.3.1 1.1.1.3.2
1.1.1.3.3 1.1.1.3.4 1.1.1.4.1 1.1.1.4.2 1.1.1.4.3 1.1.1.4.4
1.1.1.5.1 1.1.1.5.2 1.1.1.5.3 1.1.1.5.4 1.1.1.6.1 1.1.1.6.2
1.1.1.6.3 1.1.1.6.4 1.1.1.7.1 1.1.1.7.2 1.1.1.7.3 1.1.1.7.4
1.1.1.8.1 1.1.1.8.2 1.1.1.8.3 1.1.1.8.4 1.1.2.1.1 1.1.2.1.2
1.1.2.1.3 1.1.2.1.4 1.1.2.2.1 1.1.2.2.2 1.1.2.2.3 1.1.2.2.4
1.1.2.3.1 1.1.2.3.2 1.1.2.3.3 1.1.2.3.4 1.1.2.4.1 1.1.2.4.2
1.1.2.4.3 1.1.2.4.4 1.1.2.5.1 1.1.2.5.2 1.1.2.5.3 1.1.2.5.4
1.1.2.6.1 1.1.2.6.2 1.1.2.6.3 1.1.2.6.4 1.1.2.7.1 1.1.2.7.2
1.1.2.7.3 1.1.2.7.4 1.1.2.8.1 1.1.2.8.2 1.1.2.8.3 1.1.2.8.4
1.1.3.1.1 1.1.3.1.2 1.1.3.1.3 1.1.3.1.4 1.1.3.2.1 1.1.3.2.2
1.1.3.2.3 1.1.3.2.4 1.1.3.3.1 1.1.3.3.2 1.1.3.3.3 1.1.3.3.4
1.1.3.4.1 1.1.3.4.2 1.1.3.4.3 1.1.3.4.4 1.1.3.5.1 1.1.3.5.2
1.1.3.5.3 1.1.3.5.4 1.1.3.6.1 1.1.3.6.2 1.1.3.6.3 1.1.3.6.4
1.1.3.7.1 1.1.3.7.2 1.1.3.7.3 1.1.3.7.4 1.1.3.8.1 1.1.3.8.2
1.1.3.8.3 1.1.3.8.4 1.1.4.1.1 1.1.4.1.2 1.1.4.1.3 1.1.4.1.4
1.1.4.2.1 1.1.4.2.2 1.1.4.2.3 1.1.4.2.4 1.1.4.3.1 1.1.4.3.2
1.1.4.3.3 1.1.4.3.4 1.1.4.4.1 1.1.4.4.2 1.1.4.4.3 1.1.4.4.4
1.1.4.5.1 1.1.4.5.2 1.1.4.5.3 1.1.4.5.4 1.1.4.6.1 1.1.4.6.2
1.1.4.6.3 1.1.4.6.4 1.1.4.7.1 1.1.4.7.2 1.1.4.7.3 1.1.4.7.4
1.1.4.8.1 1.1.4.8.2 1.1.4.8.3 1.1.4.8.4 1.2.1.1.1 1.2.1.1.2
1.2.1.1.3 1.2.1.1.4 1.2.1.2.1 1.2.1.2.2 1.2.1.2.3 1.2.1.2.4
1.2.1.3.1 1.2.1.3.2 1.2.1.3.3 1.2.1.3.4 1.2.1.4.1 1.2.1.4.2
1.2.1.4.3 1.2.1.4.4 1.2.1.5.1 1.2.1.5.2 1.2.1.5.3 1.2.1.5.4
1.2.1.6.1 1.2.1.6.2 1.2.1.6.3 1.2.1.6.4 1.2.1.7.1 1.2.1.7.2
1.2.1.7.3 1.2.1.7.4 1.2.1.8.1 1.2.1.8.2 1.2.1.8.3 1.2.1.8.4
1.2.2.1.1 1.2.2.1.2 1.2.2.1.3 1.2.2.1.4 1.2.2.2.1 1.2.2.2.2
1.2.2.2.3 1.2.2.2.4 1.2.2.3.1 1.2.2.3.2 1.2.2.3.3 1.2.2.3.4
1.2.2.4.1 1.2.2.4.2 1.2.2.4.3 1.2.2.4.4 1.2.2.5.1 1.2.2.5.2
1.2.2.5.3 1.2.2.5.4 1.2.2.6.1 1.2.2.6.2 1.2.2.6.3 1.2.2.6.4
1.2.2.7.1 1.2.2.7.2 1.2.2.7.3 1.2.2.7.4 1.2.2.8.1 1.2.2.8.2
1.2.2.8.3 1.2.2.8.4 1.2.3.1.1 1.2.3.1.2 1.2.3.1.3 1.2.3.1.4
1.2.3.2.1 1.2.3.2.2 1.2.3.2.3 1.2.3.2.4 1.2.3.3.1 1.2.3.3.2
1.2.3.3.3 1.2.3.3.4 1.2.3.4.1 1.2.3.4.2 1.2.3.4.3 1.2.3.4.4
1.2.3.5.1 1.2.3.5.2 1.2.3.5.3 1.2.3.5.4 1.2.3.6.1 1.2.3.6.2
1.2.3.6.3 1.2.3.6.4 1.2.3.7.1 1.2.3.7.2 1.2.3.7.3 1.2.3.7.4
1.2.3.8.1 1.2.3.8.2 1.2.3.8.3 1.2.3.8.4 1.2.4.1.1 1.2.4.1.2
1.2.4.1.3 1.2.4.1.4 1.2.4.2.1 1.2.4.2.2 1.2.4.2.3 1.2.4.2.4
1.2.4.3.1 1.2.4.3.2 1.2.4.3.3 1.2.4.3.4 1.2.4.4.1 1.2.4.4.2
1.2.4.4.3 1.2.4.4.4 1.2.4.5.1 1.2.4.5.2 1.2.4.5.3 1.2.4.5.4
1.2.4.6.1 1.2.4.6.2 1.2.4.6.3 1.2.4.6.4 1.2.4.7.1 1.2.4.7.2
1.2.4.7.3 1.2.4.7.4 1.2.4.8.1 1.2.4.8.2 1.2.4.8.3 1.2.4.8.4
1.3.1.1.1 1.3.1.1.2 1.3.1.1.3 1.3.1.1.4 1.3.1.2.1 1.3.1.2.2
1.3.1.2.3 1.3.1.2.4 1.3.1.3.1 1.3.1.3.2 1.3.1.3.3 1.3.1.3.4
1.3.1.4.1 1.3.1.4.2 1.3.1.4.3 1.3.1.4.4 1.3.1.5.1 1.3.1.5.2
1.3.1.5.3 1.3.1.5.4 1.3.1.6.1 1.3.1.6.2 1.3.1.6.3 1.3.1.6.4
1.3.1.7.1 1.3.1.7.2 1.3.1.7.3 1.3.1.7.4 1.3.1.8.1 1.3.1.8.2
1.3.1.8.3 1.3.1.8.4 1.3.2.1.1 1.3.2.1.2 1.3.2.1.3 1.3.2.1.4
1.3.2.2.1 1.3.2.2.2 1.3.2.2.3 1.3.2.2.4 1.3.2.3.1 1.3.2.3.2
1.3.2.3.3 1.3.2.3.4 1.3.2.4.1 1.3.2.4.2 1.3.2.4.3 1.3.2.4.4
1.3.2.5.1 1.3.2.5.2 1.3.2.5.3 1.3.2.5.4 1.3.2.6.1 1.3.2.6.2
1.3.2.6.3 1.3.2.6.4 1.3.2.7.1 1.3.2.7.2 1.3.2.7.3 1.3.2.7.4
1.3.2.8.1 1.3.2.8.2 1.3.2.8.3 1.3.2.8.4 1.3.3.1.1 1.3.3.1.2
1.3.3.1.3 1.3.3.1.4 1.3.3.2.1 1.3.3.2.2 1.3.3.2.3 1.3.3.2.4
1.3.3.3.1 1.3.3.3.2 1.3.3.3.3 1.3.3.3.4 1.3.3.4.1 1.3.3.4.2
1.3.3.4.3 1.3.3.4.4 1.3.3.5.1 1.3.3.5.2 1.3.3.5.3 1.3.3.5.4
1.3.3.6.1 1.3.3.6.2 1.3.3.6.3 1.3.3.6.4 1.3.3.7.1 1.3.3.7.2
1.3.3.7.3 1.3.3.7.4 1.3.3.8.1 1.3.3.8.2 1.3.3.8.3 1.3.3.8.4
1.3.4.1.1 1.3.4.1.2 1.3.4.1.3 1.3.4.1.4 1.3.4.2.1 1.3.4.2.2
1.3.4.2.3 1.3.4.2.4 1.3.4.3.1 1.3.4.3.2 1.3.4.3.3 1.3.4.3.4
1.3.4.4.1 1.3.4.4.2 1.3.4.4.3 1.3.4.4.4 1.3.4.5.1 1.3.4.5.2
1.3.4.5.3 1.3.4.5.4 1.3.4.6.1 1.3.4.6.2 1.3.4.6.3 1.3.4.6.4
1.3.4.7.1 1.3.4.7.2 1.3.4.7.3 1.3.4.7.4 1.3.4.8.1 1.3.4.8.2
1.3.4.8.3 1.3.4.8.4 1.4.1.1.1 1.4.1.1.2 1.4.1.1.3 1.4.1.1.4
1.4.1.2.1 1.4.1.2.2 1.4.1.2.3 1.4.1.2.4 1.4.1.3.1 1.4.1.3.2
1.4.1.3.3 1.4.1.3.4 1.4.1.4.1 1.4.1.4.2 1.4.1.4.3 1.4.1.4.4
1.4.1.5.1 1.4.1.5.2 1.4.1.5.3 1.4.1.5.4 1.4.1.6.1 1.4.1.6.2
1.4.1.6.3 1.4.1.6.4 1.4.1.7.1 1.4.1.7.2 1.4.1.7.3 1.4.1.7.4
1.4.1.8.1 1.4.1.8.2 1.4.1.8.3 1.4.1.8.4 1.4.2.1.1 1.4.2.1.2
1.4.2.1.3 1.4.2.1.4 1.4.2.2.1 1.4.2.2.2 1.4.2.2.3 1.4.2.2.4
1.4.2.3.1 1.4.2.3.2 1.4.2.3.3 1.4.2.3.4 1.4.2.4.1 1.4.2.4.2
1.4.2.4.3 1.4.2.4.4 1.4.2.5.1 1.4.2.5.2 1.4.2.5.3 1.4.2.5.4
1.4.2.6.1 1.4.2.6.2 1.4.2.6.3 1.4.2.6.4 1.4.2.7.1 1.4.2.7.2
1.4.2.7.3 1.4.2.7.4 1.4.2.8.1 1.4.2.8.2 1.4.2.8.3 1.4.2.8.4
1.4.3.1.1 1.4.3.1.2 1.4.3.1.3 1.4.3.1.4 1.4.3.2.1 1.4.3.2.2
1.4.3.2.3 1.4.3.2.4 1.4.3.3.1 1.4.3.3.2 1.4.3.3.3 1.4.3.3.4
1.4.3.4.1 1.4.3.4.2 1.4.3.4.3 1.4.3.4.4 1.4.3.5.1 1.4.3.5.2
1.4.3.5.3 1.4.3.5.4 1.4.3.6.1 1.4.3.6.2 1.4.3.6.3 1.4.3.6.4
1.4.3.7.1 1.4.3.7.2 1.4.3.7.3 1.4.3.7.4 1.4.3.8.1 1.4.3.8.2
1.4.3.8.3 1.4.3.8.4 1.4.4.1.1 1.4.4.1.2 1.4.4.1.3 1.4.4.1.4
1.4.4.2.1 1.4.4.2.2 1.4.4.2.3 1.4.4.2.4 1.4.4.3.1 1.4.4.3.2
1.4.4.3.3 1.4.4.3.4 1.4.4.4.1 1.4.4.4.2 1.4.4.4.3 1.4.4.4.4
1.4.4.5.1 1.4.4.5.2 1.4.4.5.3 1.4.4.5.4 1.4.4.6.1 1.4.4.6.2
1.4.4.6.3 1.4.4.6.4 1.4.4.7.1 1.4.4.7.2 1.4.4.7.3 1.4.4.7.4
1.4.4.8.1 1.4.4.8.2 1.4.4.8.3 1.4.4.8.4 1.5.1.1.1 1.5.1.1.2
1.5.1.1.3 1.5.1.1.4 1.5.1.2.1 1.5.1.2.2 1.5.1.2.3 1.5.1.2.4
1.5.1.3.1 1.5.1.3.2 1.5.1.3.3 1.5.1.3.4 1.5.1.4.1 1.5.1.4.2
1.5.1.4.3 1.5.1.4.4 1.5.1.5.1 1.5.1.5.2 1.5.1.5.3 1.5.1.5.4
1.5.1.6.1 1.5.1.6.2 1.5.1.6.3 1.5.1.6.4 1.5.1.7.1 1.5.1.7.2
1.5.1.7.3 1.5.1.7.4 1.5.1.8.1 1.5.1.8.2 1.5.1.8.3 1.5.1.8.4
1.5.2.1.1 1.5.2.1.2 1.5.2.1.3 1.5.2.1.4 1.5.2.2.1 1.5.2.2.2
1.5.2.2.3 1.5.2.2.4 1.5.2.3.1 1.5.2.3.2 1.5.2.3.3 1.5.2.3.4
1.5.2.4.1 1.5.2.4.2 1.5.2.4.3 1.5.2.4.4 1.5.2.5.1 1.5.2.5.2
1.5.2.5.3 1.5.2.5.4 1.5.2.6.1 1.5.2.6.2 1.5.2.6.3 1.5.2.6.4
1.5.2.7.1 1.5.2.7.2 1.5.2.7.3 1.5.2.7.4 1.5.2.8.1 1.5.2.8.2
1.5.2.8.3 1.5.2.8.4 1.5.3.1.1 1.5.3.1.2 1.5.3.1.3 1.5.3.1.4
1.5.3.2.1 1.5.3.2.2 1.5.3.2.3 1.5.3.2.4 1.5.3.3.1 1.5.3.3.2
1.5.3.3.3 1.5.3.3.4 1.5.3.4.1 1.5.3.4.2 1.5.3.4.3 1.5.3.4.4
1.5.3.5.1 1.5.3.5.2 1.5.3.5.3 1.5.3.5.4 1.5.3.6.1 1.5.3.6.2
1.5.3.6.3 1.5.3.6.4 1.5.3.7.1 1.5.3.7.2 1.5.3.7.3 1.5.3.7.4
1.5.3.8.1 1.5.3.8.2 1.5.3.8.3 1.5.3.8.4 1.5.4.1.1 1.5.4.1.2
1.5.4.1.3 1.5.4.1.4 1.5.4.2.1 1.5.4.2.2 1.5.4.2.3 1.5.4.2.4
1.5.4.3.1 1.5.4.3.2 1.5.4.3.3 1.5.4.3.4 1.5.4.4.1 1.5.4.4.2
1.5.4.4.3 1.5.4.4.4 1.5.4.5.1 1.5.4.5.2 1.5.4.5.3 1.5.4.5.4
1.5.4.6.1 1.5.4.6.2 1.5.4.6.3 1.5.4.6.4 1.5.4.7.1 1.5.4.7.2
1.5.4.7.3 1.5.4.7.4 1.5.4.8.1 1.5.4.8.2 1.5.4.8.3 1.5.4.8.4
1.6.1.1.1 1.6.1.1.2 1.6.1.1.3 1.6.1.1.4 1.6.1.2.1 1.6.1.2.2
1.6.1.2.3 1.6.1.2.4 1.6.1.3.1 1.6.1.3.2 1.6.1.3.3 1.6.1.3.4
1.6.1.4.1 1.6.1.4.2 1.6.1.4.3 1.6.1.4.4 1.6.1.5.1 1.6.1.5.2
1.6.1.5.3 1.6.1.5.4 1.6.1.6.1 1.6.1.6.2 1.6.1.6.3 1.6.1.6.4
1.6.1.7.1 1.6.1.7.2 1.6.1.7.3 1.6.1.7.4 1.6.1.8.1 1.6.1.8.2
1.6.1.8.3 1.6.1.8.4 1.6.2.1.1 1.6.2.1.2 1.6.2.1.3 1.6.2.1.4
1.6.2.2.1 1.6.2.2.2 1.6.2.2.3 1.6.2.2.4 1.6.2.3.1 1.6.2.3.2
1.6.2.3.3 1.6.2.3.4 1.6.2.4.1 1.6.2.4.2 1.6.2.4.3 1.6.2.4.4
1.6.2.5.1 1.6.2.5.2 1.6.2.5.3 1.6.2.5.4 1.6.2.6.1 1.6.2.6.2
1.6.2.6.3 1.6.2.6.4 1.6.2.7.1 1.6.2.7.2 1.6.2.7.3 1.6.2.7.4
1.6.2.8.1 1.6.2.8.2 1.6.2.8.3 1.6.2.8.4 1.6.3.1.1 1.6.3.1.2
1.6.3.1.3 1.6.3.1.4 1.6.3.2.1 1.6.3.2.2 1.6.3.2.3 1.6.3.2.4
1.6.3.3.1 1.6.3.3.2 1.6.3.3.3 1.6.3.3.4 1.6.3.4.1 1.6.3.4.2
1.6.3.4.3 1.6.3.4.4 1.6.3.5.1 1.6.3.5.2 1.6.3.5.3 1.6.3.5.4
1.6.3.6.1 1.6.3.6.2 1.6.3.6.3 1.6.3.6.4 1.6.3.7.1 1.6.3.7.2
1.6.3.7.3 1.6.3.7.4 1.6.3.8.1 1.6.3.8.2 1.6.3.8.3 1.6.3.8.4
1.6.4.1.1 1.6.4.1.2 1.6.4.1.3 1.6.4.1.4 1.6.4.2.1 1.6.4.2.2
1.6.4.2.3 1.6.4.2.4 1.6.4.3.1 1.6.4.3.2 1.6.4.3.3 1.6.4.3.4
1.6.4.4.1 1.6.4.4.2 1.6.4.4.3 1.6.4.4.4 1.6.4.5.1 1.6.4.5.2
1.6.4.5.3 1.6.4.5.4 1.6.4.6.1 1.6.4.6.2 1.6.4.6.3 1.6.4.6.4
1.6.4.7.1 1.6.4.7.2 1.6.4.7.3 1.6.4.7.4 1.6.4.8.1 1.6.4.8.2
1.6.4.8.3 1.6.4.8.4 1.7.1.1.1 1.7.1.1.2 1.7.1.1.3 1.7.1.1.4
1.7.1.2.1 1.7.1.2.2 1.7.1.2.3 1.7.1.2.4 1.7.1.3.1 1.7.1.3.2
1.7.1.3.3 1.7.1.3.4 1.7.1.4.1 1.7.1.4.2 1.7.1.4.3 1.7.1.4.4
1.7.1.5.1 1.7.1.5.2 1.7.1.5.3 1.7.1.5.4 1.7.1.6.1 1.7.1.6.2
1.7.1.6.3 1.7.1.6.4 1.7.1.7.1 1.7.1.7.2 1.7.1.7.3 1.7.1.7.4
1.7.1.8.1 1.7.1.8.2 1.7.1.8.3 1.7.1.8.4 1.7.2.1.1 1.7.2.1.2
1.7.2.1.3 1.7.2.1.4 1.7.2.2.1 1.7.2.2.2 1.7.2.2.3 1.7.2.2.4
1.7.2.3.1 1.7.2.3.2 1.7.2.3.3 1.7.2.3.4 1.7.2.4.1 1.7.2.4.2
1.7.2.4.3 1.7.2.4.4 1.7.2.5.1 1.7.2.5.2 1.7.2.5.3 1.7.2.5.4
1.7.2.6.1 1.7.2.6.2 1.7.2.6.3 1.7.2.6.4 1.7.2.7.1 1.7.2.7.2
1.7.2.7.3 1.7.2.7.4 1.7.2.8.1 1.7.2.8.2 1.7.2.8.3 1.7.2.8.4
1.7.3.1.1 1.7.3.1.2 1.7.3.1.3 1.7.3.1.4 1.7.3.2.1 1.7.3.2.2
1.7.3.2.3 1.7.3.2.4 1.7.3.3.1 1.7.3.3.2 1.7.3.3.3 1.7.3.3.4
1.7.3.4.1 1.7.3.4.2 1.7.3.4.3 1.7.3.4.4 1.7.3.5.1 1.7.3.5.2
1.7.3.5.3 1.7.3.5.4 1.7.3.6.1 1.7.3.6.2 1.7.3.6.3 1.7.3.6.4
1.7.3.7.1 1.7.3.7.2 1.7.3.7.3 1.7.3.7.4 1.7.3.8.1 1.7.3.8.2
1.7.3.8.3 1.7.3.8.4 1.7.4.1.1 1.7.4.1.2 1.7.4.1.3 1.7.4.1.4
1.7.4.2.1 1.7.4.2.2 1.7.4.2.3 1.7.4.2.4 1.7.4.3.1 1.7.4.3.2
1.7.4.3.3 1.7.4.3.4 1.7.4.4.1 1.7.4.4.2 1.7.4.4.3 1.7.4.4.4
1.7.4.5.1 1.7.4.5.2 1.7.4.5.3 1.7.4.5.4 1.7.4.6.1 1.7.4.6.2
1.7.4.6.3 1.7.4.6.4 1.7.4.7.1 1.7.4.7.2 1.7.4.7.3 1.7.4.7.4
1.7.4.8.1 1.7.4.8.2 1.7.4.8.3 1.7.4.8.4 1.8.1.1.1 1.8.1.1.2
1.8.1.1.3 1.8.1.1.4 1.8.1.2.1 1.8.1.2.2 1.8.1.2.3 1.8.1.2.4
1.8.1.3.1 1.8.1.3.2 1.8.1.3.3 1.8.1.3.4 1.8.1.4.1 1.8.1.4.2
1.8.1.4.3 1.8.1.4.4 1.8.1.5.1 1.8.1.5.2 1.8.1.5.3 1.8.1.5.4
1.8.1.6.1 1.8.1.6.2 1.8.1.6.3 1.8.1.6.4 1.8.1.7.1 1.8.1.7.2
1.8.1.7.3 1.8.1.7.4 1.8.1.8.1 1.8.1.8.2 1.8.1.8.3 1.8.1.8.4
1.8.2.1.1 1.8.2.1.2 1.8.2.1.3 1.8.2.1.4 1.8.2.2.1 1.8.2.2.2
1.8.2.2.3 1.8.2.2.4 1.8.2.3.1 1.8.2.3.2 1.8.2.3.3 1.8.2.3.4
1.8.2.4.1 1.8.2.4.2 1.8.2.4.3 1.8.2.4.4 1.8.2.5.1 1.8.2.5.2
1.8.2.5.3 1.8.2.5.4 1.8.2.6.1 1.8.2.6.2 1.8.2.6.3 1.8.2.6.4
1.8.2.7.1 1.8.2.7.2 1.8.2.7.3 1.8.2.7.4 1.8.2.8.1 1.8.2.8.2
1.8.2.8.3 1.8.2.8.4 1.8.3.1.1 1.8.3.1.2 1.8.3.1.3 1.8.3.1.4
1.8.3.2.1 1.8.3.2.2 1.8.3.2.3 1.8.3.2.4 1.8.3.3.1 1.8.3.3.2
1.8.3.3.3 1.8.3.3.4 1.8.3.4.1 1.8.3.4.2 1.8.3.4.3 1.8.3.4.4
1.8.3.5.1 1.8.3.5.2 1.8.3.5.3 1.8.3.5.4 1.8.3.6.1 1.8.3.6.2
1.8.3.6.3 1.8.3.6.4 1.8.3.7.1 1.8.3.7.2 1.8.3.7.3 1.8.3.7.4
1.8.3.8.1 1.8.3.8.2 1.8.3.8.3 1.8.3.8.4
1.8.4.1.1 1.8.4.1.2 1.8.4.1.3 1.8.4.1.4 1.8.4.2.1 1.8.4.2.2
1.8.4.2.3 1.8.4.2.4 1.8.4.3.1 1.8.4.3.2 1.8.4.3.3 1.8.4.3.4
1.8.4.4.1 1.8.4.4.2 1.8.4.4.3 1.8.4.4.4 1.8.4.5.1 1.8.4.5.2
1.8.4.5.3 1.8.4.5.4 1.8.4.6.1 1.8.4.6.2 1.8.4.6.3 1.8.4.6.4
1.8.4.7.1 1.8.4.7.2 1.8.4.7.3 1.8.4.7.4 1.8.4.8.1 1.8.4.8.2
1.8.4.8.3 1.8.4.8.4 2.1.1.1.1 2.1.1.1.2 2.1.1.1.3 2.1.1.1.4
2.1.1.2.1 2.1.1.2.2 2.1.1.2.3 2.1.1.2.4 2.1.1.3.1 2.1.1.3.2
2.1.1.3.3 2.1.1.3.4 2.1.1.4.1 2.1.1.4.2 2.1.1.4.3 2.1.1.4.4
2.1.1.5.1 2.1.1.5.2 2.1.1.5.3 2.1.1.5.4 2.1.1.6.1 2.1.1.6.2
2.1.1.6.3 2.1.1.6.4 2.1.1.7.1 2.1.1.7.2 2.1.1.7.3 2.1.1.7.4
2.1.1.8.1 2.1.1.8.2 2.1.1.8.3 2.1.1.8.4 2.1.2.1.1 2.1.2.1.2
2.1.2.1.3 2.1.2.1.4 2.1.2.2.1 2.1.2.2.2 2.1.2.2.3 2.1.2.2.4
2.1.2.3.1 2.1.2.3.2 2.1.2.3.3 2.1.2.3.4 2.1.2.4.1 2.1.2.4.2
2.1.2.4.3 2.1.2.4.4 2.1.2.5.1 2.1.2.5.2 2.1.2.5.3 2.1.2.5.4
2.1.2.6.1 2.1.2.6.2 2.1.2.6.3 2.1.2.6.4 2.1.2.7.1 2.1.2.7.2
2.1.2.7.3 2.1.2.7.4 2.1.2.8.1 2.1.2.8.2 2.1.2.8.3 2.1.2.8.4
2.1.3.1.1 2.1.3.1.2 2.1.3.1.3 2.1.3.1.4 2.1.3.2.1 2.1.3.2.2
2.1.3.2.3 2.1.3.2.4 2.1.3.3.1 2.1.3.3.2 2.1.3.3.3 2.1.3.3.4
2.1.3.4.1 2.1.3.4.2 2.1.3.4.3 2.1.3.4.4 2.1.3.5.1 2.1.3.5.2
2.1.3.5.3 2.1.3.5.4 2.1.3.6.1 2.1.3.6.2 2.1.3.6.3 2.1.3.6.4
2.1.3.7.1 2.1.3.7.2 2.1.3.7.3 2.1.3.7.4 2.1.3.8.1 2.1.3.8.2
2.1.3.8.3 2.1.3.8.4 2.1.4.1.1 2.1.4.1.2 2.1.4.1.3 2.1.4.1.4
2.1.4.2.1 2.1.4.2.2 2.1.4.2.3 2.1.4.2.4 2.1.4.3.1 2.1.4.3.2
2.1.4.3.3 2.1.4.3.4 2.1.4.4.1 2.1.4.4.2 2.1.4.4.3 2.1.4.4.4
2.1.4.5.1 2.1.4.5.2 2.1.4.5.3 2.1.4.5.4 2.1.4.6.1 2.1.4.6.2
2.1.4.6.3 2.1.4.6.4 2.1.4.7.1 2.1.4.7.2 2.1.4.7.3 2.1.4.7.4
2.1.4.8.1 2.1.4.8.2 2.1.4.8.3 2.1.4.8.4 2.2.1.1.1 2.2.1.1.2
2.2.1.1.3 2.2.1.1.4 2.2.1.2.1 2.2.1.2.2 2.2.1.2.3 2.2.1.2.4
2.2.1.3.1 2.2.1.3.2 2.2.1.3.3 2.2.1.3.4 2.2.1.4.1 2.2.1.4.2
2.2.1.4.3 2.2.1.4.4 2.2.1.5.1 2.2.1.5.2 2.2.1.5.3 2.2.1.5.4
2.2.1.6.1 2.2.1.6.2 2.2.1.6.3 2.2.1.6.4 2.2.1.7.1 2.2.1.7.2
2.2.1.7.3 2.2.1.7.4 2.2.1.8.1 2.2.1.8.2 2.2.1.8.3 2.2.1.8.4
2.2.2.1.1 2.2.2.1.2 2.2.2.1.3 2.2.2.1.4 2.2.2.2.1 2.2.2.2.2
2.2.2.2.3 2.2.2.2.4 2.2.2.3.1 2.2.2.3.2 2.2.2.3.3 2.2.2.3.4
2.2.2.4.1 2.2.2.4.2 2.2.2.4.3 2.2.2.4.4 2.2.2.5.1 2.2.2.5.2
2.2.2.5.3 2.2.2.5.4 2.2.2.6.1 2.2.2.6.2 2.2.2.6.3 2.2.2.6.4
2.2.2.7.1 2.2.2.7.2 2.2.2.7.3 2.2.2.7.4 2.2.2.8.1 2.2.2.8.2
2.2.2.8.3 2.2.2.8.4 2.2.3.1.1 2.2.3.1.2 2.2.3.1.3 2.2.3.1.4
2.2.3.2.1 2.2.3.2.2 2.2.3.2.3 2.2.3.2.4 2.2.3.3.1 2.2.3.3.2
2.2.3.3.3 2.2.3.3.4 2.2.3.4.1 2.2.3.4.2 2.2.3.4.3 2.2.3.4.4
2.2.3.5.1 2.2.3.5.2 2.2.3.5.3 2.2.3.5.4 2.2.3.6.1 2.2.3.6.2
2.2.3.6.3 2.2.3.6.4 2.2.3.7.1 2.2.3.7.2 2.2.3.7.3 2.2.3.7.4
2.2.3.8.1 2.2.3.8.2 2.2.3.8.3 2.2.3.8.4 2.2.4.1.1 2.2.4.1.2
2.2.4.1.3 2.2.4.1.4 2.2.4.2.1 2.2.4.2.2 2.2.4.2.3 2.2.4.2.4
2.2.4.3.1 2.2.4.3.2 2.2.4.3.3 2.2.4.3.4 2.2.4.4.1 2.2.4.4.2
2.2.4.4.3 2.2.4.4.4 2.2.4.5.1 2.2.4.5.2 2.2.4.5.3 2.2.4.5.4
2.2.4.6.1 2.2.4.6.2 2.2.4.6.3 2.2.4.6.4 2.2.4.7.1 2.2.4.7.2
2.2.4.7.3 2.2.4.7.4 2.2.4.8.1 2.2.4.8.2 2.2.4.8.3 2.2.4.8.4
2.3.1.1.1 2.3.1.1.2 2.3.1.1.3 2.3.1.1.4 2.3.1.2.1 2.3.1.2.2
2.3.1.2.3 2.3.1.2.4 2.3.1.3.1 2.3.1.3.2 2.3.1.3.3 2.3.1.3.4
2.3.1.4.1 2.3.1.4.2 2.3.1.4.3 2.3.1.4.4 2.3.1.5.1 2.3.1.5.2
2.3.1.5.3 2.3.1.5.4 2.3.1.6.1 2.3.1.6.2 2.3.1.6.3 2.3.1.6.4
2.3.1.7.1 2.3.1.7.2 2.3.1.7.3 2.3.1.7.4 2.3.1.8.1 2.3.1.8.2
2.3.1.8.3 2.3.1.8.4 2.3.2.1.1 2.3.2.1.2 2.3.2.1.3 2.3.2.1.4
2.3.2.2.1 2.3.2.2.2 2.3.2.2.3 2.3.2.2.4 2.3.2.3.1 2.3.2.3.2
2.3.2.3.3 2.3.2.3.4 2.3.2.4.1 2.3.2.4.2 2.3.2.4.3 2.3.2.4.4
2.3.2.5.1 2.3.2.5.2 2.3.2.5.3 2.3.2.5.4 2.3.2.6.1 2.3.2.6.2
2.3.2.6.3 2.3.2.6.4 2.3.2.7.1 2.3.2.7.2 2.3.2.7.3 2.3.2.7.4
2.3.2.8.1 2.3.2.8.2 2.3.2.8.3 2.3.2.8.4 2.3.3.1.1 2.3.3.1.2
2.3.3.1.3 2.3.3.1.4 2.3.3.2.1 2.3.3.2.2 2.3.3.2.3 2.3.3.2.4
2.3.3.3.1 2.3.3.3.2 2.3.3.3.3 2.3.3.3.4 2.3.3.4.1 2.3.3.4.2
2.3.3.4.3 2.3.3.4.4 2.3.3.5.1 2.3.3.5.2 2.3.3.5.3 2.3.3.5.4
2.3.3.6.1 2.3.3.6.2 2.3.3.6.3 2.3.3.6.4 2.3.3.7.1 2.3.3.7.2
2.3.3.7.3 2.3.3.7.4 2.3.3.8.1 2.3.3.8.2 2.3.3.8.3 2.3.3.8.4
2.3.4.1.1 2.3.4.1.2 2.3.4.1.3 2.3.4.1.4 2.3.4.2.1 2.3.4.2.2
2.3.4.2.3 2.3.4.2.4 2.3.4.3.1 2.3.4.3.2 2.3.4.3.3 2.3.4.3.4
2.3.4.4.1 2.3.4.4.2 2.3.4.4.3 2.3.4.4.4 2.3.4.5.1 2.3.4.5.2
2.3.4.5.3 2.3.4.5.4 2.3.4.6.1 2.3.4.6.2 2.3.4.6.3 2.3.4.6.4
2.3.4.7.1 2.3.4.7.2 2.3.4.7.3 2.3.4.7.4 2.3.4.8.1 2.3.4.8.2
2.3.4.8.3 2.3.4.8.4 2.4.1.1.1 2.4.1.1.2 2.4.1.1.3 2.4.1.1.4
2.4.1.2.1 2.4.1.2.2 2.4.1.2.3 2.4.1.2.4 2.4.1.3.1 2.4.1.3.2
2.4.1.3.3 2.4.1.3.4 2.4.1.4.1 2.4.1.4.2 2.4.1.4.3 2.4.1.4.4
2.4.1.5.1 2.4.1.5.2 2.4.1.5.3 2.4.1.5.4 2.4.1.6.1 2.4.1.6.2
2.4.1.6.3 2.4.1.6.4 2.4.1.7.1 2.4.1.7.2 2.4.1.7.3 2.4.1.7.4
2.4.1.8.1 2.4.1.8.2 2.4.1.8.3 2.4.1.8.4 2.4.2.1.1 2.4.2.1.2
2.4.2.1.3 2.4.2.1.4 2.4.2.2.1 2.4.2.2.2 2.4.2.2.3 2.4.2.2.4
2.4.2.3.1 2.4.2.3.2 2.4.2.3.3 2.4.2.3.4 2.4.2.4.1 2.4.2.4.2
2.4.2.4.3 2.4.2.4.4 2.4.2.5.1 2.4.2.5.2 2.4.2.5.3 2.4.2.5.4
2.4.2.6.1 2.4.2.6.2 2.4.2.6.3 2.4.2.6.4 2.4.2.7.1 2.4.2.7.2
2.4.2.7.3 2.4.2.7.4 2.4.2.8.1 2.4.2.8.2 2.4.2.8.3 2.4.2.8.4
2.4.3.1.1 2.4.3.1.2 2.4.3.1.3 2.4.3.1.4 2.4.3.2.1 2.4.3.2.2
2.4.3.2.3 2.4.3.2.4 2.4.3.3.1 2.4.3.3.2 2.4.3.3.3 2.4.3.3.4
2.4.3.4.1 2.4.3.4.2 2.4.3.4.3 2.4.3.4.4 2.4.3.5.1 2.4.3.5.2
2.4.3.5.3 2.4.3.5.4 2.4.3.6.1 2.4.3.6.2 2.4.3.6.3 2.4.3.6.4
2.4.3.7.1 2.4.3.7.2 2.4.3.7.3 2.4.3.7.4 2.4.3.8.1 2.4.3.8.2
2.4.3.8.3 2.4.3.8.4 2.4.4.1.1 2.4.4.1.2 2.4.4.1.3 2.4.4.1.4
2.4.4.2.1 2.4.4.2.2 2.4.4.2.3 2.4.4.2.4 2.4.4.3.1 2.4.4.3.2
2.4.4.3.3 2.4.4.3.4 2.4.4.4.1 2.4.4.4.2 2.4.4.4.3 2.4.4.4.4
2.4.4.5.1 2.4.4.5.2 2.4.4.5.3 2.4.4.5.4 2.4.4.6.1 2.4.4.6.2
2.4.4.6.3 2.4.4.6.4 2.4.4.7.1 2.4.4.7.2 2.4.4.7.3 2.4.4.7.4
2.4.4.8.1 2.4.4.8.2 2.4.4.8.3 2.4.4.8.4 2.5.1.1.1 2.5.1.1.2
2.5.1.1.3 2.5.1.1.4 2.5.1.2.1 2.5.1.2.2 2.5.1.2.3 2.5.1.2.4
2.5.1.3.1 2.5.1.3.2 2.5.1.3.3 2.5.1.3.4 2.5.1.4.1 2.5.1.4.2
2.5.1.4.3 2.5.1.4.4 2.5.1.5.1 2.5.1.5.2 2.5.1.5.3 2.5.1.5.4
2.5.1.6.1 2.5.1.6.2 2.5.1.6.3 2.5.1.6.4 2.5.1.7.1 2.5.1.7.2
2.5.1.7.3 2.5.1.7.4 2.5.1.8.1 2.5.1.8.2 2.5.1.8.3 2.5.1.8.4
2.5.2.1.1 2.5.2.1.2 2.5.2.1.3 2.5.2.1.4 2.5.2.2.1 2.5.2.2.2
2.5.2.2.3 2.5.2.2.4 2.5.2.3.1 2.5.2.3.2 2.5.2.3.3 2.5.2.3.4
2.5.2.4.1 2.5.2.4.2 2.5.2.4.3 2.5.2.4.4 2.5.2.5.1 2.5.2.5.2
2.5.2.5.3 2.5.2.5.4 2.5.2.6.1 2.5.2.6.2 2.5.2.6.3 2.5.2.6.4
2.5.2.7.1 2.5.2.7.2 2.5.2.7.3 2.5.2.7.4 2.5.2.8.1 2.5.2.8.2
2.5.2.8.3 2.5.2.8.4 2.5.3.1.1 2.5.3.1.2 2.5.3.1.3 2.5.3.1.4
2.5.3.2.1 2.5.3.2.2 2.5.3.2.3 2.5.3.2.4 2.5.3.3.1 2.5.3.3.2
2.5.3.3.3 2.5.3.3.4 2.5.3.4.1 2.5.3.4.2 2.5.3.4.3 2.5.3.4.4
2.5.3.5.1 2.5.3.5.2 2.5.3.5.3 2.5.3.5.4 2.5.3.6.1 2.5.3.6.2
2.5.3.6.3 2.5.3.6.4 2.5.3.7.1 2.5.3.7.2 2.5.3.7.3 2.5.3.7.4
2.5.3.8.1 2.5.3.8.2 2.5.3.8.3 2.5.3.8.4 2.5.4.1.1 2.5.4.1.2
2.5.4.1.3 2.5.4.1.4 2.5.4.2.1 2.5.4.2.2 2.5.4.2.3 2.5.4.2.4
2.5.4.3.1 2.5.4.3.2 2.5.4.3.3 2.5.4.3.4 2.5.4.4.1 2.5.4.4.2
2.5.4.4.3 2.5.4.4.4 2.5.4.5.1 2.5.4.5.2 2.5.4.5.3 2.5.4.5.4
2.5.4.6.1 2.5.4.6.2 2.5.4.6.3 2.5.4.6.4 2.5.4.7.1 2.5.4.7.2
2.5.4.7.3 2.5.4.7.4 2.5.4.8.1 2.5.4.8.2 2.5.4.8.3 2.5.4.8.4
2.6.1.1.1 2.6.1.1.2 2.6.1.1.3 2.6.1.1.4 2.6.1.2.1 2.6.1.2.2
2.6.1.2.3 2.6.1.2.4 2.6.1.3.1 2.6.1.3.2 2.6.1.3.3 2.6.1.3.4
2.6.1.4.1 2.6.1.4.2 2.6.1.4.3 2.6.1.4.4 2.6.1.5.1 2.6.1.5.2
2.6.1.5.3 2.6.1.5.4 2.6.1.6.1 2.6.1.6.2 2.6.1.6.3 2.6.1.6.4
2.6.1.7.1 2.6.1.7.2 2.6.1.7.3 2.6.1.7.4 2.6.1.8.1 2.6.1.8.2
2.6.1.8.3 2.6.1.8.4 2.6.2.1.1 2.6.2.1.2 2.6.2.1.3 2.6.2.1.4
2.6.2.2.1 2.6.2.2.2 2.6.2.2.3 2.6.2.2.4 2.6.2.3.1 2.6.2.3.2
2.6.2.3.3 2.6.2.3.4 2.6.2.4.1 2.6.2.4.2 2.6.2.4.3 2.6.2.4.4
2.6.2.5.1 2.6.2.5.2 2.6.2.5.3 2.6.2.5.4 2.6.2.6.1 2.6.2.6.2
2.6.2.6.3 2.6.2.6.4 2.6.2.7.1 2.6.2.7.2 2.6.2.7.3 2.6.2.7.4
2.6.2.8.1 2.6.2.8.2 2.6.2.8.3 2.6.2.8.4 2.6.3.1.1 2.6.3.1.2
2.6.3.1.3 2.6.3.1.4 2.6.3.2.1 2.6.3.2.2 2.6.3.2.3 2.6.3.2.4
2.6.3.3.1 2.6.3.3.2 2.6.3.3.3 2.6.3.3.4 2.6.3.4.1 2.6.3.4.2
2.6.3.4.3 2.6.3.4.4 2.6.3.5.1 2.6.3.5.2 2.6.3.5.3 2.6.3.5.4
2.6.3.6.1 2.6.3.6.2 2.6.3.6.3 2.6.3.6.4 2.6.3.7.1 2.6.3.7.2
2.6.3.7.3 2.6.3.7.4 2.6.3.8.1 2.6.3.8.2 2.6.3.8.3 2.6.3.8.4
2.6.4.1.1 2.6.4.1.2 2.6.4.1.3 2.6.4.1.4 2.6.4.2.1 2.6.4.2.2
2.6.4.2.3 2.6.4.2.4 2.6.4.3.1 2.6.4.3.2 2.6.4.3.3 2.6.4.3.4
2.6.4.4.1 2.6.4.4.2 2.6.4.4.3 2.6.4.4.4 2.6.4.5.1 2.6.4.5.2
2.6.4.5.3 2.6.4.5.4 2.6.4.6.1 2.6.4.6.2 2.6.4.6.3 2.6.4.6.4
2.6.4.7.1 2.6.4.7.2 2.6.4.7.3 2.6.4.7.4 2.6.4.8.1 2.6.4.8.2
2.6.4.8.3 2.6.4.8.4 2.7.1.1.1 2.7.1.1.2 2.7.1.1.3 2.7.1.1.4
2.7.1.2.1 2.7.1.2.2 2.7.1.2.3 2.7.1.2.4 2.7.1.3.1 2.7.1.3.2
2.7.1.3.3 2.7.1.3.4 2.7.1.4.1 2.7.1.4.2 2.7.1.4.3 2.7.1.4.4
2.7.1.5.1 2.7.1.5.2 2.7.1.5.3 2.7.1.5.4 2.7.1.6.1 2.7.1.6.2
2.7.1.6.3 2.7.1.6.4 2.7.1.7.1 2.7.1.7.2 2.7.1.7.3 2.7.1.7.4
2.7.1.8.1 2.7.1.8.2 2.7.1.8.3 2.7.1.8.4 2.7.2.1.1 2.7.2.1.2
2.7.2.1.3 2.7.2.1.4 2.7.2.2.1 2.7.2.2.2 2.7.2.2.3 2.7.2.2.4
2.7.2.3.1 2.7.2.3.2 2.7.2.3.3 2.7.2.3.4 2.7.2.4.1 2.7.2.4.2
2.7.2.4.3 2.7.2.4.4 2.7.2.5.1 2.7.2.5.2 2.7.2.5.3 2.7.2.5.4
2.7.2.6.1 2.7.2.6.2 2.7.2.6.3 2.7.2.6.4 2.7.2.7.1 2.7.2.7.2
2.7.2.7.3 2.7.2.7.4 2.7.2.8.1 2.7.2.8.2 2.7.2.8.3 2.7.2.8.4
2.7.3.1.1 2.7.3.1.2 2.7.3.1.3 2.7.3.1.4 2.7.3.2.1 2.7.3.2.2
2.7.3.2.3 2.7.3.2.4 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3 2.7.3.3.4
2.7.3.4.1 2.7.3.4.2 2.7.3.4.3 2.7.3.4.4 2.7.3.5.1 2.7.3.5.2
2.7.3.5.3 2.7.3.5.4 2.7.3.6.1 2.7.3.6.2 2.7.3.6.3 2.7.3.6.4
2.7.3.7.1 2.7.3.7.2 2.7.3.7.3 2.7.3.7.4 2.7.3.8.1 2.7.3.8.2
2.7.3.8.3 2.7.3.8.4 2.7.4.1.1 2.7.4.1.2 2.7.4.1.3 2.7.4.1.4
2.7.4.2.1 2.7.4.2.2 2.7.4.2.3 2.7.4.2.4 2.7.4.3.1 2.7.4.3.2
2.7.4.3.3 2.7.4.3.4 2.7.4.4.1 2.7.4.4.2 2.7.4.4.3 2.7.4.4.4
2.7.4.5.1 2.7.4.5.2 2.7.4.5.3 2.7.4.5.4 2.7.4.6.1 2.7.4.6.2
2.7.4.6.3 2.7.4.6.4 2.7.4.7.1 2.7.4.7.2 2.7.4.7.3 2.7.4.7.4
2.7.4.8.1 2.7.4.8.2 2.7.4.8.3 2.7.4.8.4 2.8.1.1.1 2.8.1.1.2
2.8.1.1.3 2.8.1.1.4 2.8.1.2.1 2.8.1.2.2 2.8.1.2.3 2.8.1.2.4
2.8.1.3.1 2.8.1.3.2 2.8.1.3.3 2.8.1.3.4 2.8.1.4.1 2.8.1.4.2
2.8.1.4.3 2.8.1.4.4 2.8.1.5.1 2.8.1.5.2 2.8.1.5.3 2.8.1.5.4
2.8.1.6.1 2.8.1.6.2 2.8.1.6.3 2.8.1.6.4 2.8.1.7.1 2.8.1.7.2
2.8.1.7.3 2.8.1.7.4 2.8.1.8.1 2.8.1.8.2 2.8.1.8.3 2.8.1.8.4
2.8.2.1.1 2.8.2.1.2 2.8.2.1.3 2.8.2.1.4 2.8.2.2.1 2.8.2.2.2
2.8.2.2.3 2.8.2.2.4 2.8.2.3.1 2.8.2.3.2 2.8.2.3.3 2.8.2.3.4
2.8.2.4.1 2.8.2.4.2 2.8.2.4.3 2.8.2.4.4 2.8.2.5.1 2.8.2.5.2
2.8.2.5.3 2.8.2.5.4 2.8.2.6.1 2.8.2.6.2 2.8.2.6.3 2.8.2.6.4
2.8.2.7.1 2.8.2.7.2 2.8.2.7.3 2.8.2.7.4 2.8.2.8.1 2.8.2.8.2
2.8.2.8.3 2.8.2.8.4 2.8.3.1.1 2.8.3.1.2 2.8.3.1.3 2.8.3.1.4
2.8.3.2.1 2.8.3.2.2 2.8.3.2.3 2.8.3.2.4 2.8.3.3.1 2.8.3.3.2
2.8.3.3.3 2.8.3.3.4 2.8.3.4.1 2.8.3.4.2 2.8.3.4.3
2.8.3.4.4 2.8.3.5.1 2.8.3.5.2 2.8.3.5.3 2.8.3.5.4 2.8.3.6.1
2.8.3.6.2 2.8.3.6.3 2.8.3.6.4 2.8.3.7.1 2.8.3.7.2 2.8.3.7.3
2.8.3.7.4 2.8.3.8.1 2.8.3.8.2 2.8.3.8.3 2.8.3.8.4 2.8.4.1.1
2.8.4.1.2 2.8.4.1.3 2.8.4.1.4 2.8.4.2.1 2.8.4.2.2 2.8.4.2.3
2.8.4.2.4 2.8.4.3.1 2.8.4.3.2 2.8.4.3.3 2.8.4.3.4 2.8.4.4.1
2.8.4.4.2 2.8.4.4.3 2.8.4.4.4 2.8.4.5.1 2.8.4.5.2 2.8.4.5.3
2.8.4.5.4 2.8.4.6.1 2.8.4.6.2 2.8.4.6.3 2.8.4.6.4 2.8.4.7.1
2.8.4.7.2 2.8.4.7.3 2.8.4.7.4 2.8.4.8.1 2.8.4.8.2 2.8.4.8.3
2.8.4.8.4 3.1.1.1.1 3.1.1.1.2 3.1.1.1.3 3.1.1.1.4 3.1.1.2.1
3.1.1.2.2 3.1.1.2.3 3.1.1.2.4 3.1.1.3.1 3.1.1.3.2 3.1.1.3.3
3.1.1.3.4 3.1.1.4.1 3.1.1.4.2 3.1.1.4.3 3.1.1.4.4 3.1.1.5.1
3.1.1.5.2 3.1.1.5.3 3.1.1.5.4 3.1.1.6.1 3.1.1.6.2 3.1.1.6.3
3.1.1.6.4 3.1.1.7.1 3.1.1.7.2 3.1.1.7.3 3.1.1.7.4 3.1.1.8.1
3.1.1.8.2 3.1.1.8.3 3.1.1.8.4 3.1.2.1.1 3.1.2.1.2 3.1.2.1.3
3.1.2.1.4 3.1.2.2.1 3.1.2.2.2 3.1.2.2.3 3.1.2.2.4 3.1.2.3.1
3.1.2.3.2 3.1.2.3.3 3.1.2.3.4 3.1.2.4.1 3.1.2.4.2 3.1.2.4.3
3.1.2.4.4 3.1.2.5.1 3.1.2.5.2 3.1.2.5.3 3.1.2.5.4 3.1.2.6.1
3.1.2.6.2 3.1.2.6.3 3.1.2.6.4 3.1.2.7.1 3.1.2.7.2 3.1.2.7.3
3.1.2.7.4 3.1.2.8.1 3.1.2.8.2 3.1.2.8.3 3.1.2.8.4 3.1.3.1.1
3.1.3.1.2 3.1.3.1.3 3.1.3.1.4 3.1.3.2.1 3.1.3.2.2 3.1.3.2.3
3.1.3.2.4 3.1.3.3.1 3.1.3.3.2 3.1.3.3.3 3.1.3.3.4 3.1.3.4.1
3.1.3.4.2 3.1.3.4.3 3.1.3.4.4 3.1.3.5.1 3.1.3.5.2 3.1.3.5.3
3.1.3.5.4 3.1.3.6.1 3.1.3.6.2 3.1.3.6.3 3.1.3.6.4 3.1.3.7.1
3.1.3.7.2 3.1.3.7.3 3.1.3.7.4 3.1.3.8.1 3.1.3.8.2 3.1.3.8.3
3.1.3.8.4 3.1.4.1.1 3.1.4.1.2 3.1.4.1.3 3.1.4.1.4 3.1.4.2.1
3.1.4.2.2 3.1.4.2.3 3.1.4.2.4 3.1.4.3.1 3.1.4.3.2 3.1.4.3.3
3.1.4.3.4 3.1.4.4.1 3.1.4.4.2 3.1.4.4.3 3.1.4.4.4 3.1.4.5.1
3.1.4.5.2 3.1.4.5.3 3.1.4.5.4 3.1.4.6.1 3.1.4.6.2 3.1.4.6.3
3.1.4.6.4 3.1.4.7.1 3.1.4.7.2 3.1.4.7.3 3.1.4.7.4 3.1.4.8.1
3.1.4.8.2 3.1.4.8.3 3.1.4.8.4 3.2.1.1.1 3.2.1.1.2 3.2.1.1.3
3.2.1.1.4 3.2.1.2.1 3.2.1.2.2 3.2.1.2.3 3.2.1.2.4 3.2.1.3.1
3.2.1.3.2 3.2.1.3.3 3.2.1.3.4 3.2.1.4.1 3.2.1.4.2 3.2.1.4.3
3.2.1.4.4 3.2.1.5.1 3.2.1.5.2 3.2.1.5.3 3.2.1.5.4 3.2.1.6.1
3.2.1.6.2 3.2.1.6.3 3.2.1.6.4 3.2.1.7.1 3.2.1.7.2 3.2.1.7.3
3.2.1.7.4 3.2.1.8.1 3.2.1.8.2 3.2.1.8.3 3.2.1.8.4 3.2.2.1.1
3.2.2.1.2 3.2.2.1.3 3.2.2.1.4 3.2.2.2.1 3.2.2.2.2 3.2.2.2.3
3.2.2.2.4 3.2.2.3.1 3.2.2.3.2 3.2.2.3.3 3.2.2.3.4 3.2.2.4.1
3.2.2.4.2 3.2.2.4.3 3.2.2.4.4 3.2.2.5.1 3.2.2.5.2 3.2.2.5.3
3.2.2.5.4 3.2.2.6.1 3.2.2.6.2 3.2.2.6.3 3.2.2.6.4 3.2.2.7.1
3.2.2.7.2 3.2.2.7.3 3.2.2.7.4 3.2.2.8.1 3.2.2.8.2 3.2.2.8.3
3.2.2.8.4 3.2.3.1.1 3.2.3.1.2 3.2.3.1.3 3.2.3.1.4 3.2.3.2.1
3.2.3.2.2 3.2.3.2.3 3.2.3.2.4 3.2.3.3.1 3.2.3.3.2 3.2.3.3.3
3.2.3.3.4 3.2.3.4.1 3.2.3.4.2 3.2.3.4.3 3.2.3.4.4 3.2.3.5.1
3.2.3.5.2 3.2.3.5.3 3.2.3.5.4 3.2.3.6.1 3.2.3.6.2 3.2.3.6.3
3.2.3.6.4 3.2.3.7.1 3.2.3.7.2 3.2.3.7.3 3.2.3.7.4 3.2.3.8.1
3.2.3.8.2 3.2.3.8.3 3.2.3.8.4 3.2.4.1.1 3.2.4.1.2 3.2.4.1.3
3.2.4.1.4 3.2.4.2.1 3.2.4.2.2 3.2.4.2.3 3.2.4.2.4 3.2.4.3.1
3.2.4.3.2 3.2.4.3.3 3.2.4.3.4 3.2.4.4.1 3.2.4.4.2 3.2.4.4.3
3.2.4.4.4 3.2.4.5.1 3.2.4.5.2 3.2.4.5.3 3.2.4.5.4 3.2.4.6.1
3.2.4.6.2 3.2.4.6.3 3.2.4.6.4 3.2.4.7.1 3.2.4.7.2 3.2.4.7.3
3.2.4.7.4 3.2.4.8.1 3.2.4.8.2 3.2.4.8.3 3.2.4.8.4 3.3.1.1.1
3.3.1.1.2 3.3.1.1.3 3.3.1.1.4 3.3.1.2.1 3.3.1.2.2 3.3.1.2.3
3.3.1.2.4 3.3.1.3.1 3.3.1.3.2 3.3.1.3.3 3.3.1.3.4 3.3.1.4.1
3.3.1.4.2 3.3.1.4.3 3.3.1.4.4 3.3.1.5.1 3.3.1.5.2 3.3.1.5.3
3.3.1.5.4 3.3.1.6.1 3.3.1.6.2 3.3.1.6.3 3.3.1.6.4 3.3.1.7.1
3.3.1.7.2 3.3.1.7.3 3.3.1.7.4 3.3.1.8.1 3.3.1.8.2 3.3.1.8.3
3.3.1.8.4 3.3.2.1.1 3.3.2.1.2 3.3.2.1.3 3.3.2.1.4 3.3.2.2.1
3.3.2.2.2 3.3.2.2.3 3.3.2.2.4 3.3.2.3.1 3.3.2.3.2 3.3.2.3.3
3.3.2.3.4 3.3.2.4.1 3.3.2.4.2 3.3.2.4.3 3.3.2.4.4 3.3.2.5.1
3.3.2.5.2 3.3.2.5.3 3.3.2.5.4 3.3.2.6.1 3.3.2.6.2 3.3.2.6.3
3.3.2.6.4 3.3.2.7.1 3.3.2.7.2 3.3.2.7.3 3.3.2.7.4 3.3.2.8.1
3.3.2.8.2 3.3.2.8.3 3.3.2.8.4 3.3.3.1.1 3.3.3.1.2 3.3.3.1.3
3.3.3.1.4 3.3.3.2.1 3.3.3.2.2 3.3.3.2.3 3.3.3.2.4 3.3.3.3.1
3.3.3.3.2 3.3.3.3.3 3.3.3.3.4 3.3.3.4.1 3.3.3.4.2 3.3.3.4.3
3.3.3.4.4 3.3.3.5.1 3.3.3.5.2 3.3.3.5.3 3.3.3.5.4 3.3.3.6.1
3.3.3.6.2 3.3.3.6.3 3.3.3.6.4 3.3.3.7.1 3.3.3.7.2 3.3.3.7.3
3.3.3.7.4 3.3.3.8.1 3.3.3.8.2 3.3.3.8.3 3.3.3.8.4 3.3.4.1.1
3.3.4.1.2 3.3.4.1.3 3.3.4.1.4 3.3.4.2.1 3.3.4.2.2 3.3.4.2.3
3.3.4.2.4 3.3.4.3.1 3.3.4.3.2 3.3.4.3.3 3.3.4.3.4 3.3.4.4.1
3.3.4.4.2 3.3.4.4.3 3.3.4.4.4 3.3.4.5.1 3.3.4.5.2 3.3.4.5.3
3.3.4.5.4 3.3.4.6.1 3.3.4.6.2 3.3.4.6.3 3.3.4.6.4 3.3.4.7.1
3.3.4.7.2 3.3.4.7.3 3.3.4.7.4 3.3.4.8.1 3.3.4.8.2 3.3.4.8.3
3.3.4.8.4 3.4.1.1.1 3.4.1.1.2 3.4.1.1.3 3.4.1.1.4 3.4.1.2.1
3.4.1.2.2 3.4.1.2.3 3.4.1.2.4 3.4.1.3.1 3.4.1.3.2 3.4.1.3.3
3.4.1.3.4 3.4.1.4.1 3.4.1.4.2 3.4.1.4.3 3.4.1.4.4 3.4.1.5.1
3.4.1.5.2 3.4.1.5.3 3.4.1.5.4 3.4.1.6.1 3.4.1.6.2 3.4.1.6.3
3.4.1.6.4 3.4.1.7.1 3.4.1.7.2 3.4.1.7.3 3.4.1.7.4 3.4.1.8.1
3.4.1.8.2 3.4.1.8.3 3.4.1.8.4 3.4.2.1.1 3.4.2.1.2 3.4.2.1.3
3.4.2.1.4 3.4.2.2.1 3.4.2.2.2 3.4.2.2.3 3.4.2.2.4 3.4.2.3.1
3.4.2.3.2 3.4.2.3.3 3.4.2.3.4 3.4.2.4.1 3.4.2.4.2 3.4.2.4.3
3.4.2.4.4 3.4.2.5.1 3.4.2.5.2 3.4.2.5.3 3.4.2.5.4 3.4.2.6.1
3.4.2.6.2 3.4.2.6.3 3.4.2.6.4 3.4.2.7.1 3.4.2.7.2 3.4.2.7.3
3.4.2.7.4 3.4.2.8.1 3.4.2.8.2 3.4.2.8.3 3.4.2.8.4 3.4.3.1.1
3.4.3.1.2 3.4.3.1.3 3.4.3.1.4 3.4.3.2.1 3.4.3.2.2 3.4.3.2.3
3.4.3.2.4 3.4.3.3.1 3.4.3.3.2 3.4.3.3.3 3.4.3.3.4 3.4.3.4.1
3.4.3.4.2 3.4.3.4.3 3.4.3.4.4 3.4.3.5.1 3.4.3.5.2 3.4.3.5.3
3.4.3.5.4 3.4.3.6.1 3.4.3.6.2 3.4.3.6.3 3.4.3.6.4 3.4.3.7.1
3.4.3.7.2 3.4.3.7.3 3.4.3.7.4 3.4.3.8.1 3.4.3.8.2 3.4.3.8.3
3.4.3.8.4 3.4.4.1.1 3.4.4.1.2 3.4.4.1.3 3.4.4.1.4 3.4.4.2.1
3.4.4.2.2 3.4.4.2.3 3.4.4.2.4 3.4.4.3.1 3.4.4.3.2 3.4.4.3.3
3.4.4.3.4 3.4.4.4.1 3.4.4.4.2 3.4.4.4.3 3.4.4.4.4 3.4.4.5.1
3.4.4.5.2 3.4.4.5.3 3.4.4.5.4 3.4.4.6.1 3.4.4.6.2 3.4.4.6.3
3.4.4.6.4 3.4.4.7.1 3.4.4.7.2 3.4.4.7.3 3.4.4.7.4 3.4.4.8.1
3.4.4.8.2 3.4.4.8.3 3.4.4.8.4 3.5.1.1.1 3.5.1.1.2 3.5.1.1.3
3.5.1.1.4 3.5.1.2.1 3.5.1.2.2 3.5.1.2.3 3.5.1.2.4 3.5.1.3.1
3.5.1.3.2 3.5.1.3.3 3.5.1.3.4 3.5.1.4.1 3.5.1.4.2 3.5.1.4.3
3.5.1.4.4 3.5.1.5.1 3.5.1.5.2 3.5.1.5.3 3.5.1.5.4 3.5.1.6.1
3.5.1.6.2 3.5.1.6.3 3.5.1.6.4 3.5.1.7.1 3.5.1.7.2 3.5.1.7.3
3.5.1.7.4 3.5.1.8.1 3.5.1.8.2 3.5.1.8.3 3.5.1.8.4 3.5.2.1.1
3.5.2.1.2 3.5.2.1.3 3.5.2.1.4 3.5.2.2.1 3.5.2.2.2 3.5.2.2.3
3.5.2.2.4 3.5.2.3.1 3.5.2.3.2 3.5.2.3.3 3.5.2.3.4 3.5.2.4.1
3.5.2.4.2 3.5.2.4.3 3.5.2.4.4 3.5.2.5.1 3.5.2.5.2 3.5.2.5.3
3.5.2.5.4 3.5.2.6.1 3.5.2.6.2 3.5.2.6.3 3.5.2.6.4 3.5.2.7.1
3.5.2.7.2 3.5.2.7.3 3.5.2.7.4 3.5.2.8.1 3.5.2.8.2 3.5.2.8.3
3.5.2.8.4 3.5.3.1.1 3.5.3.1.2 3.5.3.1.3 3.5.3.1.4 3.5.3.2.1
3.5.3.2.2 3.5.3.2.3 3.5.3.2.4 3.5.3.3.1 3.5.3.3.2 3.5.3.3.3
3.5.3.3.4 3.5.3.4.1 3.5.3.4.2 3.5.3.4.3 3.5.3.4.4 3.5.3.5.1
3.5.3.5.2 3.5.3.5.3 3.5.3.5.4 3.5.3.6.1 3.5.3.6.2 3.5.3.6.3
3.5.3.6.4 3.5.3.7.1 3.5.3.7.2 3.5.3.7.3 3.5.3.7.4 3.5.3.8.1
3.5.3.8.2 3.5.3.8.3 3.5.3.8.4 3.5.4.1.1 3.5.4.1.2 3.5.4.1.3
3.5.4.1.4 3.5.4.2.1 3.5.4.2.2 3.5.4.2.3 3.5.4.2.4 3.5.4.3.1
3.5.4.3.2 3.5.4.3.3 3.5.4.3.4 3.5.4.4.1 3.5.4.4.2 3.5.4.4.3
3.5.4.4.4 3.5.4.5.1 3.5.4.5.2 3.5.4.5.3 3.5.4.5.4 3.5.4.6.1
3.5.4.6.2 3.5.4.6.3 3.5.4.6.4 3.5.4.7.1 3.5.4.7.2 3.5.4.7.3
3.5.4.7.4 3.5.4.8.1 3.5.4.8.2 3.5.4.8.3 3.5.4.8.4 3.6.1.1.1
3.6.1.1.2 3.6.1.1.3 3.6.1.1.4 3.6.1.2.1 3.6.1.2.2 3.6.1.2.3
3.6.1.2.4 3.6.1.3.1 3.6.1.3.2 3.6.1.3.3 3.6.1.3.4 3.6.1.4.1
3.6.1.4.2 3.6.1.4.3 3.6.1.4.4 3.6.1.5.1 3.6.1.5.2 3.6.1.5.3
3.6.1.5.4 3.6.1.6.1 3.6.1.6.2 3.6.1.6.3 3.6.1.6.4 3.6.1.7.1
3.6.1.7.2 3.6.1.7.3 3.6.1.7.4 3.6.1.8.1 3.6.1.8.2 3.6.1.8.3
3.6.1.8.4 3.6.2.1.1 3.6.2.1.2 3.6.2.1.3 3.6.2.1.4 3.6.2.2.1
3.6.2.2.2 3.6.2.2.3 3.6.2.2.4 3.6.2.3.1 3.6.2.3.2 3.6.2.3.3
3.6.2.3.4 3.6.2.4.1 3.6.2.4.2 3.6.2.4.3 3.6.2.4.4 3.6.2.5.1
3.6.2.5.2 3.6.2.5.3 3.6.2.5.4 3.6.2.6.1 3.6.2.6.2 3.6.2.6.3
3.6.2.6.4 3.6.2.7.1 3.6.2.7.2 3.6.2.7.3 3.6.2.7.4 3.6.2.8.1
3.6.2.8.2 3.6.2.8.3 3.6.2.8.4 3.6.3.1.1 3.6.3.1.2 3.6.3.1.3
3.6.3.1.4 3.6.3.2.1 3.6.3.2.2 3.6.3.2.3 3.6.3.2.4 3.6.3.3.1
3.6.3.3.2 3.6.3.3.3 3.6.3.3.4 3.6.3.4.1 3.6.3.4.2 3.6.3.4.3
3.6.3.4.4 3.6.3.5.1 3.6.3.5.2 3.6.3.5.3 3.6.3.5.4 3.6.3.6.1
3.6.3.6.2 3.6.3.6.3 3.6.3.6.4 3.6.3.7.1 3.6.3.7.2 3.6.3.7.3
3.6.3.7.4 3.6.3.8.1 3.6.3.8.2 3.6.3.8.3 3.6.3.8.4 3.6.4.1.1
3.6.4.1.2 3.6.4.1.3 3.6.4.1.4 3.6.4.2.1 3.6.4.2.2 3.6.4.2.3
3.6.4.2.4 3.6.4.3.1 3.6.4.3.2 3.6.4.3.3 3.6.4.3.4 3.6.4.4.1
3.6.4.4.2 3.6.4.4.3 3.6.4.4.4 3.6.4.5.1 3.6.4.5.2 3.6.4.5.3
3.6.4.5.4 3.6.4.6.1 3.6.4.6.2 3.6.4.6.3 3.6.4.6.4 3.6.4.7.1
3.6.4.7.2 3.6.4.7.3 3.6.4.7.4 3.6.4.8.1 3.6.4.8.2 3.6.4.8.3
3.6.4.8.4 3.7.1.1.1 3.7.1.1.2 3.7.1.1.3 3.7.1.1.4 3.7.1.2.1
3.7.1.2.2 3.7.1.2.3 3.7.1.2.4 3.7.1.3.1 3.7.1.3.2 3.7.1.3.3
3.7.1.3.4 3.7.1.4.1 3.7.1.4.2 3.7.1.4.3 3.7.1.4.4 3.7.1.5.1
3.7.1.5.2 3.7.1.5.3 3.7.1.5.4 3.7.1.6.1 3.7.1.6.2 3.7.1.6.3
3.7.1.6.4 3.7.1.7.1 3.7.1.7.2 3.7.1.7.3 3.7.1.7.4 3.7.1.8.1
3.7.1.8.2 3.7.1.8.3 3.7.1.8.4 3.7.2.1.1 3.7.2.1.2 3.7.2.1.3
3.7.2.1.4 3.7.2.2.1 3.7.2.2.2 3.7.2.2.3 3.7.2.2.4 3.7.2.3.1
3.7.2.3.2 3.7.2.3.3 3.7.2.3.4 3.7.2.4.1 3.7.2.4.2 3.7.2.4.3
3.7.2.4.4 3.7.2.5.1 3.7.2.5.2 3.7.2.5.3 3.7.2.5.4 3.7.2.6.1
3.7.2.6.2 3.7.2.6.3 3.7.2.6.4 3.7.2.7.1 3.7.2.7.2 3.7.2.7.3
3.7.2.7.4 3.7.2.8.1 3.7.2.8.2 3.7.2.8.3 3.7.2.8.4 3.7.3.1.1
3.7.3.1.2 3.7.3.1.3 3.7.3.1.4 3.7.3.2.1 3.7.3.2.2 3.7.3.2.3
3.7.3.2.4 3.7.3.3.1 3.7.3.3.2 3.7.3.3.3 3.7.3.3.4 3.7.3.4.1
3.7.3.4.2 3.7.3.4.3 3.7.3.4.4 3.7.3.5.1 3.7.3.5.2 3.7.3.5.3
3.7.3.5.4 3.7.3.6.1 3.7.3.6.2 3.7.3.6.3 3.7.3.6.4 3.7.3.7.1
3.7.3.7.2 3.7.3.7.3 3.7.3.7.4 3.7.3.8.1 3.7.3.8.2 3.7.3.8.3
3.7.3.8.4 3.7.4.1.1 3.7.4.1.2 3.7.4.1.3 3.7.4.1.4 3.7.4.2.1
3.7.4.2.2 3.7.4.2.3 3.7.4.2.4 3.7.4.3.1 3.7.4.3.2 3.7.4.3.3
3.7.4.3.4 3.7.4.4.1 3.7.4.4.2 3.7.4.4.3 3.7.4.4.4 3.7.4.5.1
3.7.4.5.2 3.7.4.5.3 3.7.4.5.4 3.7.4.6.1 3.7.4.6.2 3.7.4.6.3
3.7.4.6.4 3.7.4.7.1 3.7.4.7.2 3.7.4.7.3 3.7.4.7.4 3.7.4.8.1
3.7.4.8.2 3.7.4.8.3 3.7.4.8.4 3.8.1.1.1 3.8.1.1.2 3.8.1.1.3
3.8.1.1.4 3.8.1.2.1 3.8.1.2.2 3.8.1.2.3 3.8.1.2.4 3.8.1.3.1
3.8.1.3.2 3.8.1.3.3 3.8.1.3.4 3.8.1.4.1 3.8.1.4.2 3.8.1.4.3
3.8.1.4.4 3.8.1.5.1 3.8.1.5.2 3.8.1.5.3 3.8.1.5.4 3.8.1.6.1
3.8.1.6.2 3.8.1.6.3 3.8.1.6.4 3.8.1.7.1 3.8.1.7.2 3.8.1.7.3
3.8.1.7.4 3.8.1.8.1 3.8.1.8.2 3.8.1.8.3 3.8.1.8.4 3.8.2.1.1
3.8.2.1.2 3.8.2.1.3 3.8.2.1.4 3.8.2.2.1 3.8.2.2.2 3.8.2.2.3
3.8.2.2.4 3.8.2.3.1 3.8.2.3.2 3.8.2.3.3 3.8.2.3.4 3.8.2.4.1
3.8.2.4.2 3.8.2.4.3 3.8.2.4.4 3.8.2.5.1 3.8.2.5.2 3.8.2.5.3
3.8.2.5.4 3.8.2.6.1 3.8.2.6.2 3.8.2.6.3 3.8.2.6.4
3.8.2.7.1 3.8.2.7.2 3.8.2.7.3 3.8.2.7.4 3.8.2.8.1 3.8.2.8.2
3.8.2.8.3 3.8.2.8.4 3.8.3.1.1 3.8.3.1.2 3.8.3.1.3 3.8.3.1.4
3.8.3.2.1 3.8.3.2.2 3.8.3.2.3 3.8.3.2.4 3.8.3.3.1 3.8.3.3.2
3.8.3.3.3 3.8.3.3.4 3.8.3.4.1 3.8.3.4.2 3.8.3.4.3 3.8.3.4.4
3.8.3.5.1 3.8.3.5.2 3.8.3.5.3 3.8.3.5.4 3.8.3.6.1 3.8.3.6.2
3.8.3.6.3 3.8.3.6.4 3.8.3.7.1 3.8.3.7.2 3.8.3.7.3 3.8.3.7.4
3.8.3.8.1 3.8.3.8.2 3.8.3.8.3 3.8.3.8.4 3.8.4.1.1 3.8.4.1.2
3.8.4.1.3 3.8.4.1.4 3.8.4.2.1 3.8.4.2.2 3.8.4.2.3 3.8.4.2.4
3.8.4.3.1 3.8.4.3.2 3.8.4.3.3 3.8.4.3.4 3.8.4.4.1 3.8.4.4.2
3.8.4.4.3 3.8.4.4.4 3.8.4.5.1 3.8.4.5.2 3.8.4.5.3 3.8.4.5.4
3.8.4.6.1 3.8.4.6.2 3.8.4.6.3 3.8.4.6.4 3.8.4.7.1 3.8.4.7.2
3.8.4.7.3 3.8.4.7.4 3.8.4.8.1 3.8.4.8.2 3.8.4.8.3 3.8.4.8.4
4.1.1.1.1 4.1.1.1.2 4.1.1.1.3 4.1.1.1.4 4.1.1.2.1 4.1.1.2.2
4.1.1.2.3 4.1.1.2.4 4.1.1.3.1 4.1.1.3.2 4.1.1.3.3 4.1.1.3.4
4.1.1.4.1 4.1.1.4.2 4.1.1.4.3 4.1.1.4.4 4.1.1.5.1 4.1.1.5.2
4.1.1.5.3 4.1.1.5.4 4.1.1.6.1 4.1.1.6.2 4.1.1.6.3 4.1.1.6.4
4.1.1.7.1 4.1.1.7.2 4.1.1.7.3 4.1.1.7.4 4.1.1.8.1 4.1.1.8.2
4.1.1.8.3 4.1.1.8.4 4.1.2.1.1 4.1.2.1.2 4.1.2.1.3 4.1.2.1.4
4.1.2.2.1 4.1.2.2.2 4.1.2.2.3 4.1.2.2.4 4.1.2.3.1 4.1.2.3.2
4.1.2.3.3 4.1.2.3.4 4.1.2.4.1 4.1.2.4.2 4.1.2.4.3 4.1.2.4.4
4.1.2.5.1 4.1.2.5.2 4.1.2.5.3 4.1.2.5.4 4.1.2.6.1 4.1.2.6.2
4.1.2.6.3 4.1.2.6.4 4.1.2.7.1 4.1.2.7.2 4.1.2.7.3 4.1.2.7.4
4.1.2.8.1 4.1.2.8.2 4.1.2.8.3 4.1.2.8.4 4.1.3.1.1 4.1.3.1.2
4.1.3.1.3 4.1.3.1.4 4.1.3.2.1 4.1.3.2.2 4.1.3.2.3 4.1.3.2.4
4.1.3.3.1 4.1.3.3.2 4.1.3.3.3 4.1.3.3.4 4.1.3.4.1 4.1.3.4.2
4.1.3.4.3 4.1.3.4.4 4.1.3.5.1 4.1.3.5.2 4.1.3.5.3 4.1.3.5.4
4.1.3.6.1 4.1.3.6.2 4.1.3.6.3 4.1.3.6.4 4.1.3.7.1 4.1.3.7.2
4.1.3.7.3 4.1.3.7.4 4.1.3.8.1 4.1.3.8.2 4.1.3.8.3 4.1.3.8.4
4.1.4.1.1 4.1.4.1.2 4.1.4.1.3 4.1.4.1.4 4.1.4.2.1 4.1.4.2.2
4.1.4.2.3 4.1.4.2.4 4.1.4.3.1 4.1.4.3.2 4.1.4.3.3 4.1.4.3.4
4.1.4.4.1 4.1.4.4.2 4.1.4.4.3 4.1.4.4.4 4.1.4.5.1 4.1.4.5.2
4.1.4.5.3 4.1.4.5.4 4.1.4.6.1 4.1.4.6.2 4.1.4.6.3 4.1.4.6.4
4.1.4.7.1 4.1.4.7.2 4.1.4.7.3 4.1.4.7.4 4.1.4.8.1 4.1.4.8.2
4.1.4.8.3 4.1.4.8.4 4.2.1.1.1 4.2.1.1.2 4.2.1.1.3 4.2.1.1.4
4.2.1.2.1 4.2.1.2.2 4.2.1.2.3 4.2.1.2.4 4.2.1.3.1 4.2.1.3.2
4.2.1.3.3 4.2.1.3.4 4.2.1.4.1 4.2.1.4.2 4.2.1.4.3 4.2.1.4.4
4.2.1.5.1 4.2.1.5.2 4.2.1.5.3 4.2.1.5.4 4.2.1.6.1 4.2.1.6.2
4.2.1.6.3 4.2.1.6.4 4.2.1.7.1 4.2.1.7.2 4.2.1.7.3 4.2.1.7.4
4.2.1.8.1 4.2.1.8.2 4.2.1.8.3 4.2.1.8.4 4.2.2.1.1 4.2.2.1.2
4.2.2.1.3 4.2.2.1.4 4.2.2.2.1 4.2.2.2.2 4.2.2.2.3 4.2.2.2.4
4.2.2.3.1 4.2.2.3.2 4.2.2.3.3 4.2.2.3.4 4.2.2.4.1 4.2.2.4.2
4.2.2.4.3 4.2.2.4.4 4.2.2.5.1 4.2.2.5.2 4.2.2.5.3 4.2.2.5.4
4.2.2.6.1 4.2.2.6.2 4.2.2.6.3 4.2.2.6.4 4.2.2.7.1 4.2.2.7.2
4.2.2.7.3 4.2.2.7.4 4.2.2.8.1 4.2.2.8.2 4.2.2.8.3 4.2.2.8.4
4.2.3.1.1 4.2.3.1.2 4.2.3.1.3 4.2.3.1.4 4.2.3.2.1 4.2.3.2.2
4.2.3.2.3 4.2.3.2.4 4.2.3.3.1 4.2.3.3.2 4.2.3.3.3 4.2.3.3.4
4.2.3.4.1 4.2.3.4.2 4.2.3.4.3 4.2.3.4.4 4.2.3.5.1 4.2.3.5.2
4.2.3.5.3 4.2.3.5.4 4.2.3.6.1 4.2.3.6.2 4.2.3.6.3 4.2.3.6.4
4.2.3.7.1 4.2.3.7.2 4.2.3.7.3 4.2.3.7.4 4.2.3.8.1 4.2.3.8.2
4.2.3.8.3 4.2.3.8.4 4.2.4.1.1 4.2.4.1.2 4.2.4.1.3 4.2.4.1.4
4.2.4.2.1 4.2.4.2.2 4.2.4.2.3 4.2.4.2.4 4.2.4.3.1 4.2.4.3.2
4.2.4.3.3 4.2.4.3.4 4.2.4.4.1 4.2.4.4.2 4.2.4.4.3 4.2.4.4.4
4.2.4.5.1 4.2.4.5.2 4.2.4.5.3 4.2.4.5.4 4.2.4.6.1 4.2.4.6.2
4.2.4.6.3 4.2.4.6.4 4.2.4.7.1 4.2.4.7.2 4.2.4.7.3 4.2.4.7.4
4.2.4.8.1 4.2.4.8.2 4.2.4.8.3 4.2.4.8.4 4.3.1.1.1 4.3.1.1.2
4.3.1.1.3 4.3.1.1.4 4.3.1.2.1 4.3.1.2.2 4.3.1.2.3 4.3.1.2.4
4.3.1.3.1 4.3.1.3.2 4.3.1.3.3 4.3.1.3.4 4.3.1.4.1 4.3.1.4.2
4.3.1.4.3 4.3.1.4.4 4.3.1.5.1 4.3.1.5.2 4.3.1.5.3 4.3.1.5.4
4.3.1.6.1 4.3.1.6.2 4.3.1.6.3 4.3.1.6.4 4.3.1.7.1 4.3.1.7.2
4.3.1.7.3 4.3.1.7.4 4.3.1.8.1 4.3.1.8.2 4.3.1.8.3 4.3.1.8.4
4.3.2.1.1 4.3.2.1.2 4.3.2.1.3 4.3.2.1.4 4.3.2.2.1 4.3.2.2.2
4.3.2.2.3 4.3.2.2.4 4.3.2.3.1 4.3.2.3.2 4.3.2.3.3 4.3.2.3.4
4.3.2.4.1 4.3.2.4.2 4.3.2.4.3 4.3.2.4.4 4.3.2.5.1 4.3.2.5.2
4.3.2.5.3 4.3.2.5.4 4.3.2.6.1 4.3.2.6.2 4.3.2.6.3 4.3.2.6.4
4.3.2.7.1 4.3.2.7.2 4.3.2.7.3 4.3.2.7.4 4.3.2.8.1 4.3.2.8.2
4.3.2.8.3 4.3.2.8.4 4.3.3.1.1 4.3.3.1.2 4.3.3.1.3 4.3.3.1.4
4.3.3.2.1 4.3.3.2.2 4.3.3.2.3 4.3.3.2.4 4.3.3.3.1 4.3.3.3.2
4.3.3.3.3 4.3.3.3.4 4.3.3.4.1 4.3.3.4.2 4.3.3.4.3 4.3.3.4.4
4.3.3.5.1 4.3.3.5.2 4.3.3.5.3 4.3.3.5.4 4.3.3.6.1 4.3.3.6.2
4.3.3.6.3 4.3.3.6.4 4.3.3.7.1 4.3.3.7.2 4.3.3.7.3 4.3.3.7.4
4.3.3.8.1 4.3.3.8.2 4.3.3.8.3 4.3.3.8.4 4.3.4.1.1 4.3.4.1.2
4.3.4.1.3 4.3.4.1.4 4.3.4.2.1 4.3.4.2.2 4.3.4.2.3 4.3.4.2.4
4.3.4.3.1 4.3.4.3.2 4.3.4.3.3 4.3.4.3.4 4.3.4.4.1 4.3.4.4.2
4.3.4.4.3 4.3.4.4.4 4.3.4.5.1 4.3.4.5.2 4.3.4.5.3 4.3.4.5.4
4.3.4.6.1 4.3.4.6.2 4.3.4.6.3 4.3.4.6.4 4.3.4.7.1 4.3.4.7.2
4.3.4.7.3 4.3.4.7.4 4.3.4.8.1 4.3.4.8.2 4.3.4.8.3 4.3.4.8.4
4.4.1.1.1 4.4.1.1.2 4.4.1.1.3 4.4.1.1.4 4.4.1.2.1 4.4.1.2.2
4.4.1.2.3 4.4.1.2.4 4.4.1.3.1 4.4.1.3.2 4.4.1.3.3 4.4.1.3.4
4.4.1.4.1 4.4.1.4.2 4.4.1.4.3 4.4.1.4.4 4.4.1.5.1 4.4.1.5.2
4.4.1.5.3 4.4.1.5.4 4.4.1.6.1 4.4.1.6.2 4.4.1.6.3 4.4.1.6.4
4.4.1.7.1 4.4.1.7.2 4.4.1.7.3 4.4.1.7.4 4.4.1.8.1 4.4.1.8.2
4.4.1.8.3 4.4.1.8.4 4.4.2.1.1 4.4.2.1.2 4.4.2.1.3 4.4.2.1.4
4.4.2.2.1 4.4.2.2.2 4.4.2.2.3 4.4.2.2.4 4.4.2.3.1 4.4.2.3.2
4.4.2.3.3 4.4.2.3.4 4.4.2.4.1 4.4.2.4.2 4.4.2.4.3 4.4.2.4.4
4.4.2.5.1 4.4.2.5.2 4.4.2.5.3 4.4.2.5.4 4.4.2.6.1 4.4.2.6.2
4.4.2.6.3 4.4.2.6.4 4.4.2.7.1 4.4.2.7.2 4.4.2.7.3 4.4.2.7.4
4.4.2.8.1 4.4.2.8.2 4.4.2.8.3 4.4.2.8.4 4.4.3.1.1 4.4.3.1.2
4.4.3.1.3 4.4.3.1.4 4.4.3.2.1 4.4.3.2.2 4.4.3.2.3 4.4.3.2.4
4.4.3.3.1 4.4.3.3.2 4.4.3.3.3 4.4.3.3.4 4.4.3.4.1 4.4.3.4.2
4.4.3.4.3 4.4.3.4.4 4.4.3.5.1 4.4.3.5.2 4.4.3.5.3 4.4.3.5.4
4.4.3.6.1 4.4.3.6.2 4.4.3.6.3 4.4.3.6.4 4.4.3.7.1 4.4.3.7.2
4.4.3.7.3 4.4.3.7.4 4.4.3.8.1 4.4.3.8.2 4.4.3.8.3 4.4.3.8.4
4.4.4.1.1 4.4.4.1.2 4.4.4.1.3 4.4.4.1.4 4.4.4.2.1 4.4.4.2.2
4.4.4.2.3 4.4.4.2.4 4.4.4.3.1 4.4.4.3.2 4.4.4.3.3 4.4.4.3.4
4.4.4.4.1 4.4.4.4.2 4.4.4.4.3 4.4.4.4.4 4.4.4.5.1 4.4.4.5.2
4.4.4.5.3 4.4.4.5.4 4.4.4.6.1 4.4.4.6.2 4.4.4.6.3 4.4.4.6.4
4.4.4.7.1 4.4.4.7.2 4.4.4.7.3 4.4.4.7.4 4.4.4.8.1 4.4.4.8.2
4.4.4.8.3 4.4.4.8.4 4.5.1.1.1 4.5.1.1.2 4.5.1.1.3 4.5.1.1.4
4.5.1.2.1 4.5.1.2.2 4.5.1.2.3 4.5.1.2.4 4.5.1.3.1 4.5.1.3.2
4.5.1.3.3 4.5.1.3.4 4.5.1.4.1 4.5.1.4.2 4.5.1.4.3 4.5.1.4.4
4.5.1.5.1 4.5.1.5.2 4.5.1.5.3 4.5.1.5.4 4.5.1.6.1 4.5.1.6.2
4.5.1.6.3 4.5.1.6.4 4.5.1.7.1 4.5.1.7.2 4.5.1.7.3 4.5.1.7.4
4.5.1.8.1 4.5.1.8.2 4.5.1.8.3 4.5.1.8.4 4.5.2.1.1 4.5.2.1.2
4.5.2.1.3 4.5.2.1.4 4.5.2.2.1 4.5.2.2.2 4.5.2.2.3 4.5.2.2.4
4.5.2.3.1 4.5.2.3.2 4.5.2.3.3 4.5.2.3.4 4.5.2.4.1 4.5.2.4.2
4.5.2.4.3 4.5.2.4.4 4.5.2.5.1 4.5.2.5.2 4.5.2.5.3 4.5.2.5.4
4.5.2.6.1 4.5.2.6.2 4.5.2.6.3 4.5.2.6.4 4.5.2.7.1 4.5.2.7.2
4.5.2.7.3 4.5.2.7.4 4.5.2.8.1 4.5.2.8.2 4.5.2.8.3 4.5.2.8.4
4.5.3.1.1 4.5.3.1.2 4.5.3.1.3 4.5.3.1.4 4.5.3.2.1 4.5.3.2.2
4.5.3.2.3 4.5.3.2.4 4.5.3.3.1 4.5.3.3.2 4.5.3.3.3 4.5.3.3.4
4.5.3.4.1 4.5.3.4.2 4.5.3.4.3 4.5.3.4.4 4.5.3.5.1 4.5.3.5.2
4.5.3.5.3 4.5.3.5.4 4.5.3.6.1 4.5.3.6.2 4.5.3.6.3 4.5.3.6.4
4.5.3.7.1 4.5.3.7.2 4.5.3.7.3 4.5.3.7.4 4.5.3.8.1 4.5.3.8.2
4.5.3.8.3 4.5.3.8.4 4.5.4.1.1 4.5.4.1.2 4.5.4.1.3 4.5.4.1.4
4.5.4.2.1 4.5.4.2.2 4.5.4.2.3 4.5.4.2.4 4.5.4.3.1 4.5.4.3.2
4.5.4.3.3 4.5.4.3.4 4.5.4.4.1 4.5.4.4.2 4.5.4.4.3 4.5.4.4.4
4.5.4.5.1 4.5.4.5.2 4.5.4.5.3 4.5.4.5.4 4.5.4.6.1 4.5.4.6.2
4.5.4.6.3 4.5.4.6.4 4.5.4.7.1 4.5.4.7.2 4.5.4.7.3 4.5.4.7.4
4.5.4.8.1 4.5.4.8.2 4.5.4.8.3 4.5.4.8.4 4.6.1.1.1 4.6.1.1.2
4.6.1.1.3 4.6.1.1.4 4.6.1.2.1 4.6.1.2.2 4.6.1.2.3 4.6.1.2.4
4.6.1.3.1 4.6.1.3.2 4.6.1.3.3 4.6.1.3.4 4.6.1.4.1 4.6.1.4.2
4.6.1.4.3 4.6.1.4.4 4.6.1.5.1 4.6.1.5.2 4.6.1.5.3 4.6.1.5.4
4.6.1.6.1 4.6.1.6.2 4.6.1.6.3 4.6.1.6.4 4.6.1.7.1 4.6.1.7.2
4.6.1.7.3 4.6.1.7.4 4.6.1.8.1 4.6.1.8.2 4.6.1.8.3 4.6.1.8.4
4.6.2.1.1 4.6.2.1.2 4.6.2.1.3 4.6.2.1.4 4.6.2.2.1 4.6.2.2.2
4.6.2.2.3 4.6.2.2.4 4.6.2.3.1 4.6.2.3.2 4.6.2.3.3 4.6.2.3.4
4.6.2.4.1 4.6.2.4.2 4.6.2.4.3 4.6.2.4.4 4.6.2.5.1 4.6.2.5.2
4.6.2.5.3 4.6.2.5.4 4.6.2.6.1 4.6.2.6.2 4.6.2.6.3 4.6.2.6.4
4.6.2.7.1 4.6.2.7.2 4.6.2.7.3 4.6.2.7.4 4.6.2.8.1 4.6.2.8.2
4.6.2.8.3 4.6.2.8.4 4.6.3.1.1 4.6.3.1.2 4.6.3.1.3 4.6.3.1.4
4.6.3.2.1 4.6.3.2.2 4.6.3.2.3 4.6.3.2.4 4.6.3.3.1 4.6.3.3.2
4.6.3.3.3 4.6.3.3.4 4.6.3.4.1 4.6.3.4.2 4.6.3.4.3 4.6.3.4.4
4.6.3.5.1 4.6.3.5.2 4.6.3.5.3 4.6.3.5.4 4.6.3.6.1 4.6.3.6.2
4.6.3.6.3 4.6.3.6.4 4.6.3.7.1 4.6.3.7.2 4.6.3.7.3 4.6.3.7.4
4.6.3.8.1 4.6.3.8.2 4.6.3.8.3 4.6.3.8.4 4.6.4.1.1 4.6.4.1.2
4.6.4.1.3 4.6.4.1.4 4.6.4.2.1 4.6.4.2.2 4.6.4.2.3 4.6.4.2.4
4.6.4.3.1 4.6.4.3.2 4.6.4.3.3 4.6.4.3.4 4.6.4.4.1 4.6.4.4.2
4.6.4.4.3 4.6.4.4.4 4.6.4.5.1 4.6.4.5.2 4.6.4.5.3 4.6.4.5.4
4.6.4.6.1 4.6.4.6.2 4.6.4.6.3 4.6.4.6.4 4.6.4.7.1 4.6.4.7.2
4.6.4.7.3 4.6.4.7.4 4.6.4.8.1 4.6.4.8.2 4.6.4.8.3 4.6.4.8.4
4.7.1.1.1 4.7.1.1.2 4.7.1.1.3 4.7.1.1.4 4.7.1.2.1 4.7.1.2.2
4.7.1.2.3 4.7.1.2.4 4.7.1.3.1 4.7.1.3.2 4.7.1.3.3 4.7.1.3.4
4.7.1.4.1 4.7.1.4.2 4.7.1.4.3 4.7.1.4.4 4.7.1.5.1 4.7.1.5.2
4.7.1.5.3 4.7.1.5.4 4.7.1.6.1 4.7.1.6.2 4.7.1.6.3 4.7.1.6.4
4.7.1.7.1 4.7.1.7.2 4.7.1.7.3 4.7.1.7.4 4.7.1.8.1 4.7.1.8.2
4.7.1.8.3 4.7.1.8.4 4.7.2.1.1 4.7.2.1.2 4.7.2.1.3 4.7.2.1.4
4.7.2.2.1 4.7.2.2.2 4.7.2.2.3 4.7.2.2.4 4.7.2.3.1 4.7.2.3.2
4.7.2.3.3 4.7.2.3.4 4.7.2.4.1 4.7.2.4.2 4.7.2.4.3 4.7.2.4.4
4.7.2.5.1 4.7.2.5.2 4.7.2.5.3 4.7.2.5.4 4.7.2.6.1 4.7.2.6.2
4.7.2.6.3 4.7.2.6.4 4.7.2.7.1 4.7.2.7.2 4.7.2.7.3 4.7.2.7.4
4.7.2.8.1 4.7.2.8.2 4.7.2.8.3 4.7.2.8.4 4.7.3.1.1 4.7.3.1.2
4.7.3.1.3 4.7.3.1.4 4.7.3.2.1 4.7.3.2.2 4.7.3.2.3 4.7.3.2.4
4.7.3.3.1 4.7.3.3.2 4.7.3.3.3 4.7.3.3.4 4.7.3.4.1 4.7.3.4.2
4.7.3.4.3 4.7.3.4.4 4.7.3.5.1 4.7.3.5.2 4.7.3.5.3 4.7.3.5.4
4.7.3.6.1 4.7.3.6.2 4.7.3.6.3 4.7.3.6.4 4.7.3.7.1 4.7.3.7.2
4.7.3.7.3 4.7.3.7.4 4.7.3.8.1 4.7.3.8.2 4.7.3.8.3 4.7.3.8.4
4.7.4.1.1 4.7.4.1.2 4.7.4.1.3 4.7.4.1.4 4.7.4.2.1 4.7.4.2.2
4.7.4.2.3 4.7.4.2.4 4.7.4.3.1 4.7.4.3.2 4.7.4.3.3 4.7.4.3.4
4.7.4.4.1 4.7.4.4.2 4.7.4.4.3 4.7.4.4.4 4.7.4.5.1 4.7.4.5.2
4.7.4.5.3 4.7.4.5.4 4.7.4.6.1 4.7.4.6.2 4.7.4.6.3 4.7.4.6.4
4.7.4.7.1 4.7.4.7.2 4.7.4.7.3 4.7.4.7.4 4.7.4.8.1 4.7.4.8.2
4.7.4.8.3 4.7.4.8.4 4.8.1.1.1 4.8.1.1.2 4.8.1.1.3 4.8.1.1.4
4.8.1.2.1 4.8.1.2.2 4.8.1.2.3 4.8.1.2.4 4.8.1.3.1 4.8.1.3.2
4.8.1.3.3 4.8.1.3.4 4.8.1.4.1 4.8.1.4.2 4.8.1.4.3 4.8.1.4.4
4.8.1.5.1 4.8.1.5.2 4.8.1.5.3 4.8.1.5.4 4.8.1.6.1 4.8.1.6.2
4.8.1.6.3 4.8.1.6.4 4.8.1.7.1 4.8.1.7.2 4.8.1.7.3 4.8.1.7.4
4.8.1.8.1 4.8.1.8.2 4.8.1.8.3 4.8.1.8.4 4.8.2.1.1 4.8.2.1.2
4.8.2.1.3 4.8.2.1.4 4.8.2.2.1 4.8.2.2.2 4.8.2.2.3
4.8.2.2.4 4.8.2.3.1 4.8.2.3.2 4.8.2.3.3 4.8.2.3.4 4.8.2.4.1
4.8.2.4.2 4.8.2.4.3 4.8.2.4.4 4.8.2.5.1 4.8.2.5.2 4.8.2.5.3
4.8.2.5.4 4.8.2.6.1 4.8.2.6.2 4.8.2.6.3 4.8.2.6.4 4.8.2.7.1
4.8.2.7.2 4.8.2.7.3 4.8.2.7.4 4.8.2.8.1 4.8.2.8.2 4.8.2.8.3
4.8.2.8.4 4.8.3.1.1 4.8.3.1.2 4.8.3.1.3 4.8.3.1.4 4.8.3.2.1
4.8.3.2.2 4.8.3.2.3 4.8.3.2.4 4.8.3.3.1 4.8.3.3.2 4.8.3.3.3
4.8.3.3.4 4.8.3.4.1 4.8.3.4.2 4.8.3.4.3 4.8.3.4.4 4.8.3.5.1
4.8.3.5.2 4.8.3.5.3 4.8.3.5.4 4.8.3.6.1 4.8.3.6.2 4.8.3.6.3
4.8.3.6.4 4.8.3.7.1 4.8.3.7.2 4.8.3.7.3 4.8.3.7.4 4.8.3.8.1
4.8.3.8.2 4.8.3.8.3 4.8.3.8.4 4.8.4.1.1 4.8.4.1.2 4.8.4.1.3
4.8.4.1.4 4.8.4.2.1 4.8.4.2.2 4.8.4.2.3 4.8.4.2.4 4.8.4.3.1
4.8.4.3.2 4.8.4.3.3 4.8.4.3.4 4.8.4.4.1 4.8.4.4.2 4.8.4.4.3
4.8.4.4.4 4.8.4.5.1 4.8.4.5.2 4.8.4.5.3 4.8.4.5.4 4.8.4.6.1
4.8.4.6.2 4.8.4.6.3 4.8.4.6.4 4.8.4.7.1 4.8.4.7.2 4.8.4.7.3
4.8.4.7.4 4.8.4.8.1 4.8.4.8.2 4.8.4.8.3 4.8.4.8.4 5.1.1.1.1
5.1.1.1.2 5.1.1.1.3 5.1.1.1.4 5.1.1.2.1 5.1.1.2.2 5.1.1.2.3
5.1.1.2.4 5.1.1.3.1 5.1.1.3.2 5.1.1.3.3 5.1.1.3.4 5.1.1.4.1
5.1.1.4.2 5.1.1.4.3 5.1.1.4.4 5.1.1.5.1 5.1.1.5.2 5.1.1.5.3
5.1.1.5.4 5.1.1.6.1 5.1.1.6.2 5.1.1.6.3 5.1.1.6.4 5.1.1.7.1
5.1.1.7.2 5.1.1.7.3 5.1.1.7.4 5.1.1.8.1 5.1.1.8.2 5.1.1.8.3
5.1.1.8.4 5.1.2.1.1 5.1.2.1.2 5.1.2.1.3 5.1.2.1.4 5.1.2.2.1
5.1.2.2.2 5.1.2.2.3 5.1.2.2.4 5.1.2.3.1 5.1.2.3.2 5.1.2.3.3
5.1.2.3.4 5.1.2.4.1 5.1.2.4.2 5.1.2.4.3 5.1.2.4.4 5.1.2.5.1
5.1.2.5.2 5.1.2.5.3 5.1.2.5.4 5.1.2.6.1 5.1.2.6.2 5.1.2.6.3
5.1.2.6.4 5.1.2.7.1 5.1.2.7.2 5.1.2.7.3 5.1.2.7.4 5.1.2.8.1
5.1.2.8.2 5.1.2.8.3 5.1.2.8.4 5.1.3.1.1 5.1.3.1.2 5.1.3.1.3
5.1.3.1.4 5.1.3.2.1 5.1.3.2.2 5.1.3.2.3 5.1.3.2.4 5.1.3.3.1
5.1.3.3.2 5.1.3.3.3 5.1.3.3.4 5.1.3.4.1 5.1.3.4.2 5.1.3.4.3
5.1.3.4.4 5.1.3.5.1 5.1.3.5.2 5.1.3.5.3 5.1.3.5.4 5.1.3.6.1
5.1.3.6.2 5.1.3.6.3 5.1.3.6.4 5.1.3.7.1 5.1.3.7.2 5.1.3.7.3
5.1.3.7.4 5.1.3.8.1 5.1.3.8.2 5.1.3.8.3 5.1.3.8.4 5.1.4.1.1
5.1.4.1.2 5.1.4.1.3 5.1.4.1.4 5.1.4.2.1 5.1.4.2.2 5.1.4.2.3
5.1.4.2.4 5.1.4.3.1 5.1.4.3.2 5.1.4.3.3 5.1.4.3.4 5.1.4.4.1
5.1.4.4.2 5.1.4.4.3 5.1.4.4.4 5.1.4.5.1 5.1.4.5.2 5.1.4.5.3
5.1.4.5.4 5.1.4.6.1 5.1.4.6.2 5.1.4.6.3 5.1.4.6.4 5.1.4.7.1
5.1.4.7.2 5.1.4.7.3 5.1.4.7.4 5.1.4.8.1 5.1.4.8.2 5.1.4.8.3
5.1.4.8.4 5.2.1.1.1 5.2.1.1.2 5.2.1.1.3 5.2.1.1.4 5.2.1.2.1
5.2.1.2.2 5.2.1.2.3 5.2.1.2.4 5.2.1.3.1 5.2.1.3.2 5.2.1.3.3
5.2.1.3.4 5.2.1.4.1 5.2.1.4.2 5.2.1.4.3 5.2.1.4.4 5.2.1.5.1
5.2.1.5.2 5.2.1.5.3 5.2.1.5.4 5.2.1.6.1 5.2.1.6.2 5.2.1.6.3
5.2.1.6.4 5.2.1.7.1 5.2.1.7.2 5.2.1.7.3 5.2.1.7.4 5.2.1.8.1
5.2.1.8.2 5.2.1.8.3 5.2.1.8.4 5.2.2.1.1 5.2.2.1.2 5.2.2.1.3
5.2.2.1.4 5.2.2.2.1 5.2.2.2.2 5.2.2.2.3 5.2.2.2.4 5.2.2.3.1
5.2.2.3.2 5.2.2.3.3 5.2.2.3.4 5.2.2.4.1 5.2.2.4.2 5.2.2.4.3
5.2.2.4.4 5.2.2.5.1 5.2.2.5.2 5.2.2.5.3 5.2.2.5.4 5.2.2.6.1
5.2.2.6.2 5.2.2.6.3 5.2.2.6.4 5.2.2.7.1 5.2.2.7.2 5.2.2.7.3
5.2.2.7.4 5.2.2.8.1 5.2.2.8.2 5.2.2.8.3 5.2.2.8.4 5.2.3.1.1
5.2.3.1.2 5.2.3.1.3 5.2.3.1.4 5.2.3.2.1 5.2.3.2.2 5.2.3.2.3
5.2.3.2.4 5.2.3.3.1 5.2.3.3.2 5.2.3.3.3 5.2.3.3.4 5.2.3.4.1
5.2.3.4.2 5.2.3.4.3 5.2.3.4.4 5.2.3.5.1 5.2.3.5.2 5.2.3.5.3
5.2.3.5.4 5.2.3.6.1 5.2.3.6.2 5.2.3.6.3 5.2.3.6.4 5.2.3.7.1
5.2.3.7.2 5.2.3.7.3 5.2.3.7.4 5.2.3.8.1 5.2.3.8.2 5.2.3.8.3
5.2.3.8.4 5.2.4.1.1 5.2.4.1.2 5.2.4.1.3 5.2.4.1.4 5.2.4.2.1
5.2.4.2.2 5.2.4.2.3 5.2.4.2.4 5.2.4.3.1 5.2.4.3.2 5.2.4.3.3
5.2.4.3.4 5.2.4.4.1 5.2.4.4.2 5.2.4.4.3 5.2.4.4.4 5.2.4.5.1
5.2.4.5.2 5.2.4.5.3 5.2.4.5.4 5.2.4.6.1 5.2.4.6.2 5.2.4.6.3
5.2.4.6.4 5.2.4.7.1 5.2.4.7.2 5.2.4.7.3 5.2.4.7.4 5.2.4.8.1
5.2.4.8.2 5.2.4.8.3 5.2.4.8.4 5.3.1.1.1 5.3.1.1.2 5.3.1.1.3
5.3.1.1.4 5.3.1.2.1 5.3.1.2.2 5.3.1.2.3 5.3.1.2.4 5.3.1.3.1
5.3.1.3.2 5.3.1.3.3 5.3.1.3.4 5.3.1.4.1 5.3.1.4.2 5.3.1.4.3
5.3.1.4.4 5.3.1.5.1 5.3.1.5.2 5.3.1.5.3 5.3.1.5.4 5.3.1.6.1
5.3.1.6.2 5.3.1.6.3 5.3.1.6.4 5.3.1.7.1 5.3.1.7.2 5.3.1.7.3
5.3.1.7.4 5.3.1.8.1 5.3.1.8.2 5.3.1.8.3 5.3.1.8.4 5.3.2.1.1
5.3.2.1.2 5.3.2.1.3 5.3.2.1.4 5.3.2.2.1 5.3.2.2.2 5.3.2.2.3
5.3.2.2.4 5.3.2.3.1 5.3.2.3.2 5.3.2.3.3 5.3.2.3.4 5.3.2.4.1
5.3.2.4.2 5.3.2.4.3 5.3.2.4.4 5.3.2.5.1 5.3.2.5.2 5.3.2.5.3
5.3.2.5.4 5.3.2.6.1 5.3.2.6.2 5.3.2.6.3 5.3.2.6.4 5.3.2.7.1
5.3.2.7.2 5.3.2.7.3 5.3.2.7.4 5.3.2.8.1 5.3.2.8.2 5.3.2.8.3
5.3.2.8.4 5.3.3.1.1 5.3.3.1.2 5.3.3.1.3 5.3.3.1.4 5.3.3.2.1
5.3.3.2.2 5.3.3.2.3 5.3.3.2.4 5.3.3.3.1 5.3.3.3.2 5.3.3.3.3
5.3.3.3.4 5.3.3.4.1 5.3.3.4.2 5.3.3.4.3 5.3.3.4.4 5.3.3.5.1
5.3.3.5.2 5.3.3.5.3 5.3.3.5.4 5.3.3.6.1 5.3.3.6.2 5.3.3.6.3
5.3.3.6.4 5.3.3.7.1 5.3.3.7.2 5.3.3.7.3 5.3.3.7.4 5.3.3.8.1
5.3.3.8.2 5.3.3.8.3 5.3.3.8.4 5.3.4.1.1 5.3.4.1.2 5.3.4.1.3
5.3.4.1.4 5.3.4.2.1 5.3.4.2.2 5.3.4.2.3 5.3.4.2.4 5.3.4.3.1
5.3.4.3.2 5.3.4.3.3 5.3.4.3.4 5.3.4.4.1 5.3.4.4.2 5.3.4.4.3
5.3.4.4.4 5.3.4.5.1 5.3.4.5.2 5.3.4.5.3 5.3.4.5.4 5.3.4.6.1
5.3.4.6.2 5.3.4.6.3 5.3.4.6.4 5.3.4.7.1 5.3.4.7.2 5.3.4.7.3
5.3.4.7.4 5.3.4.8.1 5.3.4.8.2 5.3.4.8.3 5.3.4.8.4 5.4.1.1.1
5.4.1.1.2 5.4.1.1.3 5.4.1.1.4 5.4.1.2.1 5.4.1.2.2 5.4.1.2.3
5.4.1.2.4 5.4.1.3.1 5.4.1.3.2 5.4.1.3.3 5.4.1.3.4 5.4.1.4.1
5.4.1.4.2 5.4.1.4.3 5.4.1.4.4 5.4.1.5.1 5.4.1.5.2 5.4.1.5.3
5.4.1.5.4 5.4.1.6.1 5.4.1.6.2 5.4.1.6.3 5.4.1.6.4 5.4.1.7.1
5.4.1.7.2 5.4.1.7.3 5.4.1.7.4 5.4.1.8.1 5.4.1.8.2 5.4.1.8.3
5.4.1.8.4 5.4.2.1.1 5.4.2.1.2 5.4.2.1.3 5.4.2.1.4 5.4.2.2.1
5.4.2.2.2 5.4.2.2.3 5.4.2.2.4 5.4.2.3.1 5.4.2.3.2 5.4.2.3.3
5.4.2.3.4 5.4.2.4.1 5.4.2.4.2 5.4.2.4.3 5.4.2.4.4 5.4.2.5.1
5.4.2.5.2 5.4.2.5.3 5.4.2.5.4 5.4.2.6.1 5.4.2.6.2 5.4.2.6.3
5.4.2.6.4 5.4.2.7.1 5.4.2.7.2 5.4.2.7.3 5.4.2.7.4 5.4.2.8.1
5.4.2.8.2 5.4.2.8.3 5.4.2.8.4 5.4.3.1.1 5.4.3.1.2 5.4.3.1.3
5.4.3.1.4 5.4.3.2.1 5.4.3.2.2 5.4.3.2.3 5.4.3.2.4 5.4.3.3.1
5.4.3.3.2 5.4.3.3.3 5.4.3.3.4 5.4.3.4.1 5.4.3.4.2 5.4.3.4.3
5.4.3.4.4 5.4.3.5.1 5.4.3.5.2 5.4.3.5.3 5.4.3.5.4 5.4.3.6.1
5.4.3.6.2 5.4.3.6.3 5.4.3.6.4 5.4.3.7.1 5.4.3.7.2 5.4.3.7.3
5.4.3.7.4 5.4.3.8.1 5.4.3.8.2 5.4.3.8.3 5.4.3.8.4 5.4.4.1.1
5.4.4.1.2 5.4.4.1.3 5.4.4.1.4 5.4.4.2.1 5.4.4.2.2 5.4.4.2.3
5.4.4.2.4 5.4.4.3.1 5.4.4.3.2 5.4.4.3.3 5.4.4.3.4 5.4.4.4.1
5.4.4.4.2 5.4.4.4.3 5.4.4.4.4 5.4.4.5.1 5.4.4.5.2 5.4.4.5.3
5.4.4.5.4 5.4.4.6.1 5.4.4.6.2 5.4.4.6.3 5.4.4.6.4 5.4.4.7.1
5.4.4.7.2 5.4.4.7.3 5.4.4.7.4 5.4.4.8.1 5.4.4.8.2 5.4.4.8.3
5.4.4.8.4 5.5.1.1.1 5.5.1.1.2 5.5.1.1.3 5.5.1.1.4 5.5.1.2.1
5.5.1.2.2 5.5.1.2.3 5.5.1.2.4 5.5.1.3.1 5.5.1.3.2 5.5.1.3.3
5.5.1.3.4 5.5.1.4.1 5.5.1.4.2 5.5.1.4.3 5.5.1.4.4 5.5.1.5.1
5.5.1.5.2 5.5.1.5.3 5.5.1.5.4 5.5.1.6.1 5.5.1.6.2 5.5.1.6.3
5.5.1.6.4 5.5.1.7.1 5.5.1.7.2 5.5.1.7.3 5.5.1.7.4 5.5.1.8.1
5.5.1.8.2 5.5.1.8.3 5.5.1.8.4 5.5.2.1.1 5.5.2.1.2 5.5.2.1.3
5.5.2.1.4 5.5.2.2.1 5.5.2.2.2 5.5.2.2.3 5.5.2.2.4 5.5.2.3.1
5.5.2.3.2 5.5.2.3.3 5.5.2.3.4 5.5.2.4.1 5.5.2.4.2 5.5.2.4.3
5.5.2.4.4 5.5.2.5.1 5.5.2.5.2 5.5.2.5.3 5.5.2.5.4 5.5.2.6.1
5.5.2.6.2 5.5.2.6.3 5.5.2.6.4 5.5.2.7.1 5.5.2.7.2 5.5.2.7.3
5.5.2.7.4 5.5.2.8.1 5.5.2.8.2 5.5.2.8.3 5.5.2.8.4 5.5.3.1.1
5.5.3.1.2 5.5.3.1.3 5.5.3.1.4 5.5.3.2.1 5.5.3.2.2 5.5.3.2.3
5.5.3.2.4 5.5.3.3.1 5.5.3.3.2 5.5.3.3.3 5.5.3.3.4 5.5.3.4.1
5.5.3.4.2 5.5.3.4.3 5.5.3.4.4 5.5.3.5.1 5.5.3.5.2 5.5.3.5.3
5.5.3.5.4 5.5.3.6.1 5.5.3.6.2 5.5.3.6.3 5.5.3.6.4 5.5.3.7.1
5.5.3.7.2 5.5.3.7.3 5.5.3.7.4 5.5.3.8.1 5.5.3.8.2 5.5.3.8.3
5.5.3.8.4 5.5.4.1.1 5.5.4.1.2 5.5.4.1.3 5.5.4.1.4 5.5.4.2.1
5.5.4.2.2 5.5.4.2.3 5.5.4.2.4 5.5.4.3.1 5.5.4.3.2 5.5.4.3.3
5.5.4.3.4 5.5.4.4.1 5.5.4.4.2 5.5.4.4.3 5.5.4.4.4 5.5.4.5.1
5.5.4.5.2 5.5.4.5.3 5.5.4.5.4 5.5.4.6.1 5.5.4.6.2 5.5.4.6.3
5.5.4.6.4 5.5.4.7.1 5.5.4.7.2 5.5.4.7.3 5.5.4.7.4 5.5.4.8.1
5.5.4.8.2 5.5.4.8.3 5.5.4.8.4 5.6.1.1.1 5.6.1.1.2 5.6.1.1.3
5.6.1.1.4 5.6.1.2.1 5.6.1.2.2 5.6.1.2.3 5.6.1.2.4 5.6.1.3.1
5.6.1.3.2 5.6.1.3.3 5.6.1.3.4 5.6.1.4.1 5.6.1.4.2 5.6.1.4.3
5.6.1.4.4 5.6.1.5.1 5.6.1.5.2 5.6.1.5.3 5.6.1.5.4 5.6.1.6.1
5.6.1.6.2 5.6.1.6.3 5.6.1.6.4 5.6.1.7.1 5.6.1.7.2 5.6.1.7.3
5.6.1.7.4 5.6.1.8.1 5.6.1.8.2 5.6.1.8.3 5.6.1.8.4 5.6.2.1.1
5.6.2.1.2 5.6.2.1.3 5.6.2.1.4 5.6.2.2.1 5.6.2.2.2 5.6.2.2.3
5.6.2.2.4 5.6.2.3.1 5.6.2.3.2 5.6.2.3.3 5.6.2.3.4 5.6.2.4.1
5.6.2.4.2 5.6.2.4.3 5.6.2.4.4 5.6.2.5.1 5.6.2.5.2 5.6.2.5.3
5.6.2.5.4 5.6.2.6.1 5.6.2.6.2 5.6.2.6.3 5.6.2.6.4 5.6.2.7.1
5.6.2.7.2 5.6.2.7.3 5.6.2.7.4 5.6.2.8.1 5.6.2.8.2 5.6.2.8.3
5.6.2.8.4 5.6.3.1.1 5.6.3.1.2 5.6.3.1.3 5.6.3.1.4 5.6.3.2.1
5.6.3.2.2 5.6.3.2.3 5.6.3.2.4 5.6.3.3.1 5.6.3.3.2 5.6.3.3.3
5.6.3.3.4 5.6.3.4.1 5.6.3.4.2 5.6.3.4.3 5.6.3.4.4 5.6.3.5.1
5.6.3.5.2 5.6.3.5.3 5.6.3.5.4 5.6.3.6.1 5.6.3.6.2 5.6.3.6.3
5.6.3.6.4 5.6.3.7.1 5.6.3.7.2 5.6.3.7.3 5.6.3.7.4 5.6.3.8.1
5.6.3.8.2 5.6.3.8.3 5.6.3.8.4 5.6.4.1.1 5.6.4.1.2 5.6.4.1.3
5.6.4.1.4 5.6.4.2.1 5.6.4.2.2 5.6.4.2.3 5.6.4.2.4 5.6.4.3.1
5.6.4.3.2 5.6.4.3.3 5.6.4.3.4 5.6.4.4.1 5.6.4.4.2 5.6.4.4.3
5.6.4.4.4 5.6.4.5.1 5.6.4.5.2 5.6.4.5.3 5.6.4.5.4 5.6.4.6.1
5.6.4.6.2 5.6.4.6.3 5.6.4.6.4 5.6.4.7.1 5.6.4.7.2 5.6.4.7.3
5.6.4.7.4 5.6.4.8.1 5.6.4.8.2 5.6.4.8.3 5.6.4.8.4 5.7.1.1.1
5.7.1.1.2 5.7.1.1.3 5.7.1.1.4 5.7.1.2.1 5.7.1.2.2 5.7.1.2.3
5.7.1.2.4 5.7.1.3.1 5.7.1.3.2 5.7.1.3.3 5.7.1.3.4 5.7.1.4.1
5.7.1.4.2 5.7.1.4.3 5.7.1.4.4 5.7.1.5.1 5.7.1.5.2 5.7.1.5.3
5.7.1.5.4 5.7.1.6.1 5.7.1.6.2 5.7.1.6.3 5.7.1.6.4 5.7.1.7.1
5.7.1.7.2 5.7.1.7.3 5.7.1.7.4 5.7.1.8.1 5.7.1.8.2 5.7.1.8.3
5.7.1.8.4 5.7.2.1.1 5.7.2.1.2 5.7.2.1.3 5.7.2.1.4 5.7.2.2.1
5.7.2.2.2 5.7.2.2.3 5.7.2.2.4 5.7.2.3.1 5.7.2.3.2 5.7.2.3.3
5.7.2.3.4 5.7.2.4.1 5.7.2.4.2 5.7.2.4.3 5.7.2.4.4 5.7.2.5.1
5.7.2.5.2 5.7.2.5.3 5.7.2.5.4 5.7.2.6.1 5.7.2.6.2 5.7.2.6.3
5.7.2.6.4 5.7.2.7.1 5.7.2.7.2 5.7.2.7.3 5.7.2.7.4 5.7.2.8.1
5.7.2.8.2 5.7.2.8.3 5.7.2.8.4 5.7.3.1.1 5.7.3.1.2 5.7.3.1.3
5.7.3.1.4 5.7.3.2.1 5.7.3.2.2 5.7.3.2.3 5.7.3.2.4 5.7.3.3.1
5.7.3.3.2 5.7.3.3.3 5.7.3.3.4 5.7.3.4.1 5.7.3.4.2 5.7.3.4.3
5.7.3.4.4 5.7.3.5.1 5.7.3.5.2 5.7.3.5.3 5.7.3.5.4 5.7.3.6.1
5.7.3.6.2 5.7.3.6.3 5.7.3.6.4 5.7.3.7.1 5.7.3.7.2 5.7.3.7.3
5.7.3.7.4 5.7.3.8.1 5.7.3.8.2 5.7.3.8.3 5.7.3.8.4 5.7.4.1.1
5.7.4.1.2 5.7.4.1.3 5.7.4.1.4 5.7.4.2.1 5.7.4.2.2 5.7.4.2.3
5.7.4.2.4 5.7.4.3.1 5.7.4.3.2 5.7.4.3.3 5.7.4.3.4 5.7.4.4.1
5.7.4.4.2 5.7.4.4.3 5.7.4.4.4 5.7.4.5.1 5.7.4.5.2 5.7.4.5.3
5.7.4.5.4 5.7.4.6.1 5.7.4.6.2 5.7.4.6.3 5.7.4.6.4 5.7.4.7.1
5.7.4.7.2 5.7.4.7.3 5.7.4.7.4 5.7.4.8.1 5.7.4.8.2 5.7.4.8.3
5.7.4.8.4 5.8.1.1.1 5.8.1.1.2 5.8.1.1.3 5.8.1.1.4 5.8.1.2.1
5.8.1.2.2 5.8.1.2.3 5.8.1.2.4 5.8.1.3.1 5.8.1.3.2 5.8.1.3.3
5.8.1.3.4 5.8.1.4.1 5.8.1.4.2 5.8.1.4.3 5.8.1.4.4
5.8.1.5.1 5.8.1.5.2 5.8.1.5.3 5.8.1.5.4 5.8.1.6.1 5.8.1.6.2
5.8.1.6.3 5.8.1.6.4 5.8.1.7.1 5.8.1.7.2 5.8.1.7.3 5.8.1.7.4
5.8.1.8.1 5.8.1.8.2 5.8.1.8.3 5.8.1.8.4 5.8.2.1.1 5.8.2.1.2
5.8.2.1.3 5.8.2.1.4 5.8.2.2.1 5.8.2.2.2 5.8.2.2.3 5.8.2.2.4
5.8.2.3.1 5.8.2.3.2 5.8.2.3.3 5.8.2.3.4 5.8.2.4.1 5.8.2.4.2
5.8.2.4.3 5.8.2.4.4 5.8.2.5.1 5.8.2.5.2 5.8.2.5.3 5.8.2.5.4
5.8.2.6.1 5.8.2.6.2 5.8.2.6.3 5.8.2.6.4 5.8.2.7.1 5.8.2.7.2
5.8.2.7.3 5.8.2.7.4 5.8.2.8.1 5.8.2.8.2 5.8.2.8.3 5.8.2.8.4
5.8.3.1.1 5.8.3.1.2 5.8.3.1.3 5.8.3.1.4 5.8.3.2.1 5.8.3.2.2
5.8.3.2.3 5.8.3.2.4 5.8.3.3.1 5.8.3.3.2 5.8.3.3.3 5.8.3.3.4
5.8.3.4.1 5.8.3.4.2 5.8.3.4.3 5.8.3.4.4 5.8.3.5.1 5.8.3.5.2
5.8.3.5.3 5.8.3.5.4 5.8.3.6.1 5.8.3.6.2 5.8.3.6.3 5.8.3.6.4
5.8.3.7.1 5.8.3.7.2 5.8.3.7.3 5.8.3.7.4 5.8.3.8.1 5.8.3.8.2
5.8.3.8.3 5.8.3.8.4 5.8.4.1.1 5.8.4.1.2 5.8.4.1.3 5.8.4.1.4
5.8.4.2.1 5.8.4.2.2 5.8.4.2.3 5.8.4.2.4 5.8.4.3.1 5.8.4.3.2
5.8.4.3.3 5.8.4.3.4 5.8.4.4.1 5.8.4.4.2 5.8.4.4.3 5.8.4.4.4
5.8.4.5.1 5.8.4.5.2 5.8.4.5.3 5.8.4.5.4 5.8.4.6.1 5.8.4.6.2
5.8.4.6.3 5.8.4.6.4 5.8.4.7.1 5.8.4.7.2 5.8.4.7.3 5.8.4.7.4
5.8.4.8.1 5.8.4.8.2 5.8.4.8.3 5.8.4.8.4 6.1.1.1.1 6.1.1.1.2
6.1.1.1.3 6.1.1.1.4 6.1.1.2.1 6.1.1.2.2 6.1.1.2.3 6.1.1.2.4
6.1.1.3.1 6.1.1.3.2 6.1.1.3.3 6.1.1.3.4 6.1.1.4.1 6.1.1.4.2
6.1.1.4.3 6.1.1.4.4 6.1.1.5.1 6.1.1.5.2 6.1.1.5.3 6.1.1.5.4
6.1.1.6.1 6.1.1.6.2 6.1.1.6.3 6.1.1.6.4 6.1.1.7.1 6.1.1.7.2
6.1.1.7.3 6.1.1.7.4 6.1.1.8.1 6.1.1.8.2 6.1.1.8.3 6.1.1.8.4
6.1.2.1.1 6.1.2.1.2 6.1.2.1.3 6.1.2.1.4 6.1.2.2.1 6.1.2.2.2
6.1.2.2.3 6.1.2.2.4 6.1.2.3.1 6.1.2.3.2 6.1.2.3.3 6.1.2.3.4
6.1.2.4.1 6.1.2.4.2 6.1.2.4.3 6.1.2.4.4 6.1.2.5.1 6.1.2.5.2
6.1.2.5.3 6.1.2.5.4 6.1.2.6.1 6.1.2.6.2 6.1.2.6.3 6.1.2.6.4
6.1.2.7.1 6.1.2.7.2 6.1.2.7.3 6.1.2.7.4 6.1.2.8.1 6.1.2.8.2
6.1.2.8.3 6.1.2.8.4 6.1.3.1.1 6.1.3.1.2 6.1.3.1.3 6.1.3.1.4
6.1.3.2.1 6.1.3.2.2 6.1.3.2.3 6.1.3.2.4 6.1.3.3.1 6.1.3.3.2
6.1.3.3.3 6.1.3.3.4 6.1.3.4.1 6.1.3.4.2 6.1.3.4.3 6.1.3.4.4
6.1.3.5.1 6.1.3.5.2 6.1.3.5.3 6.1.3.5.4 6.1.3.6.1 6.1.3.6.2
6.1.3.6.3 6.1.3.6.4 6.1.3.7.1 6.1.3.7.2 6.1.3.7.3 6.1.3.7.4
6.1.3.8.1 6.1.3.8.2 6.1.3.8.3 6.1.3.8.4 6.1.4.1.1 6.1.4.1.2
6.1.4.1.3 6.1.4.1.4 6.1.4.2.1 6.1.4.2.2 6.1.4.2.3 6.1.4.2.4
6.1.4.3.1 6.1.4.3.2 6.1.4.3.3 6.1.4.3.4 6.1.4.4.1 6.1.4.4.2
6.1.4.4.3 6.1.4.4.4 6.1.4.5.1 6.1.4.5.2 6.1.4.5.3 6.1.4.5.4
6.1.4.6.1 6.1.4.6.2 6.1.4.6.3 6.1.4.6.4 6.1.4.7.1 6.1.4.7.2
6.1.4.7.3 6.1.4.7.4 6.1.4.8.1 6.1.4.8.2 6.1.4.8.3 6.1.4.8.4
6.2.1.1.1 6.2.1.1.2 6.2.1.1.3 6.2.1.1.4 6.2.1.2.1 6.2.1.2.2
6.2.1.2.3 6.2.1.2.4 6.2.1.3.1 6.2.1.3.2 6.2.1.3.3 6.2.1.3.4
6.2.1.4.1 6.2.1.4.2 6.2.1.4.3 6.2.1.4.4 6.2.1.5.1 6.2.1.5.2
6.2.1.5.3 6.2.1.5.4 6.2.1.6.1 6.2.1.6.2 6.2.1.6.3 6.2.1.6.4
6.2.1.7.1 6.2.1.7.2 6.2.1.7.3 6.2.1.7.4 6.2.1.8.1 6.2.1.8.2
6.2.1.8.3 6.2.1.8.4 6.2.2.1.1 6.2.2.1.2 6.2.2.1.3 6.2.2.1.4
6.2.2.2.1 6.2.2.2.2 6.2.2.2.3 6.2.2.2.4 6.2.2.3.1 6.2.2.3.2
6.2.2.3.3 6.2.2.3.4 6.2.2.4.1 6.2.2.4.2 6.2.2.4.3 6.2.2.4.4
6.2.2.5.1 6.2.2.5.2 6.2.2.5.3 6.2.2.5.4 6.2.2.6.1 6.2.2.6.2
6.2.2.6.3 6.2.2.6.4 6.2.2.7.1 6.2.2.7.2 6.2.2.7.3 6.2.2.7.4
6.2.2.8.1 6.2.2.8.2 6.2.2.8.3 6.2.2.8.4 6.2.3.1.1 6.2.3.1.2
6.2.3.1.3 6.2.3.1.4 6.2.3.2.1 6.2.3.2.2 6.2.3.2.3 6.2.3.2.4
6.2.3.3.1 6.2.3.3.2 6.2.3.3.3 6.2.3.3.4 6.2.3.4.1 6.2.3.4.2
6.2.3.4.3 6.2.3.4.4 6.2.3.5.1 6.2.3.5.2 6.2.3.5.3 6.2.3.5.4
6.2.3.6.1 6.2.3.6.2 6.2.3.6.3 6.2.3.6.4 6.2.3.7.1 6.2.3.7.2
6.2.3.7.3 6.2.3.7.4 6.2.3.8.1 6.2.3.8.2 6.2.3.8.3 6.2.3.8.4
6.2.4.1.1 6.2.4.1.2 6.2.4.1.3 6.2.4.1.4 6.2.4.2.1 6.2.4.2.2
6.2.4.2.3 6.2.4.2.4 6.2.4.3.1 6.2.4.3.2 6.2.4.3.3 6.2.4.3.4
6.2.4.4.1 6.2.4.4.2 6.2.4.4.3 6.2.4.4.4 6.2.4.5.1 6.2.4.5.2
6.2.4.5.3 6.2.4.5.4 6.2.4.6.1 6.2.4.6.2 6.2.4.6.3 6.2.4.6.4
6.2.4.7.1 6.2.4.7.2 6.2.4.7.3 6.2.4.7.4 6.2.4.8.1 6.2.4.8.2
6.2.4.8.3 6.2.4.8.4 6.3.1.1.1 6.3.1.1.2 6.3.1.1.3 6.3.1.1.4
6.3.1.2.1 6.3.1.2.2 6.3.1.2.3 6.3.1.2.4 6.3.1.3.1 6.3.1.3.2
6.3.1.3.3 6.3.1.3.4 6.3.1.4.1 6.3.1.4.2 6.3.1.4.3 6.3.1.4.4
6.3.1.5.1 6.3.1.5.2 6.3.1.5.3 6.3.1.5.4 6.3.1.6.1 6.3.1.6.2
6.3.1.6.3 6.3.1.6.4 6.3.1.7.1 6.3.1.7.2 6.3.1.7.3 6.3.1.7.4
6.3.1.8.1 6.3.1.8.2 6.3.1.8.3 6.3.1.8.4 6.3.2.1.1 6.3.2.1.2
6.3.2.1.3 6.3.2.1.4 6.3.2.2.1 6.3.2.2.2 6.3.2.2.3 6.3.2.2.4
6.3.2.3.1 6.3.2.3.2 6.3.2.3.3 6.3.2.3.4 6.3.2.4.1 6.3.2.4.2
6.3.2.4.3 6.3.2.4.4 6.3.2.5.1 6.3.2.5.2 6.3.2.5.3 6.3.2.5.4
6.3.2.6.1 6.3.2.6.2 6.3.2.6.3 6.3.2.6.4 6.3.2.7.1 6.3.2.7.2
6.3.2.7.3 6.3.2.7.4 6.3.2.8.1 6.3.2.8.2 6.3.2.8.3 6.3.2.8.4
6.3.3.1.1 6.3.3.1.2 6.3.3.1.3 6.3.3.1.4 6.3.3.2.1 6.3.3.2.2
6.3.3.2.3 6.3.3.2.4 6.3.3.3.1 6.3.3.3.2 6.3.3.3.3 6.3.3.3.4
6.3.3.4.1 6.3.3.4.2 6.3.3.4.3 6.3.3.4.4 6.3.3.5.1 6.3.3.5.2
6.3.3.5.3 6.3.3.5.4 6.3.3.6.1 6.3.3.6.2 6.3.3.6.3 6.3.3.6.4
6.3.3.7.1 6.3.3.7.2 6.3.3.7.3 6.3.3.7.4 6.3.3.8.1 6.3.3.8.2
6.3.3.8.3 6.3.3.8.4 6.3.4.1.1 6.3.4.1.2 6.3.4.1.3 6.3.4.1.4
6.3.4.2.1 6.3.4.2.2 6.3.4.2.3 6.3.4.2.4 6.3.4.3.1 6.3.4.3.2
6.3.4.3.3 6.3.4.3.4 6.3.4.4.1 6.3.4.4.2 6.3.4.4.3 6.3.4.4.4
6.3.4.5.1 6.3.4.5.2 6.3.4.5.3 6.3.4.5.4 6.3.4.6.1 6.3.4.6.2
6.3.4.6.3 6.3.4.6.4 6.3.4.7.1 6.3.4.7.2 6.3.4.7.3 6.3.4.7.4
6.3.4.8.1 6.3.4.8.2 6.3.4.8.3 6.3.4.8.4 6.4.1.1.1 6.4.1.1.2
6.4.1.1.3 6.4.1.1.4 6.4.1.2.1 6.4.1.2.2 6.4.1.2.3 6.4.1.2.4
6.4.1.3.1 6.4.1.3.2 6.4.1.3.3 6.4.1.3.4 6.4.1.4.1 6.4.1.4.2
6.4.1.4.3 6.4.1.4.4 6.4.1.5.1 6.4.1.5.2 6.4.1.5.3 6.4.1.5.4
6.4.1.6.1 6.4.1.6.2 6.4.1.6.3 6.4.1.6.4 6.4.1.7.1 6.4.1.7.2
6.4.1.7.3 6.4.1.7.4 6.4.1.8.1 6.4.1.8.2 6.4.1.8.3 6.4.1.8.4
6.4.2.1.1 6.4.2.1.2 6.4.2.1.3 6.4.2.1.4 6.4.2.2.1 6.4.2.2.2
6.4.2.2.3 6.4.2.2.4 6.4.2.3.1 6.4.2.3.2 6.4.2.3.3 6.4.2.3.4
6.4.2.4.1 6.4.2.4.2 6.4.2.4.3 6.4.2.4.4 6.4.2.5.1 6.4.2.5.2
6.4.2.5.3 6.4.2.5.4 6.4.2.6.1 6.4.2.6.2 6.4.2.6.3 6.4.2.6.4
6.4.2.7.1 6.4.2.7.2 6.4.2.7.3 6.4.2.7.4 6.4.2.8.1 6.4.2.8.2
6.4.2.8.3 6.4.2.8.4 6.4.3.1.1 6.4.3.1.2 6.4.3.1.3 6.4.3.1.4
6.4.3.2.1 6.4.3.2.2 6.4.3.2.3 6.4.3.2.4 6.4.3.3.1 6.4.3.3.2
6.4.3.3.3 6.4.3.3.4 6.4.3.4.1 6.4.3.4.2 6.4.3.4.3 6.4.3.4.4
6.4.3.5.1 6.4.3.5.2 6.4.3.5.3 6.4.3.5.4 6.4.3.6.1 6.4.3.6.2
6.4.3.6.3 6.4.3.6.4 6.4.3.7.1 6.4.3.7.2 6.4.3.7.3 6.4.3.7.4
6.4.3.8.1 6.4.3.8.2 6.4.3.8.3 6.4.3.8.4 6.4.4.1.1 6.4.4.1.2
6.4.4.1.3 6.4.4.1.4 6.4.4.2.1 6.4.4.2.2 6.4.4.2.3 6.4.4.2.4
6.4.4.3.1 6.4.4.3.2 6.4.4.3.3 6.4.4.3.4 6.4.4.4.1 6.4.4.4.2
6.4.4.4.3 6.4.4.4.4 6.4.4.5.1 6.4.4.5.2 6.4.4.5.3 6.4.4.5.4
6.4.4.6.1 6.4.4.6.2 6.4.4.6.3 6.4.4.6.4 6.4.4.7.1 6.4.4.7.2
6.4.4.7.3 6.4.4.7.4 6.4.4.8.1 6.4.4.8.2 6.4.4.8.3 6.4.4.8.4
6.5.1.1.1 6.5.1.1.2 6.5.1.1.3 6.5.1.1.4 6.5.1.2.1 6.5.1.2.2
6.5.1.2.3 6.5.1.2.4 6.5.1.3.1 6.5.1.3.2 6.5.1.3.3 6.5.1.3.4
6.5.1.4.1 6.5.1.4.2 6.5.1.4.3 6.5.1.4.4 6.5.1.5.1 6.5.1.5.2
6.5.1.5.3 6.5.1.5.4 6.5.1.6.1 6.5.1.6.2 6.5.1.6.3 6.5.1.6.4
6.5.1.7.1 6.5.1.7.2 6.5.1.7.3 6.5.1.7.4 6.5.1.8.1 6.5.1.8.2
6.5.1.8.3 6.5.1.8.4 6.5.2.1.1 6.5.2.1.2 6.5.2.1.3 6.5.2.1.4
6.5.2.2.1 6.5.2.2.2 6.5.2.2.3 6.5.2.2.4 6.5.2.3.1 6.5.2.3.2
6.5.2.3.3 6.5.2.3.4 6.5.2.4.1 6.5.2.4.2 6.5.2.4.3 6.5.2.4.4
6.5.2.5.1 6.5.2.5.2 6.5.2.5.3 6.5.2.5.4 6.5.2.6.1 6.5.2.6.2
6.5.2.6.3 6.5.2.6.4 6.5.2.7.1 6.5.2.7.2 6.5.2.7.3 6.5.2.7.4
6.5.2.8.1 6.5.2.8.2 6.5.2.8.3 6.5.2.8.4 6.5.3.1.1 6.5.3.1.2
6.5.3.1.3 6.5.3.1.4 6.5.3.2.1 6.5.3.2.2 6.5.3.2.3 6.5.3.2.4
6.5.3.3.1 6.5.3.3.2 6.5.3.3.3 6.5.3.3.4 6.5.3.4.1 6.5.3.4.2
6.5.3.4.3 6.5.3.4.4 6.5.3.5.1 6.5.3.5.2 6.5.3.5.3 6.5.3.5.4
6.5.3.6.1 6.5.3.6.2 6.5.3.6.3 6.5.3.6.4 6.5.3.7.1 6.5.3.7.2
6.5.3.7.3 6.5.3.7.4 6.5.3.8.1 6.5.3.8.2 6.5.3.8.3 6.5.3.8.4
6.5.4.1.1 6.5.4.1.2 6.5.4.1.3 6.5.4.1.4 6.5.4.2.1 6.5.4.2.2
6.5.4.2.3 6.5.4.2.4 6.5.4.3.1 6.5.4.3.2 6.5.4.3.3 6.5.4.3.4
6.5.4.4.1 6.5.4.4.2 6.5.4.4.3 6.5.4.4.4 6.5.4.5.1 6.5.4.5.2
6.5.4.5.3 6.5.4.5.4 6.5.4.6.1 6.5.4.6.2 6.5.4.6.3 6.5.4.6.4
6.5.4.7.1 6.5.4.7.2 6.5.4.7.3 6.5.4.7.4 6.5.4.8.1 6.5.4.8.2
6.5.4.8.3 6.5.4.8.4 6.6.1.1.1 6.6.1.1.2 6.6.1.1.3 6.6.1.1.4
6.6.1.2.1 6.6.1.2.2 6.6.1.2.3 6.6.1.2.4 6.6.1.3.1 6.6.1.3.2
6.6.1.3.3 6.6.1.3.4 6.6.1.4.1 6.6.1.4.2 6.6.1.4.3 6.6.1.4.4
6.6.1.5.1 6.6.1.5.2 6.6.1.5.3 6.6.1.5.4 6.6.1.6.1 6.6.1.6.2
6.6.1.6.3 6.6.1.6.4 6.6.1.7.1 6.6.1.7.2 6.6.1.7.3 6.6.1.7.4
6.6.1.8.1 6.6.1.8.2 6.6.1.8.3 6.6.1.8.4 6.6.2.1.1 6.6.2.1.2
6.6.2.1.3 6.6.2.1.4 6.6.2.2.1 6.6.2.2.2 6.6.2.2.3 6.6.2.2.4
6.6.2.3.1 6.6.2.3.2 6.6.2.3.3 6.6.2.3.4 6.6.2.4.1 6.6.2.4.2
6.6.2.4.3 6.6.2.4.4 6.6.2.5.1 6.6.2.5.2 6.6.2.5.3 6.6.2.5.4
6.6.2.6.1 6.6.2.6.2 6.6.2.6.3 6.6.2.6.4 6.6.2.7.1 6.6.2.7.2
6.6.2.7.3 6.6.2.7.4 6.6.2.8.1 6.6.2.8.2 6.6.2.8.3 6.6.2.8.4
6.6.3.1.1 6.6.3.1.2 6.6.3.1.3 6.6.3.1.4 6.6.3.2.1 6.6.3.2.2
6.6.3.2.3 6.6.3.2.4 6.6.3.3.1 6.6.3.3.2 6.6.3.3.3 6.6.3.3.4
6.6.3.4.1 6.6.3.4.2 6.6.3.4.3 6.6.3.4.4 6.6.3.5.1 6.6.3.5.2
6.6.3.5.3 6.6.3.5.4 6.6.3.6.1 6.6.3.6.2 6.6.3.6.3 6.6.3.6.4
6.6.3.7.1 6.6.3.7.2 6.6.3.7.3 6.6.3.7.4 6.6.3.8.1 6.6.3.8.2
6.6.3.8.3 6.6.3.8.4 6.6.4.1.1 6.6.4.1.2 6.6.4.1.3 6.6.4.1.4
6.6.4.2.1 6.6.4.2.2 6.6.4.2.3 6.6.4.2.4 6.6.4.3.1 6.6.4.3.2
6.6.4.3.3 6.6.4.3.4 6.6.4.4.1 6.6.4.4.2 6.6.4.4.3 6.6.4.4.4
6.6.4.5.1 6.6.4.5.2 6.6.4.5.3 6.6.4.5.4 6.6.4.6.1 6.6.4.6.2
6.6.4.6.3 6.6.4.6.4 6.6.4.7.1 6.6.4.7.2 6.6.4.7.3 6.6.4.7.4
6.6.4.8.1 6.6.4.8.2 6.6.4.8.3 6.6.4.8.4 6.7.1.1.1 6.7.1.1.2
6.7.1.1.3 6.7.1.1.4 6.7.1.2.1 6.7.1.2.2 6.7.1.2.3 6.7.1.2.4
6.7.1.3.1 6.7.1.3.2 6.7.1.3.3 6.7.1.3.4 6.7.1.4.1 6.7.1.4.2
6.7.1.4.3 6.7.1.4.4 6.7.1.5.1 6.7.1.5.2 6.7.1.5.3 6.7.1.5.4
6.7.1.6.1 6.7.1.6.2 6.7.1.6.3 6.7.1.6.4 6.7.1.7.1 6.7.1.7.2
6.7.1.7.3 6.7.1.7.4 6.7.1.8.1 6.7.1.8.2 6.7.1.8.3 6.7.1.8.4
6.7.2.1.1 6.7.2.1.2 6.7.2.1.3 6.7.2.1.4 6.7.2.2.1 6.7.2.2.2
6.7.2.2.3 6.7.2.2.4 6.7.2.3.1 6.7.2.3.2 6.7.2.3.3 6.7.2.3.4
6.7.2.4.1 6.7.2.4.2 6.7.2.4.3 6.7.2.4.4 6.7.2.5.1 6.7.2.5.2
6.7.2.5.3 6.7.2.5.4 6.7.2.6.1 6.7.2.6.2 6.7.2.6.3 6.7.2.6.4
6.7.2.7.1 6.7.2.7.2 6.7.2.7.3 6.7.2.7.4 6.7.2.8.1 6.7.2.8.2
6.7.2.8.3 6.7.2.8.4 6.7.3.1.1 6.7.3.1.2 6.7.3.1.3 6.7.3.1.4
6.7.3.2.1 6.7.3.2.2 6.7.3.2.3 6.7.3.2.4 6.7.3.3.1 6.7.3.3.2
6.7.3.3.3 6.7.3.3.4 6.7.3.4.1 6.7.3.4.2 6.7.3.4.3 6.7.3.4.4
6.7.3.5.1 6.7.3.5.2 6.7.3.5.3 6.7.3.5.4 6.7.3.6.1 6.7.3.6.2
6.7.3.6.3 6.7.3.6.4 6.7.3.7.1 6.7.3.7.2 6.7.3.7.3 6.7.3.7.4
6.7.3.8.1 6.7.3.8.2 6.7.3.8.3 6.7.3.8.4 6.7.4.1.1 6.7.4.1.2
6.7.4.1.3 6.7.4.1.4 6.7.4.2.1 6.7.4.2.2 6.7.4.2.3 6.7.4.2.4
6.7.4.3.1 6.7.4.3.2 6.7.4.3.3 6.7.4.3.4 6.7.4.4.1 6.7.4.4.2
6.7.4.4.3 6.7.4.4.4 6.7.4.5.1 6.7.4.5.2 6.7.4.5.3 6.7.4.5.4
6.7.4.6.1 6.7.4.6.2 6.7.4.6.3 6.7.4.6.4 6.7.4.7.1 6.7.4.7.2
6.7.4.7.3 6.7.4.7.4 6.7.4.8.1 6.7.4.8.2 6.7.4.8.3
6.7.4.8.4 6.8.1.1.1 6.8.1.1.2 6.8.1.1.3 6.8.1.1.4 6.8.1.2.1
6.8.1.2.2 6.8.1.2.3 6.8.1.2.4 6.8.1.3.1 6.8.1.3.2 6.8.1.3.3
6.8.1.3.4 6.8.1.4.1 6.8.1.4.2 6.8.1.4.3 6.8.1.4.4 6.8.1.5.1
6.8.1.5.2 6.8.1.5.3 6.8.1.5.4 6.8.1.6.1 6.8.1.6.2 6.8.1.6.3
6.8.1.6.4 6.8.1.7.1 6.8.1.7.2 6.8.1.7.3 6.8.1.7.4 6.8.1.8.1
6.8.1.8.2 6.8.1.8.3 6.8.1.8.4 6.8.2.1.1 6.8.2.1.2 6.8.2.1.3
6.8.2.1.4 6.8.2.2.1 6.8.2.2.2 6.8.2.2.3 6.8.2.2.4 6.8.2.3.1
6.8.2.3.2 6.8.2.3.3 6.8.2.3.4 6.8.2.4.1 6.8.2.4.2 6.8.2.4.3
6.8.2.4.4 6.8.2.5.1 6.8.2.5.2 6.8.2.5.3 6.8.2.5.4 6.8.2.6.1
6.8.2.6.2 6.8.2.6.3 6.8.2.6.4 6.8.2.7.1 6.8.2.7.2 6.8.2.7.3
6.8.2.7.4 6.8.2.8.1 6.8.2.8.2 6.8.2.8.3 6.8.2.8.4 6.8.3.1.1
6.8.3.1.2 6.8.3.1.3 6.8.3.1.4 6.8.3.2.1 6.8.3.2.2 6.8.3.2.3
6.8.3.2.4 6.8.3.3.1 6.8.3.3.2 6.8.3.3.3 6.8.3.3.4 6.8.3.4.1
6.8.3.4.2 6.8.3.4.3 6.8.3.4.4 6.8.3.5.1 6.8.3.5.2 6.8.3.5.3
6.8.3.5.4 6.8.3.6.1 6.8.3.6.2 6.8.3.6.3 6.8.3.6.4 6.8.3.7.1
6.8.3.7.2 6.8.3.7.3 6.8.3.7.4 6.8.3.8.1 6.8.3.8.2 6.8.3.8.3
6.8.3.8.4 6.8.4.1.1 6.8.4.1.2 6.8.4.1.3 6.8.4.1.4 6.8.4.2.1
6.8.4.2.2 6.8.4.2.3 6.8.4.2.4 6.8.4.3.1 6.8.4.3.2 6.8.4.3.3
6.8.4.3.4 6.8.4.4.1 6.8.4.4.2 6.8.4.4.3 6.8.4.4.4 6.8.4.5.1
6.8.4.5.2 6.8.4.5.3 6.8.4.5.4 6.8.4.6.1 6.8.4.6.2 6.8.4.6.3
6.8.4.6.4 6.8.4.7.1 6.8.4.7.2 6.8.4.7.3 6.8.4.7.4 6.8.4.8.1
6.8.4.8.2 6.8.4.8.3 6.8.4.8.4 7.1.1.1.1 7.1.1.1.2 7.1.1.1.3
7.1.1.1.4 7.1.1.2.1 7.1.1.2.2 7.1.1.2.3 7.1.1.2.4 7.1.1.3.1
7.1.1.3.2 7.1.1.3.3 7.1.1.3.4 7.1.1.4.1 7.1.1.4.2 7.1.1.4.3
7.1.1.4.4 7.1.1.5.1 7.1.1.5.2 7.1.1.5.3 7.1.1.5.4 7.1.1.6.1
7.1.1.6.2 7.1.1.6.3 7.1.1.6.4 7.1.1.7.1 7.1.1.7.2 7.1.1.7.3
7.1.1.7.4 7.1.1.8.1 7.1.1.8.2 7.1.1.8.3 7.1.1.8.4 7.1.2.1.1
7.1.2.1.2 7.1.2.1.3 7.1.2.1.4 7.1.2.2.1 7.1.2.2.2 7.1.2.2.3
7.1.2.2.4 7.1.2.3.1 7.1.2.3.2 7.1.2.3.3 7.1.2.3.4 7.1.2.4.1
7.1.2.4.2 7.1.2.4.3 7.1.2.4.4 7.1.2.5.1 7.1.2.5.2 7.1.2.5.3
7.1.2.5.4 7.1.2.6.1 7.1.2.6.2 7.1.2.6.3 7.1.2.6.4 7.1.2.7.1
7.1.2.7.2 7.1.2.7.3 7.1.2.7.4 7.1.2.8.1 7.1.2.8.2 7.1.2.8.3
7.1.2.8.4 7.1.3.1.1 7.1.3.1.2 7.1.3.1.3 7.1.3.1.4 7.1.3.2.1
7.1.3.2.2 7.1.3.2.3 7.1.3.2.4 7.1.3.3.1 7.1.3.3.2 7.1.3.3.3
7.1.3.3.4 7.1.3.4.1 7.1.3.4.2 7.1.3.4.3 7.1.3.4.4 7.1.3.5.1
7.1.3.5.2 7.1.3.5.3 7.1.3.5.4 7.1.3.6.1 7.1.3.6.2 7.1.3.6.3
7.1.3.6.4 7.1.3.7.1 7.1.3.7.2 7.1.3.7.3 7.1.3.7.4 7.1.3.8.1
7.1.3.8.2 7.1.3.8.3 7.1.3.8.4 7.1.4.1.1 7.1.4.1.2 7.1.4.1.3
7.1.4.1.4 7.1.4.2.1 7.1.4.2.2 7.1.4.2.3 7.1.4.2.4 7.1.4.3.1
7.1.4.3.2 7.1.4.3.3 7.1.4.3.4 7.1.4.4.1 7.1.4.4.2 7.1.4.4.3
7.1.4.4.4 7.1.4.5.1 7.1.4.5.2 7.1.4.5.3 7.1.4.5.4 7.1.4.6.1
7.1.4.6.2 7.1.4.6.3 7.1.4.6.4 7.1.4.7.1 7.1.4.7.2 7.1.4.7.3
7.1.4.7.4 7.1.4.8.1 7.1.4.8.2 7.1.4.8.3 7.1.4.8.4 7.2.1.1.1
7.2.1.1.2 7.2.1.1.3 7.2.1.1.4 7.2.1.2.1 7.2.1.2.2 7.2.1.2.3
7.2.1.2.4 7.2.1.3.1 7.2.1.3.2 7.2.1.3.3 7.2.1.3.4 7.2.1.4.1
7.2.1.4.2 7.2.1.4.3 7.2.1.4.4 7.2.1.5.1 7.2.1.5.2 7.2.1.5.3
7.2.1.5.4 7.2.1.6.1 7.2.1.6.2 7.2.1.6.3 7.2.1.6.4 7.2.1.7.1
7.2.1.7.2 7.2.1.7.3 7.2.1.7.4 7.2.1.8.1 7.2.1.8.2 7.2.1.8.3
7.2.1.8.4 7.2.2.1.1 7.2.2.1.2 7.2.2.1.3 7.2.2.1.4 7.2.2.2.1
7.2.2.2.2 7.2.2.2.3 7.2.2.2.4 7.2.2.3.1 7.2.2.3.2 7.2.2.3.3
7.2.2.3.4 7.2.2.4.1 7.2.2.4.2 7.2.2.4.3 7.2.2.4.4 7.2.2.5.1
7.2.2.5.2 7.2.2.5.3 7.2.2.5.4 7.2.2.6.1 7.2.2.6.2 7.2.2.6.3
7.2.2.6.4 7.2.2.7.1 7.2.2.7.2 7.2.2.7.3 7.2.2.7.4 7.2.2.8.1
7.2.2.8.2 7.2.2.8.3 7.2.2.8.4 7.2.3.1.1 7.2.3.1.2 7.2.3.1.3
7.2.3.1.4 7.2.3.2.1 7.2.3.2.2 7.2.3.2.3 7.2.3.2.4 7.2.3.3.1
7.2.3.3.2 7.2.3.3.3 7.2.3.3.4 7.2.3.4.1 7.2.3.4.2 7.2.3.4.3
7.2.3.4.4 7.2.3.5.1 7.2.3.5.2 7.2.3.5.3 7.2.3.5.4 7.2.3.6.1
7.2.3.6.2 7.2.3.6.3 7.2.3.6.4 7.2.3.7.1 7.2.3.7.2 7.2.3.7.3
7.2.3.7.4 7.2.3.8.1 7.2.3.8.2 7.2.3.8.3 7.2.3.8.4 7.2.4.1.1
7.2.4.1.2 7.2.4.1.3 7.2.4.1.4 7.2.4.2.1 7.2.4.2.2 7.2.4.2.3
7.2.4.2.4 7.2.4.3.1 7.2.4.3.2 7.2.4.3.3 7.2.4.3.4 7.2.4.4.1
7.2.4.4.2 7.2.4.4.3 7.2.4.4.4 7.2.4.5.1 7.2.4.5.2 7.2.4.5.3
7.2.4.5.4 7.2.4.6.1 7.2.4.6.2 7.2.4.6.3 7.2.4.6.4 7.2.4.7.1
7.2.4.7.2 7.2.4.7.3 7.2.4.7.4 7.2.4.8.1 7.2.4.8.2 7.2.4.8.3
7.2.4.8.4 7.3.1.1.1 7.3.1.1.2 7.3.1.1.3 7.3.1.1.4 7.3.1.2.1
7.3.1.2.2 7.3.1.2.3 7.3.1.2.4 7.3.1.3.1 7.3.1.3.2 7.3.1.3.3
7.3.1.3.4 7.3.1.4.1 7.3.1.4.2 7.3.1.4.3 7.3.1.4.4 7.3.1.5.1
7.3.1.5.2 7.3.1.5.3 7.3.1.5.4 7.3.1.6.1 7.3.1.6.2 7.3.1.6.3
7.3.1.6.4 7.3.1.7.1 7.3.1.7.2 7.3.1.7.3 7.3.1.7.4 7.3.1.8.1
7.3.1.8.2 7.3.1.8.3 7.3.1.8.4 7.3.2.1.1 7.3.2.1.2 7.3.2.1.3
7.3.2.1.4 7.3.2.2.1 7.3.2.2.2 7.3.2.2.3 7.3.2.2.4 7.3.2.3.1
7.3.2.3.2 7.3.2.3.3 7.3.2.3.4 7.3.2.4.1 7.3.2.4.2 7.3.2.4.3
7.3.2.4.4 7.3.2.5.1 7.3.2.5.2 7.3.2.5.3 7.3.2.5.4 7.3.2.6.1
7.3.2.6.2 7.3.2.6.3 7.3.2.6.4 7.3.2.7.1 7.3.2.7.2 7.3.2.7.3
7.3.2.7.4 7.3.2.8.1 7.3.2.8.2 7.3.2.8.3 7.3.2.8.4 7.3.3.1.1
7.3.3.1.2 7.3.3.1.3 7.3.3.1.4 7.3.3.2.1 7.3.3.2.2 7.3.3.2.3
7.3.3.2.4 7.3.3.3.1 7.3.3.3.2 7.3.3.3.3 7.3.3.3.4 7.3.3.4.1
7.3.3.4.2 7.3.3.4.3 7.3.3.4.4 7.3.3.5.1 7.3.3.5.2 7.3.3.5.3
7.3.3.5.4 7.3.3.6.1 7.3.3.6.2 7.3.3.6.3 7.3.3.6.4 7.3.3.7.1
7.3.3.7.2 7.3.3.7.3 7.3.3.7.4 7.3.3.8.1 7.3.3.8.2 7.3.3.8.3
7.3.3.8.4 7.3.4.1.1 7.3.4.1.2 7.3.4.1.3 7.3.4.1.4 7.3.4.2.1
7.3.4.2.2 7.3.4.2.3 7.3.4.2.4 7.3.4.3.1 7.3.4.3.2 7.3.4.3.3
7.3.4.3.4 7.3.4.4.1 7.3.4.4.2 7.3.4.4.3 7.3.4.4.4 7.3.4.5.1
7.3.4.5.2 7.3.4.5.3 7.3.4.5.4 7.3.4.6.1 7.3.4.6.2 7.3.4.6.3
7.3.4.6.4 7.3.4.7.1 7.3.4.7.2 7.3.4.7.3 7.3.4.7.4 7.3.4.8.1
7.3.4.8.2 7.3.4.8.3 7.3.4.8.4 7.4.1.1.1 7.4.1.1.2 7.4.1.1.3
7.4.1.1.4 7.4.1.2.1 7.4.1.2.2 7.4.1.2.3 7.4.1.2.4 7.4.1.3.1
7.4.1.3.2 7.4.1.3.3 7.4.1.3.4 7.4.1.4.1 7.4.1.4.2 7.4.1.4.3
7.4.1.4.4 7.4.1.5.1 7.4.1.5.2 7.4.1.5.3 7.4.1.5.4 7.4.1.6.1
7.4.1.6.2 7.4.1.6.3 7.4.1.6.4 7.4.1.7.1 7.4.1.7.2 7.4.1.7.3
7.4.1.7.4 7.4.1.8.1 7.4.1.8.2 7.4.1.8.3 7.4.1.8.4 7.4.2.1.1
7.4.2.1.2 7.4.2.1.3 7.4.2.1.4 7.4.2.2.1 7.4.2.2.2 7.4.2.2.3
7.4.2.2.4 7.4.2.3.1 7.4.2.3.2 7.4.2.3.3 7.4.2.3.4 7.4.2.4.1
7.4.2.4.2 7.4.2.4.3 7.4.2.4.4 7.4.2.5.1 7.4.2.5.2 7.4.2.5.3
7.4.2.5.4 7.4.2.6.1 7.4.2.6.2 7.4.2.6.3 7.4.2.6.4 7.4.2.7.1
7.4.2.7.2 7.4.2.7.3 7.4.2.7.4 7.4.2.8.1 7.4.2.8.2 7.4.2.8.3
7.4.2.8.4 7.4.3.1.1 7.4.3.1.2 7.4.3.1.3 7.4.3.1.4 7.4.3.2.1
7.4.3.2.2 7.4.3.2.3 7.4.3.2.4 7.4.3.3.1 7.4.3.3.2 7.4.3.3.3
7.4.3.3.4 7.4.3.4.1 7.4.3.4.2 7.4.3.4.3 7.4.3.4.4 7.4.3.5.1
7.4.3.5.2 7.4.3.5.3 7.4.3.5.4 7.4.3.6.1 7.4.3.6.2 7.4.3.6.3
7.4.3.6.4 7.4.3.7.1 7.4.3.7.2 7.4.3.7.3 7.4.3.7.4 7.4.3.8.1
7.4.3.8.2 7.4.3.8.3 7.4.3.8.4 7.4.4.1.1 7.4.4.1.2 7.4.4.1.3
7.4.4.1.4 7.4.4.2.1 7.4.4.2.2 7.4.4.2.3 7.4.4.2.4 7.4.4.3.1
7.4.4.3.2 7.4.4.3.3 7.4.4.3.4 7.4.4.4.1 7.4.4.4.2 7.4.4.4.3
7.4.4.4.4 7.4.4.5.1 7.4.4.5.2 7.4.4.5.3 7.4.4.5.4 7.4.4.6.1
7.4.4.6.2 7.4.4.6.3 7.4.4.6.4 7.4.4.7.1 7.4.4.7.2 7.4.4.7.3
7.4.4.7.4 7.4.4.8.1 7.4.4.8.2 7.4.4.8.3 7.4.4.8.4 7.5.1.1.1
7.5.1.1.2 7.5.1.1.3 7.5.1.1.4 7.5.1.2.1 7.5.1.2.2 7.5.1.2.3
7.5.1.2.4 7.5.1.3.1 7.5.1.3.2 7.5.1.3.3 7.5.1.3.4 7.5.1.4.1
7.5.1.4.2 7.5.1.4.3 7.5.1.4.4 7.5.1.5.1 7.5.1.5.2 7.5.1.5.3
7.5.1.5.4 7.5.1.6.1 7.5.1.6.2 7.5.1.6.3 7.5.1.6.4 7.5.1.7.1
7.5.1.7.2 7.5.1.7.3 7.5.1.7.4 7.5.1.8.1 7.5.1.8.2 7.5.1.8.3
7.5.1.8.4 7.5.2.1.1 7.5.2.1.2 7.5.2.1.3 7.5.2.1.4 7.5.2.2.1
7.5.2.2.2 7.5.2.2.3 7.5.2.2.4 7.5.2.3.1 7.5.2.3.2 7.5.2.3.3
7.5.2.3.4 7.5.2.4.1 7.5.2.4.2 7.5.2.4.3 7.5.2.4.4 7.5.2.5.1
7.5.2.5.2 7.5.2.5.3 7.5.2.5.4 7.5.2.6.1 7.5.2.6.2 7.5.2.6.3
7.5.2.6.4 7.5.2.7.1 7.5.2.7.2 7.5.2.7.3 7.5.2.7.4 7.5.2.8.1
7.5.2.8.2 7.5.2.8.3 7.5.2.8.4 7.5.3.1.1 7.5.3.1.2 7.5.3.1.3
7.5.3.1.4 7.5.3.2.1 7.5.3.2.2 7.5.3.2.3 7.5.3.2.4 7.5.3.3.1
7.5.3.3.2 7.5.3.3.3 7.5.3.3.4 7.5.3.4.1 7.5.3.4.2 7.5.3.4.3
7.5.3.4.4 7.5.3.5.1 7.5.3.5.2 7.5.3.5.3 7.5.3.5.4 7.5.3.6.1
7.5.3.6.2 7.5.3.6.3 7.5.3.6.4 7.5.3.7.1 7.5.3.7.2 7.5.3.7.3
7.5.3.7.4 7.5.3.8.1 7.5.3.8.2 7.5.3.8.3 7.5.3.8.4 7.5.4.1.1
7.5.4.1.2 7.5.4.1.3 7.5.4.1.4 7.5.4.2.1 7.5.4.2.2 7.5.4.2.3
7.5.4.2.4 7.5.4.3.1 7.5.4.3.2 7.5.4.3.3 7.5.4.3.4 7.5.4.4.1
7.5.4.4.2 7.5.4.4.3 7.5.4.4.4 7.5.4.5.1 7.5.4.5.2 7.5.4.5.3
7.5.4.5.4 7.5.4.6.1 7.5.4.6.2 7.5.4.6.3 7.5.4.6.4 7.5.4.7.1
7.5.4.7.2 7.5.4.7.3 7.5.4.7.4 7.5.4.8.1 7.5.4.8.2 7.5.4.8.3
7.5.4.8.4 7.6.1.1.1 7.6.1.1.2 7.6.1.1.3 7.6.1.1.4 7.6.1.2.1
7.6.1.2.2 7.6.1.2.3 7.6.1.2.4 7.6.1.3.1 7.6.1.3.2 7.6.1.3.3
7.6.1.3.4 7.6.1.4.1 7.6.1.4.2 7.6.1.4.3 7.6.1.4.4 7.6.1.5.1
7.6.1.5.2 7.6.1.5.3 7.6.1.5.4 7.6.1.6.1 7.6.1.6.2 7.6.1.6.3
7.6.1.6.4 7.6.1.7.1 7.6.1.7.2 7.6.1.7.3 7.6.1.7.4 7.6.1.8.1
7.6.1.8.2 7.6.1.8.3 7.6.1.8.4 7.6.2.1.1 7.6.2.1.2 7.6.2.1.3
7.6.2.1.4 7.6.2.2.1 7.6.2.2.2 7.6.2.2.3 7.6.2.2.4 7.6.2.3.1
7.6.2.3.2 7.6.2.3.3 7.6.2.3.4 7.6.2.4.1 7.6.2.4.2 7.6.2.4.3
7.6.2.4.4 7.6.2.5.1 7.6.2.5.2 7.6.2.5.3 7.6.2.5.4 7.6.2.6.1
7.6.2.6.2 7.6.2.6.3 7.6.2.6.4 7.6.2.7.1 7.6.2.7.2 7.6.2.7.3
7.6.2.7.4 7.6.2.8.1 7.6.2.8.2 7.6.2.8.3 7.6.2.8.4 7.6.3.1.1
7.6.3.1.2 7.6.3.1.3 7.6.3.1.4 7.6.3.2.1 7.6.3.2.2 7.6.3.2.3
7.6.3.2.4 7.6.3.3.1 7.6.3.3.2 7.6.3.3.3 7.6.3.3.4 7.6.3.4.1
7.6.3.4.2 7.6.3.4.3 7.6.3.4.4 7.6.3.5.1 7.6.3.5.2 7.6.3.5.3
7.6.3.5.4 7.6.3.6.1 7.6.3.6.2 7.6.3.6.3 7.6.3.6.4 7.6.3.7.1
7.6.3.7.2 7.6.3.7.3 7.6.3.7.4 7.6.3.8.1 7.6.3.8.2 7.6.3.8.3
7.6.3.8.4 7.6.4.1.1 7.6.4.1.2 7.6.4.1.3 7.6.4.1.4 7.6.4.2.1
7.6.4.2.2 7.6.4.2.3 7.6.4.2.4 7.6.4.3.1 7.6.4.3.2 7.6.4.3.3
7.6.4.3.4 7.6.4.4.1 7.6.4.4.2 7.6.4.4.3 7.6.4.4.4 7.6.4.5.1
7.6.4.5.2 7.6.4.5.3 7.6.4.5.4 7.6.4.6.1 7.6.4.6.2 7.6.4.6.3
7.6.4.6.4 7.6.4.7.1 7.6.4.7.2 7.6.4.7.3 7.6.4.7.4 7.6.4.8.1
7.6.4.8.2 7.6.4.8.3 7.6.4.8.4 7.7.1.1.1 7.7.1.1.2 7.7.1.1.3
7.7.1.1.4 7.7.1.2.1 7.7.1.2.2 7.7.1.2.3 7.7.1.2.4 7.7.1.3.1
7.7.1.3.2 7.7.1.3.3 7.7.1.3.4 7.7.1.4.1 7.7.1.4.2 7.7.1.4.3
7.7.1.4.4 7.7.1.5.1 7.7.1.5.2 7.7.1.5.3 7.7.1.5.4 7.7.1.6.1
7.7.1.6.2 7.7.1.6.3 7.7.1.6.4 7.7.1.7.1 7.7.1.7.2 7.7.1.7.3
7.7.1.7.4 7.7.1.8.1 7.7.1.8.2 7.7.1.8.3 7.7.1.8.4 7.7.2.1.1
7.7.2.1.2 7.7.2.1.3 7.7.2.1.4 7.7.2.2.1 7.7.2.2.2 7.7.2.2.3
7.7.2.2.4 7.7.2.3.1 7.7.2.3.2 7.7.2.3.3 7.7.2.3.4 7.7.2.4.1
7.7.2.4.2 7.7.2.4.3 7.7.2.4.4 7.7.2.5.1 7.7.2.5.2 7.7.2.5.3
7.7.2.5.4 7.7.2.6.1 7.7.2.6.2 7.7.2.6.3 7.7.2.6.4 7.7.2.7.1
7.7.2.7.2 7.7.2.7.3 7.7.2.7.4 7.7.2.8.1 7.7.2.8.2 7.7.2.8.3
7.7.2.8.4 7.7.3.1.1 7.7.3.1.2 7.7.3.1.3 7.7.3.1.4 7.7.3.2.1
7.7.3.2.2 7.7.3.2.3 7.7.3.2.4 7.7.3.3.1 7.7.3.3.2 7.7.3.3.3
7.7.3.3.4 7.7.3.4.1 7.7.3.4.2 7.7.3.4.3 7.7.3.4.4 7.7.3.5.1
7.7.3.5.2 7.7.3.5.3 7.7.3.5.4 7.7.3.6.1 7.7.3.6.2 7.7.3.6.3
7.7.3.6.4 7.7.3.7.1 7.7.3.7.2 7.7.3.7.3 7.7.3.7.4 7.7.3.8.1
7.7.3.8.2 7.7.3.8.3 7.7.3.8.4 7.7.4.1.1 7.7.4.1.2 7.7.4.1.3
7.7.4.1.4 7.7.4.2.1 7.7.4.2.2 7.7.4.2.3 7.7.4.2.4
7.7.4.3.1 7.7.4.3.2 7.7.4.3.3 7.7.4.3.4 7.7.4.4.1 7.7.4.4.2
7.7.4.4.3 7.7.4.4.4 7.7.4.5.1 7.7.4.5.2 7.7.4.5.3 7.7.4.5.4
7.7.4.6.1 7.7.4.6.2 7.7.4.6.3 7.7.4.6.4 7.7.4.7.1 7.7.4.7.2
7.7.4.7.3 7.7.4.7.4 7.7.4.8.1 7.7.4.8.2 7.7.4.8.3 7.7.4.8.4
7.8.1.1.1 7.8.1.1.2 7.8.1.1.3 7.8.1.1.4 7.8.1.2.1 7.8.1.2.2
7.8.1.2.3 7.8.1.2.4 7.8.1.3.1 7.8.1.3.2 7.8.1.3.3 7.8.1.3.4
7.8.1.4.1 7.8.1.4.2 7.8.1.4.3 7.8.1.4.4 7.8.1.5.1 7.8.1.5.2
7.8.1.5.3 7.8.1.5.4 7.8.1.6.1 7.8.1.6.2 7.8.1.6.3 7.8.1.6.4
7.8.1.7.1 7.8.1.7.2 7.8.1.7.3 7.8.1.7.4 7.8.1.8.1 7.8.1.8.2
7.8.1.8.3 7.8.1.8.4 7.8.2.1.1 7.8.2.1.2 7.8.2.1.3 7.8.2.1.4
7.8.2.2.1 7.8.2.2.2 7.8.2.2.3 7.8.2.2.4 7.8.2.3.1 7.8.2.3.2
7.8.2.3.3 7.8.2.3.4 7.8.2.4.1 7.8.2.4.2 7.8.2.4.3 7.8.2.4.4
7.8.2.5.1 7.8.2.5.2 7.8.2.5.3 7.8.2.5.4 7.8.2.6.1 7.8.2.6.2
7.8.2.6.3 7.8.2.6.4 7.8.2.7.1 7.8.2.7.2 7.8.2.7.3 7.8.2.7.4
7.8.2.8.1 7.8.2.8.2 7.8.2.8.3 7.8.2.8.4 7.8.3.1.1 7.8.3.1.2
7.8.3.1.3 7.8.3.1.4 7.8.3.2.1 7.8.3.2.2 7.8.3.2.3 7.8.3.2.4
7.8.3.3.1 7.8.3.3.2 7.8.3.3.3 7.8.3.3.4 7.8.3.4.1 7.8.3.4.2
7.8.3.4.3 7.8.3.4.4 7.8.3.5.1 7.8.3.5.2 7.8.3.5.3 7.8.3.5.4
7.8.3.6.1 7.8.3.6.2 7.8.3.6.3 7.8.3.6.4 7.8.3.7.1 7.8.3.7.2
7.8.3.7.3 7.8.3.7.4 7.8.3.8.1 7.8.3.8.2 7.8.3.8.3 7.8.3.8.4
7.8.4.1.1 7.8.4.1.2 7.8.4.1.3 7.8.4.1.4 7.8.4.2.1 7.8.4.2.2
7.8.4.2.3 7.8.4.2.4 7.8.4.3.1 7.8.4.3.2 7.8.4.3.3 7.8.4.3.4
7.8.4.4.1 7.8.4.4.2 7.8.4.4.3 7.8.4.4.4 7.8.4.5.1 7.8.4.5.2
7.8.4.5.3 7.8.4.5.4 7.8.4.6.1 7.8.4.6.2 7.8.4.6.3 7.8.4.6.4
7.8.4.7.1 7.8.4.7.2 7.8.4.7.3 7.8.4.7.4 7.8.4.8.1 7.8.4.8.2
7.8.4.8.3 7.8.4.8.4 8.1.1.1.1 8.1.1.1.2 8.1.1.1.3 8.1.1.1.4
8.1.1.2.1 8.1.1.2.2 8.1.1.2.3 8.1.1.2.4 8.1.1.3.1 8.1.1.3.2
8.1.1.3.3 8.1.1.3.4 8.1.1.4.1 8.1.1.4.2 8.1.1.4.3 8.1.1.4.4
8.1.1.5.1 8.1.1.5.2 8.1.1.5.3 8.1.1.5.4 8.1.1.6.1 8.1.1.6.2
8.1.1.6.3 8.1.1.6.4 8.1.1.7.1 8.1.1.7.2 8.1.1.7.3 8.1.1.7.4
8.1.1.8.1 8.1.1.8.2 8.1.1.8.3 8.1.1.8.4 8.1.2.1.1 8.1.2.1.2
8.1.2.1.3 8.1.2.1.4 8.1.2.2.1 8.1.2.2.2 8.1.2.2.3 8.1.2.2.4
8.1.2.3.1 8.1.2.3.2 8.1.2.3.3 8.1.2.3.4 8.1.2.4.1 8.1.2.4.2
8.1.2.4.3 8.1.2.4.4 8.1.2.5.1 8.1.2.5.2 8.1.2.5.3 8.1.2.5.4
8.1.2.6.1 8.1.2.6.2 8.1.2.6.3 8.1.2.6.4 8.1.2.7.1 8.1.2.7.2
8.1.2.7.3 8.1.2.7.4 8.1.2.8.1 8.1.2.8.2 8.1.2.8.3 8.1.2.8.4
8.1.3.1.1 8.1.3.1.2 8.1.3.1.3 8.1.3.1.4 8.1.3.2.1 8.1.3.2.2
8.1.3.2.3 8.1.3.2.4 8.1.3.3.1 8.1.3.3.2 8.1.3.3.3 8.1.3.3.4
8.1.3.4.1 8.1.3.4.2 8.1.3.4.3 8.1.3.4.4 8.1.3.5.1 8.1.3.5.2
8.1.3.5.3 8.1.3.5.4 8.1.3.6.1 8.1.3.6.2 8.1.3.6.3 8.1.3.6.4
8.1.3.7.1 8.1.3.7.2 8.1.3.7.3 8.1.3.7.4 8.1.3.8.1 8.1.3.8.2
8.1.3.8.3 8.1.3.8.4 8.1.4.1.1 8.1.4.1.2 8.1.4.1.3 8.1.4.1.4
8.1.4.2.1 8.1.4.2.2 8.1.4.2.3 8.1.4.2.4 8.1.4.3.1 8.1.4.3.2
8.1.4.3.3 8.1.4.3.4 8.1.4.4.1 8.1.4.4.2 8.1.4.4.3 8.1.4.4.4
8.1.4.5.1 8.1.4.5.2 8.1.4.5.3 8.1.4.5.4 8.1.4.6.1 8.1.4.6.2
8.1.4.6.3 8.1.4.6.4 8.1.4.7.1 8.1.4.7.2 8.1.4.7.3 8.1.4.7.4
8.1.4.8.1 8.1.4.8.2 8.1.4.8.3 8.1.4.8.4 8.2.1.1.1 8.2.1.1.2
8.2.1.1.3 8.2.1.1.4 8.2.1.2.1 8.2.1.2.2 8.2.1.2.3 8.2.1.2.4
8.2.1.3.1 8.2.1.3.2 8.2.1.3.3 8.2.1.3.4 8.2.1.4.1 8.2.1.4.2
8.2.1.4.3 8.2.1.4.4 8.2.1.5.1 8.2.1.5.2 8.2.1.5.3 8.2.1.5.4
8.2.1.6.1 8.2.1.6.2 8.2.1.6.3 8.2.1.6.4 8.2.1.7.1 8.2.1.7.2
8.2.1.7.3 8.2.1.7.4 8.2.1.8.1 8.2.1.8.2 8.2.1.8.3 8.2.1.8.4
8.2.2.1.1 8.2.2.1.2 8.2.2.1.3 8.2.2.1.4 8.2.2.2.1 8.2.2.2.2
8.2.2.2.3 8.2.2.2.4 8.2.2.3.1 8.2.2.3.2 8.2.2.3.3 8.2.2.3.4
8.2.2.4.1 8.2.2.4.2 8.2.2.4.3 8.2.2.4.4 8.2.2.5.1 8.2.2.5.2
8.2.2.5.3 8.2.2.5.4 8.2.2.6.1 8.2.2.6.2 8.2.2.6.3 8.2.2.6.4
8.2.2.7.1 8.2.2.7.2 8.2.2.7.3 8.2.2.7.4 8.2.2.8.1 8.2.2.8.2
8.2.2.8.3 8.2.2.8.4 8.2.3.1.1 8.2.3.1.2 8.2.3.1.3 8.2.3.1.4
8.2.3.2.1 8.2.3.2.2 8.2.3.2.3 8.2.3.2.4 8.2.3.3.1 8.2.3.3.2
8.2.3.3.3 8.2.3.3.4 8.2.3.4.1 8.2.3.4.2 8.2.3.4.3 8.2.3.4.4
8.2.3.5.1 8.2.3.5.2 8.2.3.5.3 8.2.3.5.4 8.2.3.6.1 8.2.3.6.2
8.2.3.6.3 8.2.3.6.4 8.2.3.7.1 8.2.3.7.2 8.2.3.7.3 8.2.3.7.4
8.2.3.8.1 8.2.3.8.2 8.2.3.8.3 8.2.3.8.4 8.2.4.1.1 8.2.4.1.2
8.2.4.1.3 8.2.4.1.4 8.2.4.2.1 8.2.4.2.2 8.2.4.2.3 8.2.4.2.4
8.2.4.3.1 8.2.4.3.2 8.2.4.3.3 8.2.4.3.4 8.2.4.4.1 8.2.4.4.2
8.2.4.4.3 8.2.4.4.4 8.2.4.5.1 8.2.4.5.2 8.2.4.5.3 8.2.4.5.4
8.2.4.6.1 8.2.4.6.2 8.2.4.6.3 8.2.4.6.4 8.2.4.7.1 8.2.4.7.2
8.2.4.7.3 8.2.4.7.4 8.2.4.8.1 8.2.4.8.2 8.2.4.8.3 8.2.4.8.4
8.3.1.1.1 8.3.1.1.2 8.3.1.1.3 8.3.1.1.4 8.3.1.2.1 8.3.1.2.2
8.3.1.2.3 8.3.1.2.4 8.3.1.3.1 8.3.1.3.2 8.3.1.3.3 8.3.1.3.4
8.3.1.4.1 8.3.1.4.2 8.3.1.4.3 8.3.1.4.4 8.3.1.5.1 8.3.1.5.2
8.3.1.5.3 8.3.1.5.4 8.3.1.6.1 8.3.1.6.2 8.3.1.6.3 8.3.1.6.4
8.3.1.7.1 8.3.1.7.2 8.3.1.7.3 8.3.1.7.4 8.3.1.8.1 8.3.1.8.2
8.3.1.8.3 8.3.1.8.4 8.3.2.1.1 8.3.2.1.2 8.3.2.1.3 8.3.2.1.4
8.3.2.2.1 8.3.2.2.2 8.3.2.2.3 8.3.2.2.4 8.3.2.3.1 8.3.2.3.2
8.3.2.3.3 8.3.2.3.4 8.3.2.4.1 8.3.2.4.2 8.3.2.4.3 8.3.2.4.4
8.3.2.5.1 8.3.2.5.2 8.3.2.5.3 8.3.2.5.4 8.3.2.6.1 8.3.2.6.2
8.3.2.6.3 8.3.2.6.4 8.3.2.7.1 8.3.2.7.2 8.3.2.7.3 8.3.2.7.4
8.3.2.8.1 8.3.2.8.2 8.3.2.8.3 8.3.2.8.4 8.3.3.1.1 8.3.3.1.2
8.3.3.1.3 8.3.3.1.4 8.3.3.2.1 8.3.3.2.2 8.3.3.2.3 8.3.3.2.4
8.3.3.3.1 8.3.3.3.2 8.3.3.3.3 8.3.3.3.4 8.3.3.4.1 8.3.3.4.2
8.3.3.4.3 8.3.3.4.4 8.3.3.5.1 8.3.3.5.2 8.3.3.5.3 8.3.3.5.4
8.3.3.6.1 8.3.3.6.2 8.3.3.6.3 8.3.3.6.4 8.3.3.7.1 8.3.3.7.2
8.3.3.7.3 8.3.3.7.4 8.3.3.8.1 8.3.3.8.2 8.3.3.8.3 8.3.3.8.4
8.3.4.1.1 8.3.4.1.2 8.3.4.1.3 8.3.4.1.4 8.3.4.2.1 8.3.4.2.2
8.3.4.2.3 8.3.4.2.4 8.3.4.3.1 8.3.4.3.2 8.3.4.3.3 8.3.4.3.4
8.3.4.4.1 8.3.4.4.2 8.3.4.4.3 8.3.4.4.4 8.3.4.5.1 8.3.4.5.2
8.3.4.5.3 8.3.4.5.4 8.3.4.6.1 8.3.4.6.2 8.3.4.6.3 8.3.4.6.4
8.3.4.7.1 8.3.4.7.2 8.3.4.7.3 8.3.4.7.4 8.3.4.8.1 8.3.4.8.2
8.3.4.8.3 8.3.4.8.4 8.4.1.1.1 8.4.1.1.2 8.4.1.1.3 8.4.1.1.4
8.4.1.2.1 8.4.1.2.2 8.4.1.2.3 8.4.1.2.4 8.4.1.3.1 8.4.1.3.2
8.4.1.3.3 8.4.1.3.4 8.4.1.4.1 8.4.1.4.2 8.4.1.4.3 8.4.1.4.4
8.4.1.5.1 8.4.1.5.2 8.4.1.5.3 8.4.1.5.4 8.4.1.6.1 8.4.1.6.2
8.4.1.6.3 8.4.1.6.4 8.4.1.7.1 8.4.1.7.2 8.4.1.7.3 8.4.1.7.4
8.4.1.8.1 8.4.1.8.2 8.4.1.8.3 8.4.1.8.4 8.4.2.1.1 8.4.2.1.2
8.4.2.1.3 8.4.2.1.4 8.4.2.2.1 8.4.2.2.2 8.4.2.2.3 8.4.2.2.4
8.4.2.3.1 8.4.2.3.2 8.4.2.3.3 8.4.2.3.4 8.4.2.4.1 8.4.2.4.2
8.4.2.4.3 8.4.2.4.4 8.4.2.5.1 8.4.2.5.2 8.4.2.5.3 8.4.2.5.4
8.4.2.6.1 8.4.2.6.2 8.4.2.6.3 8.4.2.6.4 8.4.2.7.1 8.4.2.7.2
8.4.2.7.3 8.4.2.7.4 8.4.2.8.1 8.4.2.8.2 8.4.2.8.3 8.4.2.8.4
8.4.3.1.1 8.4.3.1.2 8.4.3.1.3 8.4.3.1.4 8.4.3.2.1 8.4.3.2.2
8.4.3.2.3 8.4.3.2.4 8.4.3.3.1 8.4.3.3.2 8.4.3.3.3 8.4.3.3.4
8.4.3.4.1 8.4.3.4.2 8.4.3.4.3 8.4.3.4.4 8.4.3.5.1 8.4.3.5.2
8.4.3.5.3 8.4.3.5.4 8.4.3.6.1 8.4.3.6.2 8.4.3.6.3 8.4.3.6.4
8.4.3.7.1 8.4.3.7.2 8.4.3.7.3 8.4.3.7.4 8.4.3.8.1 8.4.3.8.2
8.4.3.8.3 8.4.3.8.4 8.4.4.1.1 8.4.4.1.2 8.4.4.1.3 8.4.4.1.4
8.4.4.2.1 8.4.4.2.2 8.4.4.2.3 8.4.4.2.4 8.4.4.3.1 8.4.4.3.2
8.4.4.3.3 8.4.4.3.4 8.4.4.4.1 8.4.4.4.2 8.4.4.4.3 8.4.4.4.4
8.4.4.5.1 8.4.4.5.2 8.4.4.5.3 8.4.4.5.4 8.4.4.6.1 8.4.4.6.2
8.4.4.6.3 8.4.4.6.4 8.4.4.7.1 8.4.4.7.2 8.4.4.7.3 8.4.4.7.4
8.4.4.8.1 8.4.4.8.2 8.4.4.8.3 8.4.4.8.4 8.5.1.1.1 8.5.1.1.2
8.5.1.1.3 8.5.1.1.4 8.5.1.2.1 8.5.1.2.2 8.5.1.2.3 8.5.1.2.4
8.5.1.3.1 8.5.1.3.2 8.5.1.3.3 8.5.1.3.4 8.5.1.4.1 8.5.1.4.2
8.5.1.4.3 8.5.1.4.4 8.5.1.5.1 8.5.1.5.2 8.5.1.5.3 8.5.1.5.4
8.5.1.6.1 8.5.1.6.2 8.5.1.6.3 8.5.1.6.4 8.5.1.7.1 8.5.1.7.2
8.5.1.7.3 8.5.1.7.4 8.5.1.8.1 8.5.1.8.2 8.5.1.8.3 8.5.1.8.4
8.5.2.1.1 8.5.2.1.2 8.5.2.1.3 8.5.2.1.4 8.5.2.2.1 8.5.2.2.2
8.5.2.2.3 8.5.2.2.4 8.5.2.3.1 8.5.2.3.2 8.5.2.3.3 8.5.2.3.4
8.5.2.4.1 8.5.2.4.2 8.5.2.4.3 8.5.2.4.4 8.5.2.5.1 8.5.2.5.2
8.5.2.5.3 8.5.2.5.4 8.5.2.6.1 8.5.2.6.2 8.5.2.6.3 8.5.2.6.4
8.5.2.7.1 8.5.2.7.2 8.5.2.7.3 8.5.2.7.4 8.5.2.8.1 8.5.2.8.2
8.5.2.8.3 8.5.2.8.4 8.5.3.1.1 8.5.3.1.2 8.5.3.1.3 8.5.3.1.4
8.5.3.2.1 8.5.3.2.2 8.5.3.2.3 8.5.3.2.4 8.5.3.3.1 8.5.3.3.2
8.5.3.3.3 8.5.3.3.4 8.5.3.4.1 8.5.3.4.2 8.5.3.4.3 8.5.3.4.4
8.5.3.5.1 8.5.3.5.2 8.5.3.5.3 8.5.3.5.4 8.5.3.6.1 8.5.3.6.2
8.5.3.6.3 8.5.3.6.4 8.5.3.7.1 8.5.3.7.2 8.5.3.7.3 8.5.3.7.4
8.5.3.8.1 8.5.3.8.2 8.5.3.8.3 8.5.3.8.4 8.5.4.1.1 8.5.4.1.2
8.5.4.1.3 8.5.4.1.4 8.5.4.2.1 8.5.4.2.2 8.5.4.2.3 8.5.4.2.4
8.5.4.3.1 8.5.4.3.2 8.5.4.3.3 8.5.4.3.4 8.5.4.4.1 8.5.4.4.2
8.5.4.4.3 8.5.4.4.4 8.5.4.5.1 8.5.4.5.2 8.5.4.5.3 8.5.4.5.4
8.5.4.6.1 8.5.4.6.2 8.5.4.6.3 8.5.4.6.4 8.5.4.7.1 8.5.4.7.2
8.5.4.7.3 8.5.4.7.4 8.5.4.8.1 8.5.4.8.2 8.5.4.8.3 8.5.4.8.4
8.6.1.1.1 8.6.1.1.2 8.6.1.1.3 8.6.1.1.4 8.6.1.2.1 8.6.1.2.2
8.6.1.2.3 8.6.1.2.4 8.6.1.3.1 8.6.1.3.2 8.6.1.3.3 8.6.1.3.4
8.6.1.4.1 8.6.1.4.2 8.6.1.4.3 8.6.1.4.4 8.6.1.5.1 8.6.1.5.2
8.6.1.5.3 8.6.1.5.4 8.6.1.6.1 8.6.1.6.2 8.6.1.6.3 8.6.1.6.4
8.6.1.7.1 8.6.1.7.2 8.6.1.7.3 8.6.1.7.4 8.6.1.8.1 8.6.1.8.2
8.6.1.8.3 8.6.1.8.4 8.6.2.1.1 8.6.2.1.2 8.6.2.1.3 8.6.2.1.4
8.6.2.2.1 8.6.2.2.2 8.6.2.2.3 8.6.2.2.4 8.6.2.3.1 8.6.2.3.2
8.6.2.3.3 8.6.2.3.4 8.6.2.4.1 8.6.2.4.2 8.6.2.4.3 8.6.2.4.4
8.6.2.5.1 8.6.2.5.2 8.6.2.5.3 8.6.2.5.4 8.6.2.6.1 8.6.2.6.2
8.6.2.6.3 8.6.2.6.4 8.6.2.7.1 8.6.2.7.2 8.6.2.7.3 8.6.2.7.4
8.6.2.8.1 8.6.2.8.2 8.6.2.8.3 8.6.2.8.4 8.6.3.1.1 8.6.3.1.2
8.6.3.1.3 8.6.3.1.4 8.6.3.2.1 8.6.3.2.2 8.6.3.2.3 8.6.3.2.4
8.6.3.3.1 8.6.3.3.2 8.6.3.3.3 8.6.3.3.4 8.6.3.4.1 8.6.3.4.2
8.6.3.4.3 8.6.3.4.4 8.6.3.5.1 8.6.3.5.2 8.6.3.5.3 8.6.3.5.4
8.6.3.6.1 8.6.3.6.2 8.6.3.6.3 8.6.3.6.4 8.6.3.7.1 8.6.3.7.2
8.6.3.7.3 8.6.3.7.4 8.6.3.8.1 8.6.3.8.2 8.6.3.8.3 8.6.3.8.4
8.6.4.1.1 8.6.4.1.2 8.6.4.1.3 8.6.4.1.4 8.6.4.2.1 8.6.4.2.2
8.6.4.2.3 8.6.4.2.4 8.6.4.3.1 8.6.4.3.2 8.6.4.3.3 8.6.4.3.4
8.6.4.4.1 8.6.4.4.2 8.6.4.4.3 8.6.4.4.4 8.6.4.5.1 8.6.4.5.2
8.6.4.5.3 8.6.4.5.4 8.6.4.6.1 8.6.4.6.2 8.6.4.6.3 8.6.4.6.4
8.6.4.7.1 8.6.4.7.2 8.6.4.7.3 8.6.4.7.4 8.6.4.8.1 8.6.4.8.2
8.6.4.8.3 8.6.4.8.4 8.7.1.1.1 8.7.1.1.2 8.7.1.1.3 8.7.1.1.4
8.7.1.2.1 8.7.1.2.2 8.7.1.2.3 8.7.1.2.4 8.7.1.3.1 8.7.1.3.2
8.7.1.3.3 8.7.1.3.4 8.7.1.4.1 8.7.1.4.2 8.7.1.4.3 8.7.1.4.4
8.7.1.5.1 8.7.1.5.2 8.7.1.5.3 8.7.1.5.4 8.7.1.6.1 8.7.1.6.2
8.7.1.6.3 8.7.1.6.4 8.7.1.7.1 8.7.1.7.2 8.7.1.7.3 8.7.1.7.4
8.7.1.8.1 8.7.1.8.2 8.7.1.8.3 8.7.1.8.4 8.7.2.1.1 8.7.2.1.2
8.7.2.1.3 8.7.2.1.4 8.7.2.2.1 8.7.2.2.2 8.7.2.2.3 8.7.2.2.4
8.7.2.3.1 8.7.2.3.2 8.7.2.3.3 8.7.2.3.4 8.7.2.4.1 8.7.2.4.2
8.7.2.4.3 8.7.2.4.4 8.7.2.5.1 8.7.2.5.2 8.7.2.5.3 8.7.2.5.4
8.7.2.6.1 8.7.2.6.2 8.7.2.6.3 8.7.2.6.4 8.7.2.7.1 8.7.2.7.2
8.7.2.7.3 8.7.2.7.4 8.7.2.8.1 8.7.2.8.2 8.7.2.8.3 8.7.2.8.4
8.7.3.1.1 8.7.3.1.2 8.7.3.1.3 8.7.3.1.4 8.7.3.2.1 8.7.3.2.2
8.7.3.2.3 8.7.3.2.4 8.7.3.3.1 8.7.3.3.2 8.7.3.3.3 8.7.3.3.4
8.7.3.4.1 8.7.3.4.2 8.7.3.4.3 8.7.3.4.4 8.7.3.5.1 8.7.3.5.2
8.7.3.5.3 8.7.3.5.4 8.7.3.6.1 8.7.3.6.2 8.7.3.6.3
8.7.3.6.4 8.7.3.7.1 8.7.3.7.2 8.7.3.7.3 8.7.3.7.4 8.7.3.8.1
8.7.3.8.2 8.7.3.8.3 8.7.3.8.4 8.7.4.1.1 8.7.4.1.2 8.7.4.1.3
8.7.4.1.4 8.7.4.2.1 8.7.4.2.2 8.7.4.2.3 8.7.4.2.4 8.7.4.3.1
8.7.4.3.2 8.7.4.3.3 8.7.4.3.4 8.7.4.4.1 8.7.4.4.2 8.7.4.4.3
8.7.4.4.4 8.7.4.5.1 8.7.4.5.2 8.7.4.5.3 8.7.4.5.4 8.7.4.6.1
8.7.4.6.2 8.7.4.6.3 8.7.4.6.4 8.7.4.7.1 8.7.4.7.2 8.7.4.7.3
8.7.4.7.4 8.7.4.8.1 8.7.4.8.2 8.7.4.8.3 8.7.4.8.4 8.8.1.1.1
8.8.1.1.2 8.8.1.1.3 8.8.1.1.4 8.8.1.2.1 8.8.1.2.2 8.8.1.2.3
8.8.1.2.4 8.9.1.3.1 8.8.1.3.2 8.8.1.3.3 8.8.1.3.4 8.8.1.4.1
8.8.1.4.2 8.8.1.4.3 8.8.1.4.4 8.8.1.5.1 8.8.1.5.2 8.8.1.5.3
8.8.1.5.4 8.8.1.6.1 8.8.1.6.2 8.8.1.6.3 8.8.1.6.4 8.8.1.7.1
8.8.1.7.2 8.8.1.7.3 8.8.1.7.4 8.8.1.8.1 8.8.1.8.2 8.8.1.8.3
8.8.1.8.4 8.8.2.1.1 8.8.2.1.2 8.8.2.1.3 8.8.2.1.4 8.8.2.2.1
8.8.2.2.2 8.8.2.2.3 8.8.2.2.4 8.8.2.3.1 8.8.2.3.2 8.8.2.3.3
8.8.2.3.4 8.8.2.4.1 8.8.2.4.2 8.8.2.4.3 8.8.2.4.4 8.8.2.5.1
8.8.2.5.2 8.8.2.5.3 8.8.2.5.4 8.8.2.6.1 8.8.2.6.2 8.8.2.6.3
8.8.2.6.4 8.8.2.7.1 8.8.2.7.2 8.8.2.7.3 8.8.2.7.4 8.8.2.8.1
8.8.2.8.2 8.8.2.8.3 8.8.2.8.4 8.8.3.1.1 8.8.3.1.2 8.8.3.1.3
8.8.3.1.4 8.8.3.2.1 8.8.3.2.2 8.8.3.2.3 8.8.3.2.4 8.8.3.3.1
8.8.3.3.2 8.8.3.3.3 8.8.3.3.4 8.8.3.4.1 8.8.3.4.2 8.8.3.4.3
8.8.3.4.4 8.8.3.5.1 8.8.3.5.2 8.8.3.5.3 8.8.3.5.4 8.8.3.6.1
8.8.3.6.2 8.8.3.6.3 8.8.3.6.4 8.8.3.7.1 8.8.3.7.2 8.8.3.7.3
8.8.3.7.4 8.8.3.8.1 8.8.3.8.2 8.8.3.8.3 8.8.3.8.4 8.8.4.1.1
8.8.4.1.2 8.8.4.1.3 8.8.4.1.4 8.8.4.2.1 8.8.4.2.2 8.8.4.2.3
8.8.4.2.4 8.8.4.3.1 8.8.4.3.2 8.8.4.3.3 8.8.4.3.4 8.8.4.4.1
8.8.4.4.2 8.8.4.4.3 8.8.4.4.4 8.8.4.5.1 8.8.4.5.2 8.8.4.5.3
8.8.4.5.4 8.8.4.6.1 8.8.4.6.2 8.8.4.6.3 8.8.4.6.4 8.8.4.7.1
8.8.4.7.2 8.8.4.7.3 8.8.4.7.4 8.8.4.8.1 8.8.4.8.2 8.8.4.8.3
8.8.4.8.4
[0253] The best mode of practicing the invention is with Compounds
of Example numbers 50.6, 50.9, 50.15, and 50.20.
Section 1
Synthesis of Compounds of Formula I
[0254] Synthesis of compounds encompassed by the present invention
typically includes some or all of the following general steps: (1)
preparation of a phosphonate prodrug; (2) deprotection of a
phosphonate ester; (3) modification of a heterocycle; (4) coupling
of a heterocycle with a phosphonate component; (5) construction of
a heterocycle; (6) ring closure to construct a heterocycle with a
phosphonate moiety present and (7) preparation of useful
intermediates. These steps are illustrated in the following scheme
for compounds of formula I wherein R.sup.5 is a 5-membered
heteroaromatic ring. Compounds of formula I wherein R.sup.5 is a
6-member heteroaromatic ring or other heteroaromatic rings are
prepared in an analogous manner.
##STR00050##
(1) Preparation of a Bisamidate Phosphonate
[0255] General synthesis of bis-phosphoroamidate prodrugs:
[0256] In general, the bis-phosphoroamidates of formula I, where
both --NR.sup.15R.sup.16 and
--N(R.sup.18)--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14 are from
the same amino acid residues, can be prepared from the activated
phosphonates for example, dichlorophosphonate, by coupling with an
amino acid ester for example, glycine ethylester with or without
base for example, N-methylimidazole. The reactive dichloridates,
can be prepared from the corresponding phosphonic acid and a
chlorinating agent for example, thionyl chloride (Starrett, et al.,
J. Med. Chem., 1994, 1857), oxalyl chloride (Stowell, et al.,
Tetrahedron Lett., 1990, 31, 3261), or phosphorous pentachloride
(Quast, et al., Synthesis, 1974, 490). These dichloridates can also
be prepared from their corresponding disilyl esters (Bhongle, et
al., Synth. Commun., 1987, 17, 1071) and dialkyl esters (Still, et
al, Tetrahedron Lett., 1983, 24, 4405; Patois, et al., Bull. Soc.
Chim. Fr., 1993, 130, 485).
[0257] Alternatively, these bis-phosphoroamidates can be prepared
by reacting the corresponding phosphonic acid with an amino acid
ester for example, glycine ethylester in presence of PPh.sub.3 and
2,2'-dipyridyl disulfide in pyridine as described in WO 95/07920 or
Mukaiyama, T. et al, J. Am. Chem. Soc., 1972, 94, 8528.
[0258] Synthesis of mixed bis-phosphoroamidates of formula I, where
--NR.sup.15R.sup.16 and
--N(R.sup.18)--(CR.sup.12R.sup.13).sub.nC(O)--R.sup.14 are
different amino acid esters or a combination of an amino acid ester
and a substituted amine, can be prepared by direct conversion via
dichloridate as described above (sequential addition) followed by
purification of the desired product (e.g., by column
chromatography). Alternatively, these unsymmetrical
bis-phosphoroamidates can be prepared starting with an appropriate
phosphonate monoester such as phenyl ester or benzyl ester to give
the mixed phosphonoesteramide via the chloridate, followed by ester
hydrolysis under conditions where the amide bond is stable. The
resultant mono-amide can be converted to a mixed bisamide by
condensation with a second amino ester or a substituted amine via
the chloridate, as described above. Synthesis of such monoesters
can be prepared using the reported procedure (EP 481 214).
(2) Deprotection of a Phosphonate Ester
[0259] Compounds of formula 2 may be prepared from phosphonate
esters using known phosphate and phosphonate ester cleavage
conditions. Silyl halides are generally used to cleave various
phosphonate esters, and subsequent mild hydrolysis of the resulting
silyl phosphonate esters give the desired phosphonic acids. When
required, acid scavengers (e.g. 1,1,1,3,3,3-hexamethyldisilazane,
2,6-lutidine, etc.) can be used for the synthesis of acid labile
compounds. Such silyl halides include chlorotrimethylsilane
(Rabinowitz, J. Org. Chem., 1963, 28: 2975), and
bromotrimethylsilane (McKenna, et al, Tetrahedron Lett., 1977,
155), and iodotrimethylsilane (Blackburn, et al, J. Chem. Soc.,
Chem. Commun., 1978, 870). Alternately, phosphonate esters can be
cleaved under strong acidic conditions (e.g. HBr or HCl: Moffatt,
et al, U.S. Pat. No. 3,524,846, 1970). These esters can also be
cleaved via dichlorophosphonates, prepared by treating the esters
with halogenating agents (e.g. phosphorus pentachloride, thionyl
chloride, BBr.sub.3: Pelchowicz et al, J. Chem. Soc., 1961, 238)
followed by aqueous hydrolysis to give phosphonic acids. Aryl and
benzyl phosphonate esters can be cleaved under hydrogenolysis
conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al,
J. Med. Chem., 1985, 28: 1208; Baddiley, et al, Nature, 1953, 171:
76) or metal reduction conditions (Shafer, et al, J. Am. Chem.
Soc., 1977, 99: 5118). Electrochemical (Shono, et al, J. Org.
Chem., 1979, 44: 4508) and pyrolysis (Gupta, et al, Synth. Commun.,
1980, 10: 299) conditions have also been used to cleave various
phosphonate esters.
(3) Modification of an Existing Heterocycle
[0260] Syntheses of the heterocycles encompassed in the disclosed
compounds have been well studied and described in numerous reviews
(see section 4). Although it is advantageous to have the desired
substituents present in these heterocycles before synthesis of
compounds of formula 4, in some cases, the desired substituents are
not compatible with subsequent reactions, and therefore
modifications of an existing heterocycle are required late in the
synthetic scheme using conventional chemistry (Larock,
Comprehensive organic transformations, VCH, New York, 1989; Trost,
Comprehensive organic synthesis; Pergamon press, New York, 1991).
For example, compounds of formula I wherein A, A'', or B is a halo
or a cyano group can be prepared from the corresponding amine group
by conversion to the diazonium group and reaction with various
copper (I) salts (e.g. CuI, CuBr, CuCl, CuCN). Halogens can also be
introduced by direct halogenations of various heterocycles. For
example, 5-unsubstituted-2-aminothiazoles can be converted to
2-amino-5-halothiazoles using various reagents (e.g. NIS, NBS,
NCS). Heteroaryl halides are also useful intermediates and are
often readily converted to other substituents (such as A, A'', B,
B'', C'', D, D'', E and E'') via transition metal assisted coupling
reactions such as Suzuki, Heck or Stille reactions (Farina et al,
Organic Reactions, Vol 50; Wiley, New York, 1997; Mitchell,
Synthesis, 1992, 808; Suzuki, Pure App. Chem., 1991, 63, 419; Heck
Palladium Reagents in Organic Synthesis; Academic Press: San Diego,
1985). Compounds of formula I wherein A is a carbamoyl group can be
made from their corresponding alkyl carboxylate esters via
aminolysis with various amines, and conventional functional group
modifications of the alkyl carboxylate esters are useful for
syntheses of compounds of formula I wherein A is a --CH.sub.2OH
group or a --CH.sub.2-halo group. Substitution reactions of
haloheterocycles (e.g. 2-bromothiazole, 5-bromothiazole) with
various nucleophiles (e.g. HSMe, HOMe, etc.) represents still
another method for introducing substituents such as A, A'', B and
B''. For example, substitution of a 2-chlorothiazole with
methanethiol gives the corresponding 2-methylthiothiazole.
[0261] It is envisioned that when necessary alkylation of nitrogen
atoms in the heterocycles (e.g. imidazoles, 1,2,4-triazoles and
1,2,3,4-tetrazoles) can be readily performed using for example
standard alkylation reactions (with an alkyl halide, an aralkyl
halide, an alkyl sulfonate or an aralkyl sulfonate), or Mitsunobu
reactions (with an alcohol).
(4) Coupling of a Heterocycle with a Phosphonate Component
[0262] When feasible compounds disclosed in the present invention
are prepared via a convergent synthetic route entailing the
coupling of a heterocycle with a phosphonate diester component.
[0263] Transition metal catalyzed coupling reactions such as Stille
or Suzuki reactions are particularly suited for the synthesis of
compounds of formula I. Coupling reactions between a heteroaryl
halide or triflate (e.g. 2-bromopyridine) and a M-PO.sub.3R'
wherein M is a 2-(5-tributylstannyl)furanyl or a
2-(5-boronyl)furanyl group under palladium catalyzed reaction
conditions (Farina et al, Organic Reactions, Vol. 50; Wiley, New
York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App.
Chem., 1991, 63, 419) yield compounds of formula I wherein X is a
furan-2,5-diyl group. It is envisioned that the nature of the
coupling partners for these reactions can also be reversed (e.g.
coupling of trialkylstannyl or boronyl heterocycles with a
halo-X--P(O)(O-alkyl).sub.2). Other coupling reactions between
organostannes and an alkenyl halide or an alkenyl triflate are also
reported which may be used to prepared compounds of formula I
wherein X is an alkenyl group. The Heck reaction may be used to
prepare compounds of formula I wherein X is an alkenyl group (Heck
Palladium Reagents in Organic Syntiesis; Academic Press: San Diego,
1985). These reactions are particularly suited for syntheses of
various heteroaromatics as R.sup.5 for compounds of formula I given
the availability of numerous halogenated heterocycles, and these
reactions are particularly suitable for parallel synthesis (e.g.
combinatorial synthesis on solid phase (Bunin, B. A., The
Combinatorial Index; Academic Press: San Diego, 1998) or in
solution phase (Flynn, D. L. et al., Curr. Op. Drug. Disc. Dev.,
1998, 1, 1367)) to generate large combinatorial libraries. For
example, ethyl 5-iodo-2-furanylphosphonate can be coupled to Wang's
resin under suitable coupling reaction conditions. The
resin-coupled 5-iodo-2-[5-(O-ethyl-O-Wang's resin)phosphono]furan
can then be subjected to transition metal catalyzed Suzuki and
Stille reactions (as described above) with organoboranes and
organotins in a parallel manner to give libraries of compounds of
formula 3 wherein X is furan-2,5-diyl.
[0264] Substitution reactions are useful for the coupling of a
heterocycle with a phosphonate diester component. For example,
cyanuric chloride can be substituted with dialkyl
mercaptoalkylphosphonates or dialkyl aminoalkylphosphonates to give
compounds of formula I wherein R.sup.5 is a 1,3,5-triazine, X is an
alkylthio or an alkylamino group. Alkylation reactions are also
used for the coupling of a heterocycle with a phosphonate diester
component. For example, a heteroaromatic thiol (e.g. a
1,3,4-thiadiazole-2-thiol) can be alkylated with a dialkyl
methylphosphonate derivative (e.g. ICH.sub.2P(O)(OEt).sub.2,
TsOCH.sub.2P(O)(OEt).sub.2, TfOCH.sub.2P(O)(OEt).sub.2) to lead to
compounds of formula I wherein X is an alkylthio group. In another
aspect, alkylation reactions of a heteroaromatic carboxylic acid
(e.g. a thiazole-4-carboxylic acid) with a dialkyl
methylphosphonate derivative (e.g. ICH.sub.2P(O)(OEt).sub.2,
TsOCH.sub.2P(O)(OEt).sub.2, TfOCH.sub.2P(O)(OEt).sub.2) lead to
compounds of formula I wherein X is an alkoxycarbonyl group, while
alkylation reactions of a heteroaromatic thiocarboxylic acid (e.g.
a thiazole-4-thiocarboxylic acid) with a dialkyl methylphosphonate
derivative (e.g. ICH.sub.2P(O)(OEt).sub.2,
TsOCH.sub.2P(O)(OEt).sub.2, TfOCH.sub.2P(O)(OEt).sub.2) lead to
compounds of formula I wherein X is an alkylthiocarbonyl group.
Substitutions of haloalkyl heterocycles (e.g. 4-haloalkylthiazole)
with nucleophiles containing the phosphonate group (diethyl
hydroxymethylphosphonate) are useful for the preparation of
compounds of formula I wherein X is an alkoxyalkyl or an
alkylthioalkyl group. For example, compounds of formula I where X
is a --CH.sub.2OCH.sub.2-- group can be prepared from
2-chloromethylpyridine or 4-chloromethylthiazole using dialkyl
hydroxymethylphosphonates and a suitable base (e.g. sodium
hydride). It is possible to reverse the nature of the nucleophiles
and electrophiles for the substitution reactions, i.e. haloalkyl-
and/or sulfonylalkylphosphonate esters can be substituted with
heterocycles containing a nucleophile (e.g. a
2-hydroxyalkylpyridine, a 2-mercaptoalkylpyridine, or a
4-hydroxyalkyloxazole).
[0265] Known amide bond formation reactions (e.g. the acyl halide
method, the mixed anhydride method, the carbodiimide method) can
also be used to couple a heteroaromatic carboxylic acid with a
phosphonate diester component leading to compounds of formula I
wherein X is an alkylaminocarbonyl or an alkoxycarbonyl group. For
example, couplings of a thiazole-4-carboxylic acid with a dialkyl
aminoalkylphosphonate or a dialkyl hydroxyalkylphosphonate give
compounds of formula I wherein R.sup.5 is a thiazole, and X is an
alkylaminocarbonyl or an alkoxycarbonyl group. Alternatively, the
nature of the coupling partners can be reversed to give compounds
of formula I wherein X is an alkylcarbonylamino group. For example,
2-aminothiazoles can be coupled with (RO).sub.2P(O)-alkyl-CO.sub.2H
(e.g. diethylphosphonoacetic acid) under these reaction conditions
to give compounds of formula I wherein R.sup.5 is a thiazole and X
is an alkylcarbonylamino group. These reactions are also useful for
parallel synthesis of compound libraries through combinatorial
chemistry on solid phase or in solution phase. For example,
HOCH.sub.2P(O)(OEt)(O-resin), H.sub.2NCH.sub.2P(O)(OEt)(O-resin)
and HOOCCH.sub.2P(O)(OEt)(O-resin) (prepared using known methods)
can be coupled to various heterocycles using the above described
reactions to give libraries of compounds of formula 3 wherein X is
a --C(O)OCH.sub.2--, or a --C(O)NHCH.sub.2--, or a
NHC(O)CH.sub.2--.
[0266] Rearrangement reactions can also be used to prepare
compounds covered in the present invention. For example, the
Curtius' rearrangement of a thiazole-4-carboxylic acid in the
presence of a dialkyl hydroxyalkylphosphonate or a dialkyl
aminoalkylphosphonate lead to compounds of formula I wherein X is
an alkylaminocarbonylamino or an alkoxycarbonylamino group. These
reactions can also be adopted for combinatorial synthesis of
various libraries of compounds of formula 3. For example, Curtius'
rearrangement reactions between a heterocyclic carboxylic acid and
HOCH.sub.2P(O)(OEt)(O-resin), or H.sub.2NCH.sub.2P(O)(OEt)(O-resin)
can lead to libraries of compounds of formula I wherein X is a
--NHC(O)OCH.sub.2--, or a NHC(O)NHCH.sub.2--.
[0267] For compounds of formula I wherein X is an alkyl group, the
phosphonate group can be introduced using other common phosphonate
formation methods such as Michaelis-Arbuzov reaction (Bhattacharya
et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction
(Blackburn et al., J. Organomet. Chem., 1988, 348: 55), and
addition reactions of phosphorus to electrophiles (such as
aldehydes, ketones, acyl halides, imines and other carbonyl
derivatives).
[0268] Phosphonate component can also be introduced via lithiation
reactions. For example, lithiation of an 2-ethynylpyridine using a
suitable base followed by trapping the thus generated anion with a
dialkyl chlorophosphonate lead to compounds of formula I wherein
R.sup.5 is a pyridyl, X is a 1-(2-phosphono)ethynyl group.
(5) Construction of a Heterocycle
[0269] Although existing heterocycles are useful for the synthesis
of compounds of formula I, when required, heterocycles can also be
constructed leading to compounds in the current invention. The
construction of heterocycles have been well described in the
literature using a variety of reaction conditions (Joule et al.,
Heterocyclic Chemistry; Chapman hall, London, 1995; Boger, Weinreb,
Hetero Diels-Alder Methodology In Organic Synthesis; Academic
press, San Diego, 1987; Padwa, 1,3-Dipolar Cycloaddition Chemistry;
Wiley, New York, 1984; Katritzsky et al., Comprehensive
Heterocyclic Chemistry; Pergamon press, Oxford; Newkome et al.,
Contemporary Heterocyclic Chemistry: Syntheses, Reaction and
Applications; Wiley, New York, 1982; Syntheses of Heterocyclic
Compounds; Consultants Bureau, New York). Some of the methods which
are useful to prepare compounds in the present invention are given
as examples in the following discussion.
(i) Construction of a Thiazole Ring System
[0270] Thiazoles useful for the present invention can be readily
prepared using a variety of well described ring-forming reactions
(Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley
& Sons, New York, 1979). Cyclization reactions of thioamides
(e.g. thioacetamide, thiourea) and alpha-halocarbonyl compounds
(such as alpha-haloketones, alpha-haloaldehydes) are particularly
useful for the construction of a thiazole ring system. For example,
cyclization reactions between thiourea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is a
thiazole, A is an amino group and X is a furan-2,5-diyl group;
cyclization reaction between thiourea and a bromopyruvate alkyl
ester give a 2-amino-4-alkoxycarbonylthiazole which is useful for
the preparations of compounds of formula I wherein R.sup.5 is a
thiazole and X is an alkylaminocarbonyl, an alkoxycarbonyl, an
alkylaminocarbonylamino, or an alkoxyacarbonylamino group.
Thioamides can be prepared using reactions reported in the
literature (Trost, Comprehensive organic synthesis, Vol. 6;
Pergamon press, New York, 1991, pages 419-434) and
alpha-halocarbonyl compounds are readily accessible via
conventional reactions (Larock, Comprehensive organic
transformations, VCH, New York, 1989). For example, amides can be
converted to thioamides using Lawesson's reagent or P.sub.2S.sub.5,
and ketones can be halogenated using various halogenating reagents
(e.g. NBS, CuBr.sub.2).
(ii) Construction of an Oxazole Ring System
[0271] Oxazoles useful for the present invention can be prepared
using various methods in the literature (Turchi, Oxazoles; Wiley
& Sons, New York, 1986). Reactions between isocyanides (e.g.
tosylmethylisocyanide) and carbonyl compounds (e.g. aldehydes and
acyl chlorides) can be used to construct oxazole ring systems (van
Leusen et al, Tetrahedron Lett., 1972, 2369). Alternatively,
cyclization reactions of amides (e.g. urea, carboxamides) and
alpha-halocarbonyl compounds are commonly used for the construction
of an oxazole ring system. For example, the reactions of urea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is an
oxazole, A is an amino group and X is a furan-2,5-diyl group.
Reactions between amines and imidates are also used to construct
the oxazole ring system (Meyers et al, J. Org. Chem., 1986, 51(26),
5111).
(III) Construction of a Pyridine Ring System
[0272] Pyridines useful for the synthesis of compounds of formula I
can be prepared using various known synthetic methods (Klingsberg,
Pyridine and Its Derivatives; Interscience Publishers, New York,
1960-1984). 1,5-Dicarbonyl compounds or their equivalents can be
reacted with ammonia or compounds which can generate ammonia to
produce 1,4-dihydropyridines which are easily dehydrogenated to
pyridines. When unsaturated 1,5-dicarbonyl compounds, or their
equivalents (e.g. pyrylium ions) are used to react with ammonia,
pyridines can be generated directly. 1,5-Dicarbonyl compounds or
their equivalents can be prepared using conventional chemistry. For
example, 1,5-diketones are accessible via a number of routes, such
as Michael addition of an enolate to an enone (or precursor Mannich
base (Gill et al, J. Am. Chem. Soc., 1952, 74, 4923)), ozonolysis
of a cyclopentene precursor, or reaction of silyl enol ethers with
3-methoxyallylic alcohols (Duhamel et al, Tetrahedron, 1986, 42,
4777). When one of the carbonyl carbons is at the acid oxidation
state, then this type of reaction produces 2-pyridones which can be
readily converted to 2-halopyridines (Isler et al, Helv. Chim.
Acta, 1955, 38, 1033) or 2-aminopyridines (Vorbruggen et al, Chem.
Ber., 1984, 117, 1523). Alternatively, a pyridine can be prepared
from an aldehyde, a 1,3-dicarbonyl compound and ammonia via the
classical Hantzsch synthesis (Bossart et al, Angew. Chem. Int. Ed.
Engl., 1981, 20, 762). Reactions of 1,3-dicarbonyl compounds (or
their equivalents) with 3-amino-enones or 3-amino-nitriles have
also been used to produce pyridines (such as the Guareschi
synthesis, Marinella, Org. Synth., Coll, Vol. IV, 1963, 210).
1,3-Dicarbonyl compounds can be made via oxidation reactions on
corresponding 1,3-diols or aldol reaction products (Mukaiyama, Org,
Reactions, 1982, 28, 203). Cycloaddition reactions have also been
used for the synthesis of pyridines, for example cycloaddition
reactions between oxazoles and alkenes (Naito et al., Chem. Pharm.
Bull, 1965, 13, 869), and Diels-Alder reactions between
1,2,4-triazines and enamines (Boger et al., J. Org. Chem., 1981,
46, 2179).
(iv) Construction of a Pyrimidine Ring System
[0273] Pyrimidine ring systems useful for the synthesis of
compounds of formula I are readily available (Brown, The
pyrimidines; Wiley, New York, 1994). One method for pyrimidine
synthesis involves the coupling of a 1,3-dicarbonyl component (or
its equivalent) with an N--C--N fragment. The selection of the
N--C--N component--urea (Sherrnan et al., Org. Synth., Coll. Vol.
IV, 1963, 247), amidine (Kenner et al., J. Chem. Soc., 1943, 125)
or guanidine (Burgess, J. Org. Chem., 1956, 21, 97; VanAllan, Org.
Synth., Coll. Vol. IV, 1963, 245)--governs the substitution at C-2
in the pyrimidine products. This method is particular useful for
the synthesis of compounds of formula I with various A groups. In
another method, pyrimidines can be prepared via cycloaddition
reactions such as aza-Diels-Alder reactions between a
1,3,5-triazine and an enamine or an ynamine (Boger et al., J. Org.
Chem., 1992, 57, 4331 and references cited therein).
(v) Construction of an Imidazole Ring System
[0274] Imidazoles useful for the synthesis of compounds of formula
I are readily prepared using a variety of different synthetic
methodologies. Various cyclization reactions are generally used to
synthesize imidazoles such as reactions between amidines and
alpha-haloketones (Mallick et al, J. Am. Chem. Soc., 1984, 106(23),
7252) or alpha-hydroxyketones (Shi et al, Synthetic Comm., 1993,
23(18), 2623), reactions between urea and alpha-haloketones, and
reactions between aldehydes and 1,2-dicarbonyl compounds in the
presence of amines.
(vi) Construction of an Isoxazole Ring System
[0275] Isoxazoles useful for the synthesis of compounds of formula
I are readily synthesized using various methodologies (such as
cycloaddition reactions between nitrile oxides and alkynes or
active methylene compounds, oximation of 1,3-dicarbonyl compounds
or alpha, beta-acetylenic carbonyl compounds or
alpha,beta-dihalocarbonyl compounds, etc.) can be used to
synthesize an isoxazole ring system (Grunanger et al., Isoxazoles;
Wiley & Sons, New York, 1991). For example, reactions between
alkynes and 5-diethylphosphono-2-chlorooximidofuran in the presence
of base (e.g. triethylamine, Hunig's base, pyridine) are useful for
the synthesis of compounds of formula I wherein R.sup.5 is an
isoxazole and X is a furan-2,5-diyl group.
(vii) Construction of a Pyrazole Ring System
[0276] Pyrazoles useful for the synthesis of compounds of formula I
are readily prepared using a variety of methods (Wiley, Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings;
Interscience Publishers, New York, 1967) such as reactions between
hydrazines and 1,3-dicarbonyl compounds or 1,3-dicarbonyl
equivalents (e.g. one of the carbonyl group is masked as an enamine
or ketal or acetal), and additions of hydrazines to acrylonitriles
followed by cyclization reactions (Dom et al, Org. Synth., 1973,
Coll. Vol. V, 39). Reaction of
2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphonofurans
with hydrazines are useful for the synthesis of compounds of
formula I wherein R.sup.5 is a pyrazole, X is a furan-2,5-diyl
group and B'' is an alkyl group.
(viii) Construction of a 1,2,4-triazole Ring System
[0277] 1,2,4-Triazoles useful for the synthesis of compounds of
formula I are readily available via various methodologies
(Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981). For example,
reactions between hydrazides and imidates or thioimidates (Sui et
al., Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al., J.
Med. Chem., 1995, 38(2), 2196), reactions between 1,3,5-triazine
and hydrazines (Grundmann et al., J. Org. Chem., 1956, 21, 1037),
and reactions between aminoguanidine and carboxylic esters (Ried et
al., Chem. Ber., 1968, 101, 2117) are used to synthesize
1,2,4-triazoles.
(6) Ring Closure to Construct a Heterocycle with a Phosphonate
[0278] Compounds of formula 4 can also be prepared using a ring
closure reaction to construct the heterocycle from precursors that
contain the phosphonate component. For example, cyclization
reactions between thiourea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is a
thiazole, A is an amino group and X is a furan-2,5-diyl group.
Oxazoles of the present invention can also be prepared using a ring
closure reaction. In this case, reactions of urea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is an
oxazole, A is an amino group and X is a furan-2,5-diyl group.
Reactions between 5-diethylphosphono-2-furaldehyde, an alkyl amine,
a 1,2-diketone and ammonium acetate are useful to synthesize
compounds of formula I wherein R.sup.5 is an imidazole and X is a
furan-2,5-diyl group. These types of ring closure reactions can
also be used for the synthesis of pyridines or pyrimidines useful
in the present invention. For example, reaction of
5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and
cyanoacetamide in the presence of base gives
5-alkyl-3-cyano-6-[2-(5-diethylphosphono)furanyl]-2-pyridones (Jain
et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversion
of these 2-pyridones to the corresponding 2-halopyridines (see
references cited in section 3 for the modifications of
heterocycles) will lead to compounds of formula I wherein R.sup.5
is a pyridine, A is a halo group, X is a furan-2,5-diyl group, and
B is an alkyl group. Reactions of
5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and
amidines in the presence of base give
5-alkyl-6-[2-(5-diethylphosphono)-furanyl]pyrimidines which will
lead to compounds of formula I wherein R.sup.5 is a pyrimidine, X
is a furan-2,5-diyl group and B is an alkyl group.
(7) Preparation of Various Precursors Useful for Cyclization
Reactions
[0279] Intermediates required for the synthesis of compounds in the
present invention are generally prepared using either an existing
method in the literature or a modification of an existing method.
Syntheses of some of the intermediates useful for the synthesis of
compounds in the present invention are described herein.
[0280] Various aryl phosphonate dialkyl esters are particularly
useful for the synthesis of compounds of formula I. For example,
compounds of formula I wherein X is a furan-2,5-diyl group can be
prepared from a variety of furanyl precursors. It is envisioned
that synthesis of other precursors may follow some or all of these
reaction steps, and some modifications of these reactions may be
required for different precursors.
5-Dialkylphosphono-2-furancarbonyl compounds (e.g.
5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran)
are well suited for the synthesis of compounds of formula I wherein
X is a furan-2,5-diyl group. These intermediates are prepared from
furan or furan derivatives using conventional chemistry such as
lithiation reactions, protection of carbonyl groups and
deprotection of carbonyl groups. For example, lithiation of furan
using known methods (Gschwend Org. React., 1979, 26: 1) followed by
addition of phosphorylating agents (e.g. CLPO.sub.3R.sub.2) gives
2-dialkylphosphono-furans (e.g. 2-diethylphosphonofuran). This
method can also be applied to a 2-substituted furan (e.g. 2-furoic
acid) to give a 5-dialkylphosphono-2-substituted furan (e.g.
5-diethylphosphono-2-furoic acid). It is envisioned that other aryl
phosphonate esters can also be prepared using this approach or a
modification of this approach. Alternatively, other methods such as
transition metal catalyzed reactions of aryl halides or triflates
(Balthazar et al. J. Org. Chem., 1980, 45: 5425; Petrakis et al. J.
Am. Chem. Soc., 1987, 109: 2831; Lu et al. Synthesis, 1987, 726)
are used to prepare aryl phosphonates. Aryl phosphonate esters can
also be prepared from aryl phosphates under anionic rearrangement
conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et
al. Synthesis, 1991, 691). N-Alkoxy aryl salts with alkali metal
derivatives of dialkyl phosphonate provide another general
synthesis for heteroaryl-2-phosphonate esters (Redmore J. Org.
Chem., 1970, 35: 4114).
[0281] A second lithiation step can be used to incorporate a second
group on the aryl phosphonate dialkyl ester such as an aldehyde
group, a trialkylstannyl or a halo group, although other methods
known to generate these functionalities (e.g. aldehydes) can be
envisioned as well (e.g. Vilsmeier-Hack reaction or Reimar-Teimann
reaction for aldehyde synthesis). In the second lithiation step,
the lithiated aromatic ring is treated with reagents that either
directly generate the desired functional group (e.g. for an
aldehyde using DMF, HCO.sub.2R, etc.) or with reagents that lead to
a group that is subsequently transformed into the desired
functional group using known chemistry (e.g. alcohols, esters,
nitrites, alkenes can be transformed into aldehydes). For example,
lithiation of a 2-dialkylphosphonofuran (e.g.
2-diethylphosphonofuran) under normal conditions (e.g. LDA in THF)
followed by trapping of the thus generated anion with an
electrophile (e.g. tributyltin chloride or iodine) produces a
5-functionalized-2-dialkylphosphonofuran (e.g.
5-tributylstannyl-2-diethylphosphonofuran or
5-iodo-2-diethylphosphonofuran). It is also envisioned that the
sequence of these reactions can be reversed, i.e. the aldehyde
moiety can be incorporated first followed by the phosphorylation
reaction. The order of the reaction will be dependent on reaction
conditions and protecting groups. Prior to the phosphorylation, it
is also envisioned that some of these functional groups may be
protected using a number of well-known methods (e.g. protection of
aldehydes as acetals, animals; protection of ketones as ketals).
The protected functional group is then unmasked after
phosphorylation. (Protective groups in Organic Synthesis, Greene,
T. W., 1991, Wiley, New York). For example, protection of
2-furaldehyde as 1,3-propanediol acetal followed by a lithiation
step (using for example LDA) and trapping the anion with a dialkyl
chlorophosphate (e.g. diethyl chlorophosphate), and subsequent
deprotection of the acetal functionality under normal deprotection
conditions produces the 5-dialkylphosphono-2-furaldehyde (e.g.
5-diethylphosphono-2-furaldehyde). Another example is the
preparation of 5-keto-2-dialkylphosphonofurans which encompass the
following steps: acylations of furan under Friedel-Crafts reaction
conditions give 2-ketofuran, subsequent protection of the ketone as
ketals (e.g. 1,3-propanediol cyclic ketal) followed by a lithiation
step as described above gives the 5-dialkylphosphono-2-furanketone
with the ketone being protected as a 1,3-propanediol cyclic ketal,
and final deprotection of the ketal under, for example, acidic
conditions gives 2-keto-5-dialkylphosphonofurans (e.g.
2-acetyl-5-diethylphosphonofuran). Alternatively, 2-ketofurans can
be synthesized via a palladium catalyzed reaction between
2-trialkylstannylfurans (e.g. 2-tributylstannylfuran) and an acyl
chloride (e.g. acetyl chloride, isobutyryl chloride). The
phosphonate moiety may be present in the 2-trialkylstannylfurans
(e.g. 2-tributylstannyl-5-diethylphosphonofuran).
2-Keto-5-dialkylphosphonofurans can also be prepared from a
5-dialkylphosphono-2-furoic acid (e.g. 5-diethylphosphono-2-furoic
acid) by conversion of the acid to the corresponding acyl chloride
and followed by additions of a Grignard reagent.
[0282] Some of the above described intermediates can also be used
for the synthesis of other useful intermediates. For example, a
2-keto-5-dialkylphosphonofuran can be further converted to a
1,3-dicarbonyl derivative which is useful for the preparation of
pyrazoles, pyridines or pyrimidines. Reaction of a
2-keto-5-dialkylphosphonofuran (e.g.
2-acetyl-5-diethylphosphonofuran) with a dialkylformamide dialkyl
acetal (e.g. dimethylformamide dimethyl acetal) gives a
1,3-dicarbonyl equivalent as a
2-(3-dialkylamino-2-alkyl-acryloyl)-5-dialkylphosphonofuran (e.g.
2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).
[0283] It is envisioned that the above described methods for the
synthesis of furan derivatives can be, either directly or with some
modifications, applied to syntheses of various other useful
intermediates such as aryl phosphonate esters (e.g. thienyl
phosphonate esters, phenyl phosphonate esters or pyridyl
phosphonate esters).
[0284] It is conceivable that when applicable the above described
synthetic methods can be adopted for parallel synthesis either on
solid phase or in solution to provide rapid SAR (structure activity
relationship) exploration of FBPase inhibitors encompassed in the
current invention, provided method development for these reactions
are successful.
Section 2
Synthesis of Compounds of Formula X
[0285] Synthesis of the compounds encompassed by the present
invention typically includes some or all of the following general
steps: (1) preparation of a phosphonate prodrug; (2) deprotection
of a phosphonate ester; (3) construction of a heterocycle; (4)
introduction of a phosphonate component; (5) synthesis of an
aniline derivative. Step (1) and step (2) were discussed in section
1, and discussions of step (3), step (4) and step (5) are given
below. These methods are also generally applicable to compounds of
Formula X.
##STR00051##
(3) Construction of a Heterocycle
(i) Benzothiazole Ring System
[0286] Compounds of formula 3 wherein G''.dbd.S, i.e.
benzothiazoles, can be prepared using various synthetic methods
reported in the literature. Two of these methods are given as
examples as discussed below. One method is the modification of
commercially available benzothiazole derivatives to give the
appropriate functionality on the benzothiazole ring. Another method
is the annulation of various anilines (e.g. compounds of formula 4)
to construct the thiazole portion of the benzothiazole ring. For
example, compounds of formula 3 wherein G''.dbd.S,
A.sup.2=NH.sub.2, L.sup.2, E.sup.2, J.sup.2=H,
X.sup.2.dbd.CH.sub.2O, and R'=Et can be prepared from the
commercially available 4-methoxy-2-amino thiazole via a two-step
sequence: conversion 4-methoxy-2-aminobenzothiazole to
4-hydroxy-2-aminobenzothiazole with reagents such as BBr.sub.3
(Node, M.; et al. J. Org. Chem. 45, 2243-2246, 1980) or AlCl.sub.3
in presence of a thiol (e.g. EtSH) (McOmie, J. F. W.; et al. Org.
Synth., Collect. Vol. V, 412, 1973) followed alkylation of the
phenol group with diethylphosphonomethyl trifluoromethylsulfonate
(Phillion, D. P.; et al. Tetrahedron Lett. 27, 1477-1484, 1986) in
presence of a suitable base (e.g. NaH) in polar aprotic solvents
(e.g. DMF) provide the required compound.
[0287] Several methods can be used to convert various anilines to
benzothiazoles (Sprague, J. M.; Land, A. H. Heterocycle. Compd. 5,
506-13, 1957). For example, 2-aminobenzothiazoles (formula 3
wherein A=NH.sub.2) can be prepared by annulation of compounds of
formula 4 wherein W.sub.2.dbd.H, using various common methods. One
method involves the treatment of a suitably substituted aniline
with a mixture of KSCN and CuSO.sub.4 in methanol to give a
substituted 2-aminobenzothiazole (Ismail, I. A.; Sharp, D. E;
Chedekel, M. R. J. Org. Chem. 45, 2243-2246, 1980). Alternatively,
a 2-aminobenzothiazole can also be prepared by the treatment of
Br.sub.2 in presence of KSCN in acetic acid (Patil, D. G.;
Chedekel, M. R. J. Org. Chem. 49, 997-1000, 1984). This reaction
can also be done in two step sequence. For example treatment of
substituted phenylthioureas with Br.sub.2 in CHCl.sub.3 gives
substituted 2-aminobenzothiazoles (Patil, D. G.; Chedekel, M. R. J.
Org. Chem. 49, 997-1000, 1984). 2-Aminobenzothiazoles can also be
made by condensation of ortho iodo anilines with thiourea in
presence of Ni catalyst (NiCl.sub.2 (PPh.sub.3).sub.2) (Takagi, K.
Chem. Lett. 265-266, 1986).
[0288] Benzothiazoles can undergo electrophilic aromatic
substitution to give 6-substituted benzothiazoles (Sprague, J. M.;
Land, A. H. Heterocycle. Compd. 5, 606-13, 1957). For example
bromination of formula 3 wherein G''=S, A.sup.2=NH.sub.2, L.sup.2,
E.sup.2, J.sup.2=H, X.sup.2.dbd.CH.sub.2O and R'=Et with bromine in
polar solvents such as AcOH gave compound of formula 3 wherein
E.sup.2=Br.
[0289] Furthermore, compounds of formula 3 wherein A is a halo, H,
alkoxy, alkylthio or an alkyl can be prepared from the
corresponding amino compound (Larock, Comprehensive organic
transformations, VCH, New York, 1989; Trost, Comprehensive organic
synthesis; Pergamon press, New York, 1991).
(ii) Benzoxazoles
[0290] Compounds of formula 3 wherein G''=O, i.e. benzoxazoles, can
be prepared by the annulation of ortho aminophenols with suitable
reagent (e.g. cyanogen halide (A=NH.sub.2; Alt, K. O.; et al J.
Heterocyclic Chem. 12, 775, 1975) or acetic acid (A=CH.sub.3; Saa,
J. M.; J. Org. Chem. 57, 589-594, 1992) or trialkyl orthoformate
(A=H; Org. Prep. Proced. Int., 22, 613, 1990)).
(4) Introduction of a Phosphonate Component
[0291] Compounds of formula 4 (wherein X.sup.2.dbd.CH.sub.2O and
R'=alkyl) can made in different ways (e.g. using alkylation and
nucleophilic substitution reactions). Typically, compounds of
formula 5 wherein M'=OH is treated with a suitable base (e.g. NaH)
in polar aprotic solvent (e.g. DMF, DMSO) and the resulting
phenoxide anion can be alkylated with a suitable electrophile often
with a phosphonate component present (e.g. diethyl
iodomethylphosphonate, diethyl trifluoromethylsulphonomethyl
phosphonate, diethyl p-methyltoluenesulphonomethylphosphonate). The
alkylation method can also be applied to the precursor compounds to
compounds of formula 5 wherein a phenol moiety is present and it
can be alkylated with a phosphonate containing component.
Alternately, compounds of formula 4 can also be made from the
nucleophilic substitution of the precursor compounds to compounds
of formula 5, for example, wherein a halo group, e.g., such as a
fluoro or a chloro, is present ortho to a nitro group. For example,
a compound of formula 4 (wherein X.sup.2.dbd.CH.sub.2O and R'=Et)
can be prepared from a 2-chloro-1-nitrobenzene derivative by
treatment with NaOCH.sub.2P(O)(OEt).sub.2 in DMF. Similarly,
compounds of formula 4 where X.sup.2=-alkyl-S-- or -alkyl-N-- can
also be made.
(5) Synthesis of an Aniline Derivative
[0292] Numerous synthetic methods have been reported for the
synthesis of aniline derivatives, these methods can be applied to
the synthesis of useful intermediates which can lead to compounds
of formula X. For example, various alkenyl or aryl groups can be
introduced on to a benzene ring via transition metal catalyzed
reactions (Kasibhatla, S. R., et al WO 98/39343 and the references
cited in); anilines can be prepared from their corresponding nitro
derivatives via reduction reactions (e.g. hydrogenation reactions
in presence of 10% Pd/C, or reduction reactions using SnCl.sub.2 in
HCl (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000,
1984)).
Section 3
Synthesis of Compounds of Formula XI
[0293] WO 98/39343 describes the synthesis of phosphonic acids and
esters of the benzimidazoles of Formula XI. The bisamidate
phosphonates of the present invention can be prepared by using
procedures described supra for compounds of Formula I.
Formulations
[0294] Compounds of the invention are administered orally in a
total daily dose in a range of about 0.01 mg/kg/dose to about 100
mg/kg/dose; and from about 0.1 mg/kg/dose to about 10 mg/kg/dose.
The use of time-release preparations to control the rate of release
of the active ingredient is contemplated. The dose may be
administered in as many divided doses as is convenient. When other
methods are used (e.g. intravenous administration), compounds are
administered to the affected tissue at a rate in the range from
0.05 to 10 mg/kg/hour; and from 0:1 to 1 mg/kg/hour. Such rates are
easily maintained when these compounds are intravenously
administered as discussed below.
[0295] For the purposes of this invention, the compounds may be
administered by a variety of means including orally, parenterally,
by inhalation spray, topically, or rectally in formulations
containing pharmaceutically acceptable carriers, adjuvants and
vehicles. The term parenteral as used here includes subcutaneous,
intravenous, intramuscular, and intraarterial injections with a
variety of infusion techniques. Intraarterial and intravenous
injection as used herein includes administration through catheters.
Oral administration is generally preferred.
[0296] Pharmaceutical compositions containing the active ingredient
may be in any form suitable for the intended method of
administration. When used for oral use for example, tablets,
troches, lozenges, aqueous or oil suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, syrups or elixirs
may be prepared. Compositions intended for oral use may be prepared
according to any method known to the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents including sweetening agents, flavoring agents,
coloring agents and preserving agents, in order to provide a
palatable preparation. Tablets containing the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipient
which are suitable for manufacture of tablets are acceptable. These
excipients may be, for example, inert diluents, such as calcium or
sodium carbonate, lactose, calcium or sodium phosphate; granulating
and disintegrating agents, such as maize starch, or alginic acid;
binding agents, such as starch, gelatin or acacia; and lubricating
agents, such as magnesium stearate, stearic acid or talc. Tablets
may be uncoated or may be coated by known techniques including
microencapsulation to delay disintegration and adsorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate alone or with a wax
may be employed.
[0297] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed with water
or an oil medium, such as peanut oil, liquid paraffin or olive
oil.
[0298] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0299] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0300] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, may also be
present.
[0301] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan monooleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan monooleate. The emulsion may also
contain sweetening and flavoring agents.
[0302] Syrups and elixirs may be formulated with sweetening agents,
such as glycerol, sorbitol or sucrose. Such formulations may also
contain a demulcent, a preservative, a flavoring or a coloring
agent.
[0303] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0304] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions. The pharmaceutical
composition can be prepared to provide easily measurable amounts
for administration. For example, an aqueous solution intended for
intravenous infusion should contain from about 3 to 330 .mu.g of
the active ingredient per milliliter of solution in order that
infusion of a suitable volume at a rate of about 30 mL/hr can
occur.
[0305] As noted above, 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 a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
administered as a bolus, electuary or paste:
[0306] 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 (e.g., povidone, gelatin, hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(e.g., sodium starch glycolate, cross-linked povidone, cross-linked
sodium carboxymethyl cellulose) surface active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent. The tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of the
active ingredient therein using, for example, hydroxypropyl
methylcellulose in varying proportions to provide the desired
release profile. Tablets may optionally be provided with an enteric
coating, to provide release in parts of the gut other than the
stomach, especially when the active ingredient is susceptible to
acid hydrolysis.
[0307] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0308] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0309] 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.
[0310] Formulations suitable for parenteral administration include
aqueous and non-aqueous isotonic sterile injection solutions which
may contain antioxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, 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. Injection solutions and suspensions may
be prepared from sterile powders, granules and tablets of the kind
previously described.
[0311] Suitable unit dosage formulations include those containing a
daily dose or unit, daily sub-dose, or an appropriate fraction
thereof, of a fructose 1,6-bisphosphatase inhibitor compound.
[0312] It will be understood, however, that the specific dose level
for any particular patient will depend on a variety of factors
including the activity of the specific compound employed; the age,
body weight, general health, sex and diet of the individual being
treated; the time and route of administration; the rate of
excretion; other drugs which have previously been administered; and
the severity of the particular disease undergoing therapy, as is
well understood by those skilled in the art.
Utility
[0313] One aspect of the invention is directed to novel
bis-phosphoramidate prodrugs of FBPase inhibitors to increase the
oral bioavailability of the parent drugs.
[0314] FBPase inhibitors and their prodrugs may be used to treat
diabetes mellitus, lower blood glucose levels, and inhibit
gluconeogenesis.
[0315] FBPase inhibitors and their prodrugs may also be used to
treat excess glycogen storage diseases. Excessive hepatic glycogen
stores are found in patients with some glycogen storage diseases.
Since the indirect pathway contributes significantly to glycogen
synthesis (Shulman, G. I. Phys. Rev..sub.--72:1019-1035, 1992),
inhibition of the indirect pathway (gluconeogenesis flux) decreases
glycogen overproduction.
[0316] FBPase inhibitors and their prodrugs may also be used to
treat or prevent diseases associated with increased insulin levels.
Increased insulin levels are associated with an increased risk of
cardiovascular complications and atherosclerosis (Folsom, et al.,
Stroke, 25:66-73, 1994; Howard, G. et al., Circulation,
93:1809-1817, 1996). FBPase inhibitors and their prodrugs are
expected to decrease postprandial glucose levels by enhancing
hepatic glucose uptake. This effect is postulated to occur in
individuals that are non-diabetic (or pre-diabetic, i.e. without
elevated hepatic glucose output "hereinafter HGO" or fasting blood
glucose levels). Increased hepatic glucose uptake will decrease
insulin secretion and thereby decrease the risk of diseases or
complications that arise from elevated insulin levels.
[0317] These aspects are described in greater detail below.
EXAMPLES
1. Synthesis of Compounds of Formula IA
Example 1
Preparation of 5-diethylnhosphono-2-furaldehyde (1)
[0318] Step A. A solution of 2-furaldehyde diethyl acetal (1 mmole)
in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at
-78.degree. C. After 1 h, diethyl chlorophosphate (1.2 mmole) was
added and the reaction was stirred for 40 min. Extraction and
evaporation gave a brown oil. Step B. The resulting brown oil was
treated with 80% acetic acid at 90.degree. C. for 4 h. Extraction
and chromatography gave compound 1 as a clear yellow oil.
Alternatively this aldehyde can be prepared from furan as described
below. Step C. A solution of furan (1 mmole) in diethyl ether was
treated with TMEDA (N,N,N'N'-tetramethylethylenediamine) (1 mmole)
and nBuLi (2 mmole) at -78.degree. C. for 0.5 h. Diethyl
chlorophosphate (1.2 mmole) was added to the reaction mixture and
stirred for another hour. Extraction and distillation gave diethyl
2-furanphosphonate as a clear oil. Step D. A solution of diethyl
2-furanphosphonate (1 mmole) in THF was treated with LDA (1.12
mmole, lithium N,N-diisopropylamide) at -78.degree. C. for 20 min.
Methyl formate (1.5 mmole) was added and the reaction was stirred
for 1 h. Extraction and chromatography gave compound 1 as a clear
yellow oil. Preferably this aldehyde can be prepared from
2-furaldehyde as described below. Step E. A solution of
2-furaldehyde (1 mmole) and N,N'-dimethylethylene diamine (1 mmole)
in toluene was refluxed while the resulting water being collected
through a Dean-Stark trap. After 2 h the solvent was removed in
vacuo and the residue was distilled to give.
furan-2-(N,N'-dimethylimidazolidine) as a clear colorless oil. bp
59-61.degree. C. (3 mm Hg). Step F. A solution of
furan-2-(N,N'-dimethylimidazolidine) (1 mmole) and TMEDA (1 mmole)
in THF was treated with nBuLi (1.3 mmole) at -40 to -48.degree. C.
The reaction was stirred at 0.degree. C. for 1.5 h and then cooled
to -55.degree. C. and treated with a solution of
diethylchlorophosphate (1.1 mmole) in THF. After stirring at
25.degree. C. for 12 h the reaction mixture was evaporated and
subjected to extraction to give
5-diethylphosphono-furan-2-(N,N'-dimethylimidazolidine) as a brown
oil. Step G. A solution of
5-diethylphosphonofuran-2-(N,N'-dimethyl- imidazolidine) (1 mmole)
in water was treated with concentrated sulfuric acid until pH=1.
Extraction and chromatography gave compound 1 as a clear yellow
oil.
Example 2
Preparation of 5-diethylphosphono-2-1[(1-oxo)alkyl]furans and
6-diethylphosphono-2-[(1-oxo)alkyl]pyridines
[0319] Step A. A solution of furan (1.3 mmole) in toluene was
treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic
anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at
56.degree. C. for 3.5 h. The cooled reaction mixture was quenched
with aqueous sodium bicarbonate (1.9 mmole), filtered through a
celite pad. Extraction, evaporation and distillation gave
2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77.degree.
C., 0.1 mm Hg). Step B. A solution of
2-[(4-methyl-1-oxo)pentyl]furan (1 mmole) in benzene was treated
with ethylene glycol (2.1 mmole) and p-toluenesulfonic acid (0.05
mmole) at reflux for 60 h while removing water via a Dean-Stark
trap. Triethyl orthoformate (0.6 mmole) was added and resulting
mixture was heated at reflux for an additional hour. Extraction and
evaporation gave 2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane as
an orange liquid. Step C. A solution of
2-(2-furanyl)-2-[(3-methyl)butyl]-1,3-dioxolane (1 mmole) in THF
was treated with TMEDA (1 mmole) and nBuLi (1.1 mmole) at
-45.degree. C., and the resulting reaction mixture was stirred at
-5 to 0.degree. C. for 1 h. The resulting reaction mixture was
cooled to -45.degree. C., and cannulated into a solution of diethyl
chlorophosphate in THF at -45.degree. C. The reaction mixture was
gradually warmed to ambient temperature over 1.25 h. Extraction and
evaporation gave
2-[2-(5-diethylphosphono)furanyl]-2-[(3-methyl)butyl]-1,3-dioxolane
as a dark oil. Step D. A solution of
2-[2-(5-diethylphosphono)furanyl]-2-[(3-methyl)butyl]-1,3-dioxolane
(1 mmole) in methanol was treated with 1 N hydrochloric acid (0.2
mmole) at 60.degree. C. for 18 h. Extraction and distillation gave
5-diethylphosphono-2-[(4-methyl-1-oxo)pentyl]furan (2.1) as a light
orange oil (bp 152-156.degree. C., 0.1 mm Hg).
[0320] The following compounds were prepared according to this
procedure:
(2.2) 5-diethylphosphono-2-acetylfuran: by 125-136.degree. C., 0.1
mm Hg. (2.3) 5-diethylphosphono-2-[(1-oxo)butyl]furan: by
130-145.degree. C., 0.08 mm Hg.
[0321] Alternatively these compounds can be prepared using the
following procedures:
Step E. A solution of 2-[(4-methyl-1-oxo)pentyl]furan (1 mmole,
prepared as in Step A) in benzene was treated with N,N-dimethyl
hydrazine (2.1 mmole) and trifluoroacetic acid (0.05 mmole) at
reflux for 6 h. Extraction and evaporation gave
2-[(4-methyl-1-oxo)pentyl]furan N,N-dimethyl hydrazone as a brown
liquid. Step F. 2-[(4-Methyl-1-oxo)pentyl]furan N,N-dimethyl
hydrazone was subjected to the procedures of Step C to give
2-[(4-methyl-1-oxo)pentyl]-5-diethylphosphonofuran N,N-dimethyl
hydrazone as a brown liquid which was treated with copper (II)
chloride (1.1 equivalent) in ethanol-water at 25.degree. C. for 6
h. Extraction and distillation gave compound 2.1 as a light orange
oil.
[0322] Some of 5-diethylphosphono-2-[(1-oxo)alkyl]furans are
prepared using the following procedures:
Step G. A solution of compound 1 (1 mmole) and 1,3-propanedithiol
(1.1 mmole) in chloroform was treated with borontrifluoride
etherate (0.1 mmole) at 25.degree. C. for 24 h. Evaporation and
chromatography gave 2-(2-(5-diethylphosphono)furanyl)-1,3-dithiane
as a light yellow oil.
[0323] A solution of 2-(2-(5-diethylphosphono)furanyl)-1,3-dithiane
(1 mmole) in THF was cooled to -78.degree. C. and treated with
nBuLi (1.2 mmole). After 1 h. at -78.degree. C. the reaction
mixture was treated with cyclopropanemethyl bromide and reaction
was stirred at -78.degree. C. for another hour. Extraction and
chromatography gave
2-(2-(5-diethylphosphono)furanyl)-2-cyclopropanemethyl-1,3-dithiane
as an oil.
[0324] A solution of
2-(2-(5-diethylphosphono)furanyl)-2-cyclopropanemethyl-1,3-dithiane
(1 mmole) in acetonitrile--water was treated with
[bis(trifluoroacetoxy)iodo]benzene (2 mmole) at 25.degree. C. for
24 h. Extraction and chromatography gave
5-diethylphosphono-2-(2-cyclopropylacetyl)furan as a light orange
oil.
[0325] The following compounds were prepared according to this
procedure:
(2.4) 5-Diethylphosphono-2-(2-ethoxycarbonylacetyl)furan (2.5)
5-Diethylphosphono-2-(2-methylthioacetyl)furan (2.6)
6-Diethylphosphono-2-acetylpyridine
Example 3
Preparation of 4-[2-(5-phosphono)furanyl]thiazoles.
4-[2-(6-phosphono)pyridyl]thiazoles and
4-[2-(5-phosphono)furanyl]selenazoles
[0326] Step A. A solution of compound 2.1 (1 mmole) in ethanol was
treated with copper (11) bromide (2.2 mmole) at reflux for 3 h. The
cooled reaction mixture was filtered and the filtrate was
evaporated to dryness. The resulting dark oil was purified by
chromatography to give
5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan as an
orange oil. Step B. A solution of
5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1
mmole) and thiourea (2 mmole) in ethanol was heated at reflux for 2
h. The cooled reaction mixture was evaporated to dryness and the
resulting yellow foam was suspended in saturated sodium bicarbonate
and water (pH=8). The resulting yellow solid was collected through
filtration to give
2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole. Step
C. A solution of
2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1
mmole) in methylene chloride was treated with bromotrimethylsilane
(10 mmole) at 25.degree. C. for 8 h. The reaction mixture was
evaporated to dryness and the residue was suspended in water. The
resulting solid was collected through filtration to give
2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (3.1) as an
off-white solid. mp>250.degree. C. Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.4PS+1.25HBr: C, 32.75; H, 4.06; N,
6.94. Found: C, 32.39; H, 4.33; N, 7.18.
[0327] According to the above procedures or in some cases with
minor modifications of these procedures using conventional
chemistry the following compounds were prepared:
(3.2) 2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.12H.sub.16NO.sub.4PS+HBr+0.1CH.sub.2Cl.sub.2: C,
37.20; H, 4.44; N, 3.58. Found: C, 37.24; H, 4.56; N, 3.30. (3.3)
4-[2-(5-Phosphono)furanyl]thiazole. Anal. calcd. for
C.sub.7H.sub.6NO.sub.4PS+0.65 HBr: C, 29.63; H, 2.36; N, 4.94.
Found: C, 29.92; H, 2.66; N, 4.57. (3.4)
2-Methyl-4-[2-(5-phosphono)furanyl]thiazole. mp 235-236.degree. C.
Anal. calcd. for C.sub.8H.sub.8NO.sub.4PS+0.25H.sub.2O: C, 38.48;
H, 3.43; N, 5.61. Found: C, 38.68; H, 3.33; N, 5.36. (3.5)
2-Phenyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.17H.sub.18NO.sub.4PS+HBr: C, 45.96; H, 4.31; N,
3.15. Found: C, 45.56; H, 4.26; N, 2.76. (3.6)
2-Isopropyl-4-[2-(5-phosphono)furanyl]thiazole. mp 194-197.degree.
C. Anal. calcd. for C.sub.10H.sub.12NO.sub.4PS: C, 43.96; H, 4.43;
N, 5.13. Found: C, 43.70; H, 4.35; N, 4.75. (3.7)
5-Isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp 164-166.degree.
C. Anal. calcd. for C.sub.11H.sub.14NO.sub.4PS: C, 45.99; H, 4.91;
N, 4.88. Found: C, 45.63; H, 5.01; N, 4.73. (3.8)
2-Aminothiocarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp
189-191.degree. C. Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.4PS.sub.2: C, 33.10; H, 2.43; N, 9.65.
Found: C, 33.14; H, 2.50; N, 9.32. (3.9)
2-(1-Piperidyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd. for C.sub.16H.sub.23N.sub.2O.sub.4PS+1.3HBr: C, 40.41;
H, 5.15; N, 5.89. Found: C, 40.46; H, 5.36; N, 5.53. (3.10)
2-(2-Thienyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.15H.sub.16NO.sub.4PS.sub.2+0.75H.sub.2O: C, 47.05;
H, 4.61; N, 3.66. Found: C, 47.39; H, 4.36; N, 3.28. (3.11)
2-(3-Pyridyl)-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.16H.sub.17N.sub.2O.sub.4PS+3.75HBr: C, 28.78; H,
3.13; N, 4.20. Found: C, 28.73; H, 2.73; N, 4.53. (3.12)
2-Acetamido-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp
179-181.degree. C. Anal. calcd. for
C.sub.13H.sub.17N.sub.2O.sub.5PS+0.25H.sub.2O: C, 44:76; H, 5.06;
N, 8.03. Found: C, 44.73; H, 5.07; N, 7.89. (3.13)
2-Amino-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for
C.sub.7H.sub.7N.sub.2O.sub.4PS: C, 34.15; H, 2.87; N, 11.38. Found:
C, 33.88; H, 2.83; N, 11.17. (3.14)
2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp
202-205.degree. C. Anal. calcd. for
C.sub.12H.sub.17N.sub.2O.sub.4PS+0.5H.sub.2O: C, 44.30; H, 5.58; N,
8.60. Found: C, 44.67; H, 5.27; N, 8.43. (3.15)
2-(N-amino-N-methyl)amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.
mp 179-181.degree. C. Anal. calcd. for
C.sub.12H.sub.18N.sub.3O.sub.4PS+1.25HBr: C, 33.33; H, 4.49; N,
9.72. Found: C, 33.46; H, 4.81; N, 9.72. (3.16)
2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]thiazole. mp
200-220.degree. C. Anal. calcd. for
C.sub.8H.sub.9N.sub.2O.sub.4PS+0.65HBr: C, 30.72; H, 3.11; N, 8.96.
Found: C, 30.86; H, 3.33; N, 8.85. (3.17)
2,5-Dimethyl-4-[2-(5-phosphono)furanyl]thiazole. mp 195.degree. C.
(decomp). Anal. calcd. for C.sub.9H.sub.10NO.sub.4PS+0.7HBr: C,
34.22; H, 3.41; N, 4.43. Found: C, 34.06; H, 3.54; N, 4.12. (3.18)
2-Aminothiocarbonyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd. for
C.sub.12H.sub.15N.sub.2O.sub.4PS.sub.2+O.1HBr+0.3EtOAc: C, 41.62;
H, 4.63; N, 7.35. Found: C, 41.72; H, 4.30; N, 7.17. (3.19)
2-Ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp
163-165.degree. C. Anal. calcd. for
C.sub.10H.sub.10NO.sub.6PS+0.5H.sub.2O: C, 38.47; H, 3.55; N, 4.49.
Found: C, 38.35; H, 3.30; N, 4.42. (3.20)
2-Amino-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.10H.sub.13N.sub.2O.sub.4PS+1HBr: C, 32.53; H,
3.82; N, 7.59. Found: C, 32.90; H, 3.78; N, 7.65. (3.21)
2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole.
mp>250.degree. C. Anal. calcd. for
C.sub.9H.sub.11N.sub.2O.sub.4PS: C, 39.42; H, 4.04; N, 10.22.
Found: C, 39.02; H, 4.15; N, 9.92. (3.22)
2-Cyanomethyl-4-[2-(5-phosphono)furanyl]thiazole. mp
204-206.degree. C. Anal. calcd. for C.sub.9H.sub.7N.sub.2O.sub.4PS:
C, 40.01; H, 2.61; N, 10.37. Found: C, 39.69; H, 2.64; N, 10.03.
(3.23)
2-Aminothiocarbonylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.
mp 177-182.degree. C. Anal. calcd. for
C.sub.12H.sub.16N.sub.3O.sub.4PS.sub.2+0.2hexane+0.3HBr: C, 39.35;
H, 4.78; N, 10.43. Found: C, 39.61; H, 4.48; N, 10.24. (3.24)
2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]thiazole. mp
235-237.degree. C. Anal. calcd. for
C.sub.10H.sub.13N.sub.2O.sub.4PS+0.3H.sub.2O: C, 40.90; H, 4.67; N,
9.54. Found: C, 40.91; H, 4.44; N, 9.37. (3.25)
2-Amino-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. mp
248-250.degree. C. Anal. calcd. for
C.sub.10H.sub.11N.sub.2O.sub.6PS+O.1HBr: C, 36.81; H, 3.43; N,
8.58. Found: C, 36.99; H, 3.35; N, 8.84. (3:26)
2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. mp
181-184.degree. C. Anal. calcd. for
C.sub.8H.sub.9N.sub.2O.sub.4PS.sub.2+0.4H.sub.2O: C, 32.08; H,
3.30; N, 9.35. Found: C, 32.09; H, 3.31; N, 9.15. (3.27)
2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.10H.sub.11N.sub.2O.sub.4PS+1H.sub.2O+0.75HBr: C,
32.91; H, 3.80; N, 7.68. Found: C, 33.10; H, 3.80; N, 7.34. (3.28)
2-Amino-5-methanesulfinyl-4-[2-(5-phosphono)furanyl]thiazole.
mp>250.degree. C. Anal. calcd. for
C.sub.8H.sub.9N.sub.2O.sub.5PS.sub.2+0.35NaCl: C, 29.23; H, 2.76;
N, 8.52. Found: C, 29.37; H, 2.52; N, 8.44. (3.29)
2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd. for C.sub.15H.sub.13N.sub.2O.sub.6PS+0.2H.sub.2O: C,
46.93; H, 3.52; N, 7.30. Found: C, 46.64; H, 3.18; N, 7.20. (3.30)
2-Amino-5-cyclobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.11H.sub.13N.sub.2O.sub.4PS+0.15 HBr+0.15H.sub.2O:
C, 41.93; H, 4.30; N, 8.89. Found: C, 42.18; H, 4.49; N, 8.53.
(3.31) 2-Amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole
hydrobromide. Anal. calcd. for
C.sub.10H.sub.11N.sub.2O.sub.4PSBr+0.73HBr+0.15MeOH+0.5H.sub.2O: C,
33.95; H, 3.74; N, 7.80; S: 8.93; Br: 16.24. Found: C, 33.72; H,
3.79; N, 7.65; S: 9.26; Br: 16.03. (3.32)
2-Amino-5-[(N,N-dimethyl)aminomethyl]-4-[2-(5-phosphono)furanyl]thiazole
dihydrobromide. Anal. calcd. for
C.sub.10H.sub.16N.sub.3O.sub.4Br.sub.2 PS+0.8CH.sub.2Cl.sub.2: C,
24.34; H, 3.33; N, 7.88. Found: C, 24.23; H, 3.35; N, 7.64. (3.33)
2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp
227.degree. C. (decomp). Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.6PS+0.1H.sub.2O+0.2HBr: C, 33.55; H,
2.94; N, 8.69. Found: C, 33.46; H, 3.02; N, 8.49. (3.34)
2-Amino-5-ethylthiocarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp
245.degree. C. (decomp). Anal. calcd. for
C.sub.10H.sub.11N.sub.2O.sub.5PS.sub.2: C, 35.93; H, 3.32; N, 8.38.
Found: C, 35.98; H, 3.13; N, 8.17. (3.35)
2-Amino-5-propyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp
245.degree. C. (decomp). Anal. calcd. for
C.sub.11H.sub.13N.sub.2O.sub.6PS: C, 39.76; H, 3.94; N, 8.43.
Found: C, 39.77; H, 3.72; N, 8.19. (3.36)
2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd.
for C.sub.14H.sub.13N.sub.2O.sub.4PS+H.sub.2O: C, 47.46; H, 4.27;
N, 7.91. Found: C, 47.24; H, 4.08; N, 7.85. (3.37)
2-Amino-5-[(N,N-diethyl)aminomethyl]-4-[2-(5-phosphono)furanyl]thiazole
dihydrobromide. Anal. calcd. for
C.sub.12H.sub.20N.sub.3O.sub.4Br.sub.2PS+0.1HBr+1.4 MeOH: C, 29.47;
H, 4.74; N, 7.69. Found: C, 29.41; H, 4.60; N, 7.32. (3.38)
2-Amino-5-[(N,N-dimethyl)carbamoyl]-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd. for
C.sub.10H.sub.12N.sub.3O.sub.5PS+1.3HBr+1.0H.sub.2O+0.3 Acetone: C,
28.59; H, 3.76; N, 9.18. Found: C, 28.40; H, 3.88; N, 9.01. (3.39)
2-Amino-5-carboxyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd.
for C.sub.8H.sub.7N.sub.2O.sub.6PS+0.2HBr+0.1H.sub.2O: C, 31.18; H,
2.42; N, 9.09. Found: C, 31.11; H, 2.42; N, 8.83. (3.40)
2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.
Mp 240.degree. C. (decomp). Anal. calcd. for
C.sub.11H.sub.13N.sub.2O.sub.6PS: C, 39.76; H, 3.94; N, 8.43.
Found: C, 39.42; H, 3.67; N, 8.09. (3.41)
2-Methyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd.
for C.sub.10H.sub.12O.sub.4PNS+0.75HBr+0.35H.sub.2O: C, 36.02; H,
4.13; N, 4.06. Found: C, 36.34; H, 3.86; N, 3.69. (3.42)
2-Methyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.11H.sub.12NO.sub.4PS+0.3HBr+0.5CHCl.sub.3: C,
37.41; H, 3.49; N, 3.79. Found: C, 37.61; H, 3.29; N, 3.41. (3.43)
2-Methyl-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.11H.sub.12NO.sub.6PS: C, 41.64; H, 3.81; N, 4.40.
Found: C, 41.61; H, 3.78; N, 4.39. (3.44)
2-[(N-acetyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd. for C.sub.11H.sub.13N.sub.2O.sub.6PS+0.15HBr: C,
38.36; H, 3.85; N, 8.13. Found: C, 38.74; H, 3.44; N, 8.13. (3.45)
2-Amino-5-(4-morpholinyl)methyl-4-[2-(5-phosphono)furanyl]thiazole
dihydrobromide. Anal. calcd. for
C.sub.12H.sub.18Br.sub.2N.sub.3O.sub.5PS+0.25HBr: C, 27.33; H,
3.49; N, 7.97. Found: C, 27.55; H, 3.75; N, 7.62. (3.46)
2-Amino-5-cyclopropylmethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.
Mp 238.degree. C. (decom p). Anal. calcd. for
C.sub.12H.sub.13N.sub.2O.sub.6PS: C, 41.86; H, 3.81; N, 8.14.
Found: C, 41.69; H, 3.70; N, 8.01. (3.47)
2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole
N,N-dicyclohexylammonium salt. Mp>250.degree. C. Anal. calcd.
for C.sub.8H.sub.9N.sub.2O.sub.4PS.sub.2+1.15 C.sub.12H.sub.23N, C,
52.28; H, 7.13; N, 8.81. Found: C, 52.12; H, 7.17; N, 8.81. (3.48)
2-[(N-Dansyl)amino]-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd for C.sub.23H.sub.26N.sub.3O.sub.6PS.sub.2+0.5HBr: C,
47.96; H, 4.64; N, 7.29. Found: C, 48.23; H, 4.67; N, 7.22. (3.49)
2-Amino-5-(2,2,2-trifluoroethyl)-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd for C.sub.9H.sub.8N.sub.2F.sub.3O.sub.4PS: C, 32.94; H,
2.46; N, 8.54. Found: C, 32.57; H, 2.64; N, 8.14. (3.50)
2-Methyl-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.9H.sub.10NO.sub.4PS.sub.2 C, 37.11; H, 3.46; N,
4.81. Found: C, 36.72; H, 3.23; N, 4.60. (3.51)
2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole ammonium
salt. Anal. calcd for C.sub.8H.sub.12N.sub.3O.sub.4PS.sub.2: C,
31.07; H, 3.91; N, 13.59. Found: C, 31.28; H, 3.75; N, 13.60.
(3.52) 2-Cyano-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.10H.sub.9N.sub.2O.sub.4PS: C, 42.26; H, 3.19; N,
9.86. Found: C, 41.96; H, 2.95; N, 9.76. (3.53)
2-Amino-5-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.8H.sub.9N.sub.2O.sub.5PS: C, 34.79; H, 3.28; N,
10.14. Found: C, 34.57; H, 3.00; N, 10.04. (3.54)
2-Cyano-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.12H.sub.13N.sub.2O.sub.4SP+0.09HBr: C, 46.15; H, 4.20; N,
8.97. Found: C, 44.81; H, 3.91; N, 8.51. (3.55)
2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]thiazole
hydrobromide. Anal. calcd for
C.sub.10H.sub.14BrN.sub.2O.sub.4PS.sub.2: C, 29.94; H, 3.52; N,
6.98. Found: C, 30.10; H, 3.20; N, 6.70. (3.56)
2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.13H.sub.11N.sub.2O.sub.4PS.sub.2: C, 44.07; H,
3.13; N, 0.91. Found: C, 43.83; H, 3.07; N, 7.74. (3.57)
2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for
C.sub.11H.sub.15N.sub.2O.sub.4PS.sub.2+0.6CH.sub.2Cl.sub.2: C,
36.16; H, 4.24; N, 7.27. Found: C, 36.39; H, 3.86; N, 7.21. (3.58)
2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]thiazole
hydrobromide. Anal. calcd for
C.sub.10H.sub.14BrN.sub.2O.sub.4PS.sub.2: C, 29.94; H, 3.52; N,
6.98. Found: C, 29.58; H, 3.50; N, 6.84. (3.59)
2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.9H.sub.11N.sub.2O.sub.4PS.sub.2+0.25HBr: C, 33.11; H,
3.47; N, 8.58. Found: C, 33.30; H, 3.42; N, 8.60. (3.60)
2-[(N-tert-butyloxycarbonyl)amino]-5-methoxymethyl-4-[2-(5-phosphono)fura-
nyl]thiazole. Anal. calcd for C.sub.14H.sub.19N.sub.2O.sub.7PS: C,
43.08; H, 4.91; N, 7.18. Found: C, 42.69; H, 4.58; N, 7.39. (3.61)
2-Hydroxyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for
C.sub.7H.sub.6NO.sub.5PS: C, 34.02; H, 2.45; N, 5.67. Found: C,
33.69; H, 2.42; N, 5.39. (3.62)
2-Hydroxyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.9H.sub.10NO.sub.5PS: C, 39.28; H, 3.66; N, 5.09. Found:
C, 39.04; H, 3.44; N, 4.93. (3.63)
2-Hydroxyl-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.10H.sub.12NO.sub.5PS+0.1HBr: C, 40.39; H, 4.10; N,
4.71. Found: C, 40.44; H, 4.11; N, 4.68. (3.64)
2-Hydroxyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.11H.sub.14NO.sub.5PS: C, 43.57; H, 4.65; N, 4.62.
Found: C, 43.45; H, 4.66; N, 4.46. (3.65)
5-Ethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.10H.sub.10NO.sub.6PS: C, 39.61; H, 3.32; N, 4.62. Found:
C, 39.60; H, 3.24; N, 4.47. (3.66)
2-Amino-5-vinyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd for
C.sub.9H.sub.9N.sub.2O.sub.4PS+0.28HCl: C, 37.66; H, 3.26; N, 9.46.
Found: C, 37.96; H, 3.37; N, 9.10. (3.67)
2-Amino-4-[2-(6-phosphono)pyridyl]thiazole hydrobromide. (3.68)
2-Methylthio-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.12H.sub.16NO.sub.4PS.sub.2: C, 43.24; H, 4.84; N,
4.20. Found: C, 43.55; H, 4.63; N, 4.46. (3.69)
2-Amino-5-isobutyl-4-[2-(3-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.11H.sub.15N.sub.2O.sub.4PS+0.1H.sub.2O: C, 43.45; H,
5.04; N, 9.21. Found: C, 43.68; H, 5.38; N, 8.98. (3.70)
2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]selenazole. Anal.
calcd for C.sub.11H.sub.15N.sub.2O.sub.4PSe+0.14HBr+0.6 EtOAc: C,
38.93; H, 4.86; N, 6.78. Found: C, 39.18; H, 4.53; N, 6.61. (3.71)
2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]selenazole. Anal.
calcd for C.sub.8H.sub.9N.sub.2O.sub.4PSSe+0.7 HBr+0.2 EtOAc: C,
25.57; H, 2.75; N, 6.78. Found: C, 25.46; H, 2.49; N, 6.74. (3.72)
2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]selenazole. Anal. calcd
for C.sub.9H.sub.11N.sub.2O.sub.4PSe+HBr: C, 26.89; H, 3.01; N,
6.97. Found: C, 26.60; H, 3.16; N, 6.81.
Example 4
Preparation of 5-halo-4-[2-(5-phosphono)furanyl]thiazoles
[0328] Step A. A solution of
2-amino-4-[2-(5-diethylphosphono)furanyl]thiazole (prepared as in
Step B of Example 3) (1 mmole) in chloroform was treated with
N-bromo succinimide (NBS) (1.5 mmole) at 25.degree. C. for 1 h.
Extraction and chromatography gave
2-amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]-thiazole as a
brown solid. Step B.
2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step C of Example 3 to give
2-amino-5-bromo-4-[2-(5-phosphono)furanyl]thiazole (4.1) as a
yellow solid. mp>230.degree. C. Anal. calcd. for
C.sub.7H.sub.6N.sub.2O.sub.4PSBr: C, 25.86; H, 1.86; N, 8.62.
[0329] Found: C, 25.93; H, 1.64; N, 8.53.
[0330] The following compounds were prepared according to this
procedure:
(4.2) 2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.7H.sub.6N.sub.2O.sub.4PSCl: C, 29.96; H, 2.16; N,
9.98. Found: C, 29.99; H, 1.97; N, 9.75. (4.3)
2-Amino-5-iodo-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for
C.sub.7H.sub.6N.sub.2O.sub.4PSI: C, 22.42; H, 2.28; N, 6.70. Found:
C, 22.32; H, 2.10; N, 6.31. (4.4)
2,5-Dibromo-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd. for
C.sub.7H.sub.4NO.sub.4PSBr.sub.2: C, 21.62; H, 1.04; N, 3.60.
Found: C, 21.88; H, 0.83; N, 3.66.
Example 5
Preparation of 2-halo-4-[2-(5-phosphono)furanyl]thiazoles
[0331] Step A. A solution of
2-amino-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole
(prepared as in Step B of Example 3) (1 mmole) in acetonitrile was
treated with copper (II) bromide (1.2 mmole) and isoamyl nitlite
(1.2 mmole) at 0.degree. C. for 1 h. Extraction and chromatography
gave 2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
as a brown solid. Step B.
2-Bromo-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step C of Example 3 to give
2-bromo-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (5.1) as a
yellow hygroscopic solid. Anal. calcd. for
C.sub.11H.sub.13NO.sub.4PSBr: C, 36.08; H, 3.58; N, 3.83. Found: C,
36.47; H, 3.66; N, 3.69.
[0332] The following compounds were prepared according to this
procedure:
(5.2) 2-Chloro-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole: Anal.
calcd. for C.sub.11H.sub.13NO.sub.4PSCl: C, 41.07; H, 4.07; N,
4.35. Found: C, 40.77; H, 4.31; N, 4.05. (5.3)
2-Bromo-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole: Anal.
calcd. for C.sub.8H.sub.7NO.sub.4PS.sub.2Br: C, 26.98; H, 1.98; N,
3.93. Found: C, 27.21; H, 1.82; N, 3.84.
Example 6
Preparation of Various 2- and 5-substituted
4-[2-(5-phosphono)furanyl]thiazoles
[0333] Step A. A solution of
2-bromo-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]thiazole (1
mmole, prepared as in the Step A of Example 5) in DMF was treated
with tributyl(vinyl)tin (5 mmole) and palladium
bis(triphenylphosphine) dichloride (0.05 mmole) at 100.degree. C.
under nitrogen. After 5 h the cooled reaction mixture was
evaporated and the residue was subjected to chromatography to give
2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as a
yellow solid. Step B.
2-Vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step C of Example 3 to give
2-vinyl-5-isobutyl-4-[2-(5-phosphono)-furanyl]thiazole (6.1) as a
yellow solid. Anal. calcd. for
C.sub.13H.sub.16NO.sub.4PS+1HBr+0.1H.sub.2O: C, 39.43; H, 4.38; N,
3.54. Found: C, 39.18; H, 4.38; N, 3.56.
[0334] This method can also be used to prepare various
5-substituted 4-[2-(5-phosphono)furanyl]thiazoles from their
corresponding halides.
Step C. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole
was subjected to Step A using 2-tributylstannylfuran as the
coupling partner to give
2-amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step D.
2-Amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step C of Example 3 to give
2-amino-5-(2-furanyl)-4-[2-(5-phosphono)furanyl]thiazole (6.2). mp
190-210.degree. C. Anal. calcd. for
C.sub.11H.sub.9N.sub.2O.sub.5PS+0.25HBr: C, 39.74; H, 2.80; N,
8.43. Found: C, 39.83; H, 2.92; N, 8.46.
[0335] The following compound was prepared according to this
procedure:
(6.3)
2-Amino-5-(2-thienyl)-4-[2-(5-diethylphosphono)furanyl]thiazole.
Anal. calcd. for
C.sub.11H.sub.9N.sub.2O.sub.4PS.sub.2+0.3EtOAc+0.11HBr: C, 40.77;
H, 3.40; N, 7.79. Found: C, 40.87; H, 3.04; N, 7.45.
Example 7
Preparation of 2-ethyl-4-[2-(5-phosphono)furanyl]-thiazoles
[0336] Step A. A solution of
2-vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole (1
mmole, prepared as in the Step A of Example 6) in ethanol was
treated with palladium on carbon (0.05 mmole) under 1 atmosphere of
hydrogen for 12 h. The reaction mixture was filtered, the filtrate
was evaporated and the residue was purified by chromatography to
give 2-ethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
as a yellow foam. Step B.
2-Ethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step C of Example 3 to give
2-ethyl-5-isobutyl-4-[2-(5-phosphono)-furanyl]thiazole (7.1) as a
yellow solid. Anal. calcd. for C.sub.13H.sub.18NO.sub.4PS+1HBr: C,
39.41; H, 4.83; N, 3.53. Found: C, 39.65; H, 4.79; N, 3.61.
Example 8
Preparation of 4-phosphonomethoxymethylthiazoles
[0337] Step A. A solution of diethyl hydroxymethylphosphonate (1
mmole) in DMF was treated with sodium hydride (1.2 mmole) followed
by 2-methyl-4-chloromethylthiazole (1 mmole) at 0.degree. C. and
stirred at 25.degree. C. for 12 h. Extraction and chromatography
gave 2-methyl-4-(diethylphosphonomethoxymethyl)thiazole. Step B.
2-Methyl-4-diethylphosphonomethoxymethylthiazole was subjected to
Step C of Example 3 to give
2-methyl-4-phosphonomethoxymethylthiazole (8.1). Anal. calcd. for
C.sub.6H.sub.10NO.sub.4PS+0.5HBr+0.5H.sub.2O: C, 26.43; H, 4.25; N,
5.14. Found: C, 26.52; H, 4.22; N, 4.84. Step C.
2-Methyl-4-diethylphosphonomethoxymethylthiazole was subjected to
Step A of Example 4 and followed by Step C of Example 3 to give
5-bromo-2-methyl-4-phosphonomethoxymethylthiazole (8.2). Anal.
calcd. for C.sub.6H.sub.9NO.sub.4PSBr+0.5HBr: C, 21.04; H, 2.80; N,
4.09. Found: C, 21.13; H, 2.69; N, 4.01. Step D. A solution of
ethyl 2-[(N-Boc)amino]-4-thiazolecarboxylate (1 mmole) in
CH.sub.2Cl.sub.2 (10 mL) was cooled to -78.degree. C., and treated
with DIBAL-H (1M, 5 mL). The reaction was stirred at -60.degree. C.
for 3 h, and quenched with a suspension of NaF/H.sub.2O (1 g/1 mL).
The resulting mixture was filtered and the filtrate was
concentrated to give 2-[(N-Boc)amino]-4-hydroxymethylthiazole as a
solid. Step E. A solution of
2-[(N-Boc)amino]-4-hydroxymethylthiazole (1 mmole) in DMF (10 mL)
was cooled to 0.degree. C., and treated with NaH (1.1 mmole). The
mixture was stirred at room temperature for 30 min, then
phosphonomethyl trifluoromethanesulfonate (1.1 mmole) was added.
After stirring at room temperature for 4 h, the reaction was
evaporated to dryness. Chromatography of the residue gave
2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole as a
solid. Step F.
2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole was
subjected to Step C of Example 3 to give
2-amino-4-phosphonomethoxymethylthiazole (8.3) as a solid. Anal.
calcd. for C.sub.5H.sub.9N.sub.2O.sub.4PS+0.16 HBr+0.1 MeOH: C,
25.49; H, 4.01; N, 11.66. Found: C, 25.68; H, 3.84; N, 11.33.
Example 9
Preparation of 2-carbamoyl-4-[2-(5-phosphono)furanyl]thiazoles
[0338] Step A. A solution of
2-ethoxycarbonyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in saturated methanolic ammonia solution at 25.degree. C.
for 12 h. Evaporation and chromatography gave
2-carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole as
a white solid. Step B.
2-Carbamoyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
was subjected to Step C of Example 3 to give
2-carbamoyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.1) as
a solid. mp 185-186.degree. C. Anal. calcd. for
C.sub.12H.sub.15N.sub.2O.sub.5PS: C, 43.64; H, 4.58; N, 8.48.
Found: C, 43.88; H, 4.70; N, 8.17.
[0339] The following compound was prepared according to this
procedure:
(9.2) 2-Carbamoyl-4-[2-(5-phosphono)furanyl]thiazole. mp
195-200.degree. C. Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.5PS+0.25H.sub.2O: C, 34.48; H, 2.71; N,
10.05. Found: C, 34.67; H, 2.44; N, 9.84.
[0340] 2-Ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazoles
can also be converted to other 2-substituted
4-[2-(5-phosphono)furanyl]thiazoles.
Step C. A solution of
2-ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazole (1
mmole) in methanol was treated with sodium borohydride (1.2 mmole)
at 25.degree. C. for 12 h. Extraction and chromatography gave
2-hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]thiazole Step D.
2-Hydroxymethyl-4-[2-(5-diethylphosphono)furanyl]-thiazole was
subjected to Step C of Example 3 to give
2-hydroxymethyl-4-[2-(5-phosphono)furanyl]thiazole (9.3). mp
205-207.degree. C. Anal. calcd. for
C.sub.8H.sub.8NO.sub.5PS+0.25H.sub.2O: C, 36.16; H, 3.22; N, 5.27.
Found: C, 35.98; H, 2.84; N, 5.15.
[0341] The following compound was prepared according to this
procedure:
(9.4)
2-Hydroxymethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp
160-170.degree. C. Anal. calcd. for
C.sub.12H.sub.16NO.sub.5PS+0.75HBr: C, 38.13; H, 4.47; N, 3.71.
Found: C, 37.90; H, 4.08; N, 3.60. Step E. A solution of
2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in methylene chloride was treated with phosphorus
tribromide (1.2 mmole) at 25.degree. C. for 2 h. Extraction and
chromatography gave
2-bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step F.
2-Bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole
was subjected to Step C of Example 3 to give
2-bromomethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.5).
mp 161-163.degree. C. Anal. calcd. for
C.sub.12H.sub.15BrNO.sub.4PS+0.25HBr: C, 35.99; H, 3.84; N, 3.50.
Found: C, 36.01; H, 3.52; N, 3.37.
[0342] The following compound was prepared according to this
procedure:
(9.6) 2-Bromomethyl-4-[2-(5-phosphono)furanyl]thiazole.
mp>250.degree. C. Anal. calcd. for C.sub.8H.sub.7BrNO.sub.4PS:
C, 29.65; H, 2.18; N, 4.32. Found: C, 29.47; H, 1.99; N, 4.16. Step
G. A solution of
2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in methylene chloride was treated with thionyl chloride
(1.2 mmole) at 25.degree. C. for 2 h. Extraction and chromatography
gave
2-chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step H.
2-Chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole
was subjected to Step C of Example 3 to give
2-chloromethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.7).
mp 160-162.degree. C. Anal. calcd. for
C.sub.12H.sub.15ClNO.sub.4PS+0.45HBr: C, 38.73; H, 4.18; N, 3.76.
Found: C, 38.78; H, 4.14; N, 3.73. Step I. A solution of
2-bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in DMF was treated with potassium phthalimide (1.2 mmole)
at 25.degree. C. for 12 h. Extraction and chromatography gave
2-phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step J.
2-Phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]--
thiazole (1 mmole) in ethanol was treated with hydrazine (1.5
mmole) at 25.degree. C. for 12 h. Filtration, evaporation and
chromatography gave
2-aminomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step K.
2-Aminomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazole
was subjected to Step C of Example 3 to give
2-aminomethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.8).
mp 235-237.degree. C. Anal. calcd. for
Cl.sub.2H.sub.17N.sub.2O.sub.4PS+0.205HBr: C, 43.30; H, 5.21; N,
8.41. Found: C, 43.66; H, 4.83; N, 8.02.
[0343] According to the above procedures or in some cases with some
minor modifications of the above procedures, the following
compounds were prepared:
(9.9) 2-Carbamoyl-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole.
Anal. calcd for C.sub.11H.sub.11N.sub.2O.sub.5PS+0.15HBr: C, 40.48;
H, 3.44; N, 8.58. Found: C, 40.28; H, 3.83; N, 8.34. (9.10)
2-Carbamoyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.10H.sub.11N.sub.2O.sub.5PS+0.75H.sub.2O: C, 38.04; H,
3.99; N, 8.87. Found: C, 37.65; H, 3.93; N, 8.76.
Example 10
Preparation of 4-[2-(5-phosphono)furanyl]oxazoles and
4-[2-(5-phosphono)furanyl]imidazoles
[0344] Step A. A solution of
5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furanyl (1
mmole) in t-BuOH was treated with urea (10 mmole) at reflux for 72
h. Filtration, evaporation and chromatography gave
2-amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole, and
2-hydroxy-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole.
Step B. 2-Amino-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole
was subjected to Step C of Example 3 to give
2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole (10.1). mp
250.degree. C. (decomp.). Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.5P: C, 46.16; H, 5.28; N, 9.79. Found:
C, 45.80; H, 5.15; N, 9.55. Step C.
2-Hydroxy-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole was
subjected to Step C of Example 3 to give
2-hydroxy-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole (10.14).
mp 205.degree. C. (decomp). Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.5P: C, 46.16; H, 5.28; N, 9.79. Found:
C, 45.80; H, 4.90; N, 9.73:
[0345] Alternatively 4-[2-(5-phosphono)furanyl]oxazoles and
4-[2-(5-phosphono)furanyl]imidazoles can be prepared as
follows:
Step D. A solution of
5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (1
mmole) in acetic acid was treated with sodium acetate (2 mmole) and
ammonium acetate (2 mmole) at 100.degree. C. for 4 h. Evaporation
and chromatography gave
2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-oxazole,
2-methyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]oxazole and
2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole.
Step E.
2-Methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]oxazole,
2-methyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]oxazole and
2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole were
subjected to Step C of Example 3 to give the following compounds:
(10.18) 2-Methyl-4-isobutyl-5-[2-(5-phosphono)furanyl]oxazole
hydrogen bromide. mp>230.degree. C.; Anal. calcd. for
C.sub.12H.sub.17BrNO.sub.5P+0.4H.sub.2O: C, 38.60; H, 4.81; N,
3.75. Found: C, 38.29; H, 4.61; N, 3.67. (10.19)
2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. Calcd. for C.sub.12H.sub.17BrNO.sub.5P: C, 39.36; H,
4.68; N, 3.83. Found: C, 39.33; H, 4.56; N, 3.85. (10.21)
2-Methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen
bromide. Anal. Calcd. for
C.sub.12H.sub.18BrN.sub.2O.sub.4P+0.2NH.sub.4Br: C, 37.46; H, 4.93;
N, 8.01. Found: C, 37.12; H, 5.11; N, 8.28.
[0346] Alternatively 4-[2-(5-phosphono)furanyl]imidazoles can be
prepared as follows:
Step F. A solution of 5-diethylphosphono-2-(bromoacetyl)furan (1
mmole) in ethanol was treated with trifluoroacetamidine (2 mmole)
at 80.degree. C. for 4 h. Evaporation and chromatography gave
2-trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole as an
oil. Step G.
2-Trifluoromethyl-4-[2-(5-diethylphosphono)furanyl]imidazole was
subjected to Step C of Example 3 to give
2-trifluoromethyl-4-[2-(5-phosphono)-furanyl]imidazole (10.22). mp
188.degree. C. (dec.); Anal. calcd. for
C.sub.8H.sub.6F.sub.3N.sub.2O.sub.4P+0.5HBr: C, 29.79; H, 2.03; N,
8.68. Found: C, 29.93; H, 2.27; N, 8.30.
[0347] Alternatively
4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]-imidazole can be
prepared as follows:
Step H. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole),
ammonium acetate (1.4 mmole), 3,4-butanedione (3 mmole) and
isobutylamine (3 mmole) in glacial acetic acid was heated at
100.degree. C. for 24 h. Evaporation and chromatography gave
4,5-dimethyl-1-isobutyl-2-[2-(5-diethylphosphono)furanyl]imidazole
as an yellow solid. Step I.
4,5-Dimethyl-1-isobutyl-2-[2-(5-diethylphosphono)furanyl]-imidazole
was subjected to Step C of Example 3 to give
4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]imidazole
(10.23); Anal. calcd. for C.sub.13H.sub.19N.sub.2O.sub.4P+1.35HBr:
C, 38.32; H, 5.03; N, 6.87. Found: C, 38.09; H, 5.04; N, 7.20.
[0348] According to the above procedures or in some cases with some
minor modifications of the above procedures, the following
compounds were prepared:
(10.2) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]oxazole. mp
250.degree. C. (decomp.); Anal. Calcd. for
C.sub.10H.sub.13N.sub.2O.sub.5P: C, 44.13; H, 4.81; N, 10.29.
Found: C, 43.74; H, 4.69; N, 9.92. (10.3)
2-Amino-5-ethyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for
C.sub.9H.sub.11N.sub.2O.sub.5P+0.4H.sub.2O: C, 40.73; H, 4.48; N,
10.56. Found: C, 40.85; H, 4.10; N, 10.21. (10.4)
2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd.
for C.sub.8H.sub.9N.sub.2O.sub.5P+0.1H.sub.2O: C, 39.07; H, 3.77 N,
11.39. Found: C, 38.96; H, 3.59; N, 11.18. (10.5)
2-Amino-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for
C.sub.7H.sub.7N.sub.2O.sub.5P+0.6H.sub.2O: C, 34.90; H, 3.43; N,
11.63. Found: C, 34.72; H, 3.08; N, 11.35. (10.6)
2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. calcd. for
C.sub.11H.sub.16N.sub.2O.sub.5BrP+0.4H.sub.2O: C, 35.29; H, 4.52;
N, 7.48. Found: C, 35.09; H, 4.21; N, 7.34. (10.7)
2-Amino-5-phenyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd.
for C.sub.13H.sub.11N.sub.2O.sub.5P: C, 50.99; H, 3.62; N, 9.15.
Found: C, 50.70; H, 3.43; N, 8.96. (10.8)
2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd.
for C.sub.14H.sub.13N.sub.2O.sub.5P+1.1H.sub.2O: C, 49.45; H, 4.51;
N, 8.24. Found: C, 49.35; H, 4.32; N, 8.04. (10.9)
2-Amino-5-cyclohexylmethyl-4-[2-(5-phosphono)furanyl]oxazole. Anal.
calcd. for C.sub.14H.sub.19N.sub.2O.sub.5P+0.3H.sub.2O: C, 50.70;
H, 5.96; N, 8.45. Found: C, 50.60; H, 5.93; N, 8.38. (10.10)
2-Amino-5-allyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for
C.sub.10H.sub.11N.sub.2O.sub.5P+0.4HBr+0.3H.sub.2O: C, 39.00; H,
3.93; N, 9.10. Found: C, 39.31; H, 3.83; N, 8.76. (10:11)
5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for
C.sub.11H.sub.14NO.sub.5P: C, 48.72; H, 5.20; N, 5.16. Found: C,
48.67; H, 5.02; N, 5.10. (10.12)
2-Amino-5-butyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd. for
C.sub.11H.sub.5N.sub.2O.sub.5P+0.2H.sub.2O: C, 45.59; H, 5.36; N,
9.67. Found: C, 45.32; H, 5.29; N, 9.50. (10.13)
5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole-2-one. Anal. calcd.
for C.sub.11H.sub.14NO.sub.6P+0.39HBr: C, 41.45; H, 4.55; N, 4.39.
Found: C, 41.79; H, 4.22; N, 4.04. (10.15)
5-Cyclohexylmethyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole.
Anal. calcd. for C.sub.14H.sub.19N.sub.2O.sub.5P+0.05HBr: C, 50.90;
H, 5.81; N, 8.48. Found: C, 51.06; H, 5.83; N, 8.25. (10.16)
5-Butyl-2-hydroxy-4-[2-(5-phosphono)furanyl]. Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.5P+0.2H.sub.2O: C, 45.59; H, 5.36; N,
9.67. Found: C, 45.77; H, 5.34; N, 9.39. (10.17)
5-Benzyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal.
calcd. for C.sub.14H.sub.13N.sub.2O.sub.5P: C, 52.51; H, 4.09; N,
8.75. Found: C, 52.29; H, 4.15; N, 8.36. (10.20)
2-Methyl-5-propyl-4-[2-(5-phosphono)furanyl]imidazole hydrogen
bromide. Anal. calcd. for
C.sub.11H.sub.16BrN.sub.2O.sub.4P+0.5H.sub.2O: C, 36.69; H, 4.76;
N, 7.78. Found: C, 36.81; H, 4.99; N, 7.42. (10.24)
2-Amino-5-(2-thienylmethyl)-4-[2-(5-phosphono)fluranyl]oxazole.
Anal. calcd for C.sub.12H.sub.11N.sub.2O.sub.5PS+0.9HBr: C, 36.12;
H, 3.01; N, 7.02. Found: C, 36.37; H, 2.72; N, 7.01. (10.25)
2-Dimethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole
hydrogen bromide. Anal. Calcd for
C.sub.13H.sub.20BrN.sub.2O.sub.5P+0.05HBr: C, 39.11; H, 5.06; N,
7.02. Found: C, 39.17; H, 4.83; N, 6.66 (10.26)
2-Isopropyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal.
Calcd for C.sub.14H.sub.20NO.sub.5P+0.8HBr: C, 44.48; H, 5.55; N,
3.71. Found: C, 44.45; H, 5.57; N, 3.73. (10.27)
2-Amino-5-ethoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp
245.degree. C. (decomp.). Anal. Calcd for
C.sub.10H.sub.11N.sub.2O.sub.7P: C, 39.75; H, 3.67; N, 9.27. Found:
C, 39.45; H, 3.71; N, 8.87 (10.28)
2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. Calcd for
C.sub.12H.sub.18BrN.sub.2O.sub.5P+0.7H.sub.2O: C, 36.60; H, 4.97;
N, 7.11. Found: C, 36.50; H, 5.09; N, 7.04. (10.29)
2-Ethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. Calcd for C.sub.13H.sub.19BrNO.sub.5P: C, 41.07; H,
5.04; N, 3.68. Found: C, 41.12; H, 4.84; N, 3:62. (10.30)
2-Ethylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. Calcd for C.sub.13H.sub.20BrN.sub.2O.sub.5P: C,
39.51; H, 5.10; N, 7.09. Found: C, 39.03; H, 5.48; N, 8.90. (10.31)
2-Vinyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd
for C.sub.13H.sub.16NO.sub.5P+0.25HBr: C, 49.18; H, 5.16; N, 4.41.
Found: C, 48.94; H, 5.15; N, 4.40. (10.32)
2-Amino-5-pentyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd for
C.sub.12H.sub.17N.sub.2O.sub.5P+0.5H.sub.2O: C, 46.61; H, 5.87; N,
9.06. Found: C, 46.38; H, 5.79; N, 9.07. (10.33)
5-Pentyl-2-hydroxy-4-[2-(5-phosphono)furanyl]imidazole. Anal.
calcd. for C.sub.12H.sub.17N.sub.2O.sub.5P: C, 48.00; H, 5.71; N,
9.33. Found: C, 48.04; H, 5.58; N, 9.26. (10.45)
2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]oxazole. mp
196.degree. C. (decomp). Anal. calcd. for
C.sub.8H.sub.9N.sub.2O.sub.5PS: C, 34.79; H, 3.28; N, 10.14. Found:
C, 34.60; H, 2.97; N, 10.00. (10.35)
2-Amino-5-benzyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp
230.degree. C. (decomp). Anal. calcd for
C.sub.15H.sub.13N.sub.2O.sub.7P+0.7H.sub.2O: C, 47.81; H, 3.85; N,
7.43. Found: C, 47.85; H, 3.88; N, 7.21. (10.36)
2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole.
mp 221.degree. C. (decomp). Anal. calcd for
C.sub.11H.sub.13N.sub.2O.sub.7P+0.9H.sub.2O: C, 39.75; H, 4.49; N,
8.43. Found: C, 39.72; H, 4.25; N, 8.20. (10.37)
2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp
240.degree. C. (decomp). Anal. calcd for
C.sub.9HgN.sub.2O.sub.7P+0.3H.sub.2O+0.1 Acetone: C, 37.31; H,
3.43; N, 9.36.
[0349] Found: C, 37.37; H, 3.19; N, 9.01.
(10.38)
2-Amino-5-[(N-methyl)carbamoyl]-4-[2-(5-phosphono)furanyl]oxazole-
. mp 235.degree. C. (decomp). Anal. calcd for
C.sub.9H.sub.10N.sub.3O.sub.6P: C, 37.64; H, 3.51; N, 14.63. Found:
C, 37.37; H, 3.22; N, 14.44. (10.39)
2-Amino-5-ethylthiocarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp
225.degree. C. (decomp). Anal. calcd for
C.sub.10H.sub.11N.sub.2O.sub.6PS: C, 37.74; H, 3.48; N, 8.80.
Found: C, 37.67; H, 3.27; N, 8.46. (10.40)
2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal.
calcd for C.sub.10H.sub.13N.sub.2O.sub.5PS+0.2HBr: C, 37.48; H,
4.15; N, 8.74. Found: C, 37.39; H, 4.11; N, 8.56. (10.41)
2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd
for C.sub.13H.sub.11N.sub.2O.sub.5PS+0.25 HBr: C, 43.55; H, 3.16;
N, 7.81. Found: C, 43.82; H, 3.28; N, 7.59. (10.42)
2-Amino-5-ethylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd
for C.sub.9H.sub.11N.sub.2O.sub.5PS+0.85HBr: C, 30.11; H, 3.33; N,
7.80. Found: C, 30.18; H, 3.44; N, 7.60. (10.43)
2-Amino-5-propylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd
for C.sub.10H.sub.13N.sub.2O.sub.5+H.sub.2O: C, 37.27; H, 4.69; N,
8.69; H.sub.2O: 5.59. Found: C, 37.27; H, 4.67; N, 8.60; H.sub.2O:
5.66. (10.44)
2-Amino-5-tert-butylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal.
calcd for C.sub.11H.sub.15N.sub.2O.sub.5PS+0.25HBr: C, 39.03; H,
4.54; N, 8.28. Found: C, 39.04; H, 4.62; N, 8.06. (10.34)
4,5-Dimethyl-2-[2-(5-phosphono)furanyl]imidazole. Anal. calcd. for
C.sub.9H.sub.11N.sub.2O.sub.4P+1.25H.sub.2O: C, 40.84; H, 5.14; N,
10.58. Found: C, 41.02; H, 5.09; N, 10.27.
Example 11
Preparation of N-alkylated 4-[2-(5-phosphono)furanyl]imidazoles and
4-[2-(5-phosphono)furanyl]oxazoles
[0350] Step A. A suspension of cesium carbonate (1.5 mmole) and
2-methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]imidazole (1
mmole) in DMF was treated with iodomethane (1.5 mmole) at
25.degree. C. for 16 h. Extraction and chromatography gave
1,2-dimethyl-4-isobutyl-5-[2-(5-diethylphosphono)-fiuanyl]imidazole
and
1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]imidazole.
Step B.
1,2-Dimethyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]-imidazole
and
1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-imidazole
were subjected to Step C of Example 3 to give the following
compounds: (11.1)
1,2-Dimethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]imidazole
hydrogen bromide. Anal. calcd. for
C.sub.13H.sub.20N.sub.2O.sub.4PBr+0.8H.sub.2O: C, 39.67; H, 5.53;
N, 7.12. Found: C, 39.63; H, 5.48; N, 7.16.
Example 12
Preparation of 2-[2-(6-phosphono)pyridyl]pyridine
[0351] Step A. A solution of 2,2'-bipyridyl (1 mmole) in
dichloromethane was treated with m-chloroperoxybenzoic acid (2
mmole) at 0.degree. C., and the reaction mixture was stirred at
25.degree. C. for 2 h. Extraction and chromatography gave
2,2'-bipyridyl-N-oxide. Step B. (Redmore, D., J. Org. Chem., 1970,
35, 4114) A solution of 2,2'-bipyridyl-N-oxide methyl ether (1
mmole, prepared from dimethyl sulfate and 2,2'-bipyridyl-N-oxide in
diethyl phosphite) was added slowly at -30.degree. C. to a solution
of n-butyl lithium (1 mmole) in diethyl phosphite at -30.degree. C.
The resulting reaction mixture was stirred at 25.degree. C. for 12
h. Extraction and chromatography gave
2-[2-(6-diethylphosphono)pyridyl]pyridine. Step C.
2-[2-(6-Diethylphosphono)pyridyl]pyridine was subjected to Step C
of Example 3 to give 2-[2-(6-phosphono)pyridyl]pyridine (12.1). mp
158-162.degree. C. Anal. calcd. for
C.sub.10H.sub.9N.sub.2O.sub.3P+0.5H.sub.2O+O.1HBr: C, 47.42; H,
4.02; N, 11.06. Found: C, 47.03; H, 3.67; N, 10.95.
Example 13
Preparation of 4,6-dimethyl-2-(phosphonomethoxymethyl)pyridine
[0352] Step A. A solution of 2,4,6-collidine (1 mmole) in carbon
tetrachloride was treated with NBS (5 mmole) and dibenzoyl peroxide
(0.25 mmole) at 80.degree. C. for 12 h. The reaction mixture was
cooled to 0.degree. C. and the precipitate was filtered. The
filtrate was concentrated under vacuum. Chromatography gave
2-bromomethyl-4,6-dimethylpyridine. Step B. A solution of diethyl
hydroxymethylphosphonate (1 mmole) in toluene was treated with
sodium hydride (1.1 mmole) at 0.degree. C., and after 15 min
2-bromomethyl-4,6-dimethylpyridine (1 mmole) was added. After 3 h
the reaction mixture was subjected to extraction and chromatography
to give 2-diethylphosphonomethyl-4,6-dimethylpyridine. Step C.
2-Diethylphosphonomethyl-4,6-dimethylpyridine was subjected to Step
C of Example 3 to give
4,6-dimethyl-2-(phosphonomethoxymethyl)pyridine (13.1). mp
109-112.degree. C. Anal. calcd. for
C.sub.9H.sub.14NO.sub.4P+1.0H.sub.2O+0.5HBr: C, 37.32; H, 5.74; N,
4.84. Found: C, 37.18; H, 5.38; N, 4.67.
[0353] The following compound was prepared similarly:
(13.2)
2-Amino-4-methyl-5-propyl-6-phosphonomethoxymethylpyrimidine. mp
153-156.degree. C. Anal. calcd. for
C.sub.10H.sub.18N.sub.3O.sub.4P+1.25H.sub.2O+1.6HBr: C, 28.11; H,
5.21; N, 9.84. Found: C, 28.25; H, 4.75; N, 9.74.
Example 14
Preparation of diethyl 5-tributylstannyl-2-furanphosphonate
[0354] A solution of diethyl 2-furanphosphonate (1 mmole, prepared
as in Step C of Example 1) in THF was cooled at -78.degree. C. and
cannulated to a solution of lithium N-isopropyl-N-cyclohexylamide
in THF at -78.degree. C. over 15 min. The resulting mixture was
stirred at -78.degree. C. for 2 h and cannulated into a solution of
tributyltin chloride (1 mmole) in THF at -78.degree. C. over 20
min. The mixture was then stirred at -78.degree. C. for 1 h, and at
25.degree. C. for 12 h. Extraction and chromatography gave compound
(14) as a light yellow oil.
Example 15
Preparation of 6-[2-(5-phosphono)furanyl]pyridines
[0355] Step A. A solution of 2,6-dichloropyridine (120 mmol) in
ethanol was treated with aqueous ammonia solution (28%, excess) at
160-165.degree. C. for 60 h in a sealed tube. Extraction and
chromatography gave 2-amino-6-chloropyridine as a white solid. Step
B. A solution of 2-amino-6-chloropyridine (1 mmole) and compound 14
(1 mmole) in p-xylene was treated with
tetrakis(triphenylphosphhine) palladium (0.05 mmole) at reflux for
12 h. Extraction and chromatography gave
2-amino-6-[2-(5-diethylphosphono)furanyl]pyridine as a light yellow
solid. Step C. 2-Amino-6-[2-(5-diethylphosphono)furanyl]pyridine
was subjected to Step C of Example 3 to give
2-amino-6-[2-(5-phosphono)furanyl]pyridine (15.1). mp
186-187.degree. C. Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.4P+0.4HBr: C, 39.67; H, 3.48; N, 10.28.
Found: C, 39.95, H, 3.36; N, 10.04. Step D. A solution of
2-amino-6-[2-(5-diethylphosphono)furanyl]pyridine (1 mmole) in
acetic acid was treated with a solution of bromine in acetic acid
(1N, 1 mmole) at 25.degree. C. for 0.5 h. Evaporation and
chromatography gave
2-amino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine and
2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine. Step
E. 2-Amino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine and
2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine were
subjected to Step C of Example 3 to give the following compounds:
(15.2) 6-Amino-3-bromo-2-[2-(5-phosphono)furanyl]pyridine. Anal.
calcd. for
C.sub.9H.sub.8BrN.sub.2O.sub.4P+0.7H.sub.2O+0.9HBr+0.12PhCH.sub.3:
C, 28.44; H, 2.73; N, 6.74. Found: C, 28.64; H, 2.79; N, 6.31.
(15.3) 6-Amino-3,5-dibromo-2-[2-(5-phosphono)furanyl]pyridine. mp
233-235.degree. C. Anal. calcd. for
C.sub.9H.sub.7Br.sub.2N.sub.2O.sub.4P+1.2HBr: C, 21.84; H, 1.67; N,
5.66. Found: C, 21.90; H, 1.52; N, 5.30. Step F. A solution of
2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)-furanyl]pyridine (1
mmole) in DMF was treated with tributyl(vinyl)tin (1.2 mmole) and
tetrakis(triphenylphosphine) palladium (0.2 mmole) at 85.degree. C.
for 4 h. Evaporation and chromatography gave
2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)furanyl]pyridine.
Step G. A solution of
2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)-furanyl]pyridine
(1 mmole) in ethyl acetate was treated with palladium on carbon
(10%) at 25.degree. C. under 1 atmosphere of hydrogen for 12 h.
Filtration, evaporation and chromatography gave
2-amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine. Step
H. 2-Amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine
was subjected to Step C of Example 3 to give
2-amino-3,5-diethyl-6-[2-(5-phosphono)furanyl]pyridine (15.4). mp
217-218.degree. C. Anal. calcd. for
C.sub.13H.sub.17N.sub.2O.sub.4P+0.7H.sub.2O+1.0HBr: C, 40.06; H,
5.02; N, 7.19. Found: C, 40.14; H, 4.70; N, 6.87. Step 1. A
solution of 2-amino-6-picoline (1 mmole) in 48% hydrobromic acid
(4.4 mmole) was treated with bromine (3 mmole) at 0.degree. C. for
1 h. An aqueous solution of sodium nitrite (2.5 mmole) was then
added and the reaction mixture was stirred at 0.degree. C. for 0.5
h. An aqueous solution of sodium hydroxide (9.4 mmole) was then
added and the reaction mixture was stirred at 25.degree. C. for 1
h. Extraction and chromatography gave 2,3-dibromo-6-picoline and
2,3,5-tribromo-6-picoline. Step J. 2,3-Dibromo-6-picoline was
subjected to Step B of Example 15 and followed by Step C of Example
3 to give 5-bromo-2-methyl-6-[2-(5-phosphono)furanyl]pyridine
(15.5). mp 207-208.degree. C. Anal. calcd. for
C.sub.10H.sub.9BrNO.sub.4P+0.6HBr: C, 32.76; H, 2.64; N, 3.88.
Found: C, 32.62; H, 2.95; N, 3.55.
[0356] Following compounds were prepared according to the above
described procedures or with some minor modifications of these
procedures using conventional chemistry.
(15.6) 2-[2-(5-Phosphono)furanyl]pyridine. mp 220-221.degree. C.
Anal. calcd. for C.sub.9H.sub.8NO.sub.4P+0.1H.sub.2O+0.45HBr: C,
41.05; H, 3.31; N, 5.32. Found: C, 41.06; H, 3.10; N, 5.10. (15.7)
2-Amino-3-nitro-6-[2-(5-phosphono)furanyl]pyridine. mp
221-222.degree. C. Anal. calcd. for
C.sub.9H.sub.8N.sub.3O.sub.6P+0.55HBr+0.02PhCH.sub.3: C, 33.12; H,
2.65; N, 12.68. Found: C, 33.22; H, 2:43; N, 12.26. (15.8)
2,3-Diamino-6-[2-(5-phosphono)furanyl]pyridine. mp 150-153.degree.
C. Anal. calcd. for
C.sub.9H.sub.10N.sub.3O.sub.4P+1.5HBr+0.05PhCH.sub.3: C, 29.46; H,
3.15; N, 11.02. Found: C, 29.50; H, 3.29; N, 10.60. (15.9)
2-Chloro-6-[2-(5-phosphono)furanyl]pyridine. mp 94-96.degree. C.
Anal. calcd. for C.sub.9H.sub.7ClNO.sub.4P+0.25HBr: C, 38.63; H,
2.61; N, 5.01. Found: C, 38.91; H, 3.00; N, 5.07. (15.10)
3,5-Dichloro-2-[2-(5-phosphono)furanyl]pyridine. mp 180-181.degree.
C. Anal. calcd. for C.sub.9H.sub.6Cl.sub.2NO.sub.4P+0.7HBr: C,
31.61; H, 2.01; N, 3.94. Found: C, 31.69; H, 2.09; N, 3.89. (15.11)
3-Chloro-5-trifluoromethyl-2-[2-(5-phosphono)furanyl]pyridine. mp
253-254.degree. C. Anal. calcd. for
C.sub.10H.sub.6ClF.sub.3NO.sub.4P: C, 36.67; H, 1.85; N, 4.28.
Found: C, 36.69; H, 1.89; N, 4.30. (15.12)
2-Amino-3-ethyl-6-[2-(5-phosphono)furanyl]pyridine. mp
220-221.degree. C. Anal. calcd. for
C.sub.11H.sub.13N.sub.2O.sub.4P+0.6HBr+0.2H.sub.2O: C, 41.24; H,
4.40; N, 8.74. Found: C, 41.02; H, 4.57; N, 8.68. (15.13)
6-Amino-3-ethyl-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd.
for C.sub.11H.sub.13N.sub.2O.sub.4P+1.0HBr+0.3H.sub.2O: C, 37.27;
H, 4.15; N, 7.90. Found: C, 37.27; H, 4.19; N, 7.51. (15.14)
6-Amino-3-propyl-2-[2-(5-phosphono)furanyl]pyridine. mp
252-253.degree. C. Anal. calcd. for
C.sub.12H.sub.15N.sub.2O.sub.4P+1.0HBr+1.0H.sub.2O+0.32PhCH.sub.3:
C, 41.65; H, 5.05; N, 6.82. Found: C, 41.97; H, 5.19; N, 6.83.
(15.15) 2,4-Dimethyl-3-bromo-6-[2-(5-phosphono)furanyl]pyridine. mp
232-233.degree. C. Anal. Calcd. for
C.sub.11H.sub.1BrNO.sub.4P+0.45HBr: C, 35.85; H, 3.13; N, 3.80.
Found: C, 35.98; H, 3.10; N, 3.71. (15.16)
2-Chloro-4-amino-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd.
for C.sub.9H.sub.8N.sub.2O.sub.4PCl+HBr+0.5H.sub.2O+MeOH: C, 30.99;
H, 3.38; N, 7.23. Found: C, 31.09; H, 3.21; N, 6.96. (15.17)
3-Hydroxyl-2-[2-(5-phosphono)furanyl]pyridine. Anal. calcd. for
C.sub.9H.sub.8NO.sub.5P+1.1HBr+0.3 CH.sub.3Ph: C, 37.26; H, 3.24;
N, 3.91. Found: C, 37.66; H, 3.55; N, 3.84. (15.19)
2-Amino-3-cyclopropyl-6-[2-(5-phosphono)furanyl]pyridine. Anal.
calcd. for C.sub.12H.sub.13N.sub.2O.sub.4PCl+HBr+0.4H.sub.2O: C,
39.13; H, 4.05; N, 7.61. Found: C, 39.06; H, 3.85; N, 7.37. (15.20)
2-Amino-5-cyclopropyl-6-[2-(5-phosphono)furanyl]pyridine. Anal.
calcd. for C.sub.12H.sub.13N.sub.2O.sub.4P+HBr+0.7 CH.sub.3Ph: C,
47.69; H, 4.64; N, 6.58. Found: C, 47.99; H, 4.62; N, 6.91. (15.21)
5-Amino-2-methoxy-6-[2-(5-phosphono)furanyl]pyridine. Anal. calcd.
for C.sub.10H.sub.11N.sub.2O.sub.5P+0.2H.sub.2O: C, 43.87; H, 4.20;
N, 10.23. Found: C, 43.71; H, 3.77; N, 9.77. (15.22)
2-Methyl-5-cyano-6-[2-(5-phosphono)furanyl]pyridine. Anal. Calcd.
for C.sub.11H.sub.9N.sub.2O.sub.4P+0.75 HBr+0.5H.sub.2O+0.5 MePh:
C, 45.84; H, 3.91; N, 7.37. Found: C, 45.93; H, 3.56; N, 7.36.
(15.23)
2-Amino-3,5-bis(cyano)-4-methyl-6-[2-(5-phosphono)furanyl]pyridine.
Anal. calcd. for C.sub.12H.sub.9N.sub.4O.sub.4P+0.7H.sub.2O: C,
45.49; H, 3.31; N, 17.68. Found: C, 45.48; H, 3.06; N, 17.51.
(15.24) 2-Chloro-4-cyano-6-[2-(5-phosphono)furanyl]pyridine. Anal.
calcd. for C.sub.10H.sub.6N.sub.2O.sub.4PCl: C, 42.20; H, 2.13; N,
9.84. Found: C, 41.95; H, 2.10; N, 9.47.
Example 16
Preparation of 2-[2-(5-phosphono)furanyl]pyrimidines and
4-[2-(5-phosphono)furanyl]pyrimidines
[0357] Step A. A solution of
5-diethylphosphono-2-[(1-oxo)pentyl]furan in N,N-dimethylformamide
dimethyl acetal was heated at reflux for 12 h. Evaporation and
chromatography gave diethyl
5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate. Step
B. A solution of diethyl
5-(2-propyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1
mmole) in ethanol was treated with guanidine hydrogen chloride (1.2
mmole) and sodium ethoxide (1 mmole) at 80.degree. C. for 12 h. The
reaction mixture was evaporated, and residue was dissolved in
water. The aqueous solution was neutralized with HCl (2 N), and
concentrated under reduced pressure. The residue was co-evaporated
with toluene to give
2-amino-5-propyl-4-[2-(5-ethylphosphono)-furanyl]pyrimidine as a
yellow solid. Step C.
2-Amino-5-propyl-4-[2-(5-ethylphosphono)furanyl]pyrimidine (1
mmole) and thionyl chloride was heated at reflux for 2 h. The
reaction mixture was evaporated to dryness and the residue was
dissolved in methylene chloride, and treated with excess pyridine
and ethanol at 25.degree. C. for 12 h. Evaporation and
chromatography gave
2-amino-5-propyl-4-[2-(5-diethylphosphono)furanyl]pyrimidine. Step
D. 2-Amino-5-propyl-4-[2-(5-diethylphosphono)furanyl]pyrimidine was
subjected to Step C of Example 3 to give
2-amino-5-propyl-4-[2-(5-phosphono)furanyl]pyrimidine (16.1). mp
258-259.degree. C. Anal. calcd. for
C.sub.11H.sub.14N.sub.3O.sub.4P+1.33H.sub.2O: C, 43.01; H, 5.47; N,
13.68. Found: C, 43.18; H, 5.31; N, 13.30.
[0358] The following compound was prepared according to this
procedure:
(16.2) 2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]pyrimidine. mp
218-220.degree. C. Anal. calcd. for
C.sub.12H.sub.16N.sub.3O.sub.4P+0.75HBr+0.3PhCH.sub.3: C, 43.92; H,
5.01; N, 10.90. Found: C, 44.02; H, 4.62; N, 10.69.
[0359] Alternatively other 4-[2-(5-phosphono)furanyl]pyrimidines
can be prepared according to the following procedures:
Step E. Compound 2.2 was subjected to Step A of Example 16 to give
diethyl 5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate as an
orange solid. Step F. A solution of diethyl
5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1 mmole),
sodium ethoxide ethanol solution (2 mmole) and guanidine
hydrochloride (1.1 mmole) was heated at 55.degree. C. for 2 h. The
reaction mixture was cooled in an ice bath and was neutralized with
1N HCl. Evaporation and chromatography gave
2-amino-4-[2-(5-diethylphosphono)-furanyl]pyrimidine as a yellow
solid. Step G. 2-Amino-4-[2-(5-diethylphosphono)furanyl]pyrimidine
was subjected to Step C of Example 3 to give
2-amino-4-[2-(5-phosphono)furanyl]-pyrimidine (16.3).
mp>230.degree. C. Anal. calcd. for
C.sub.8H.sub.8N.sub.3O.sub.4P+0.75H.sub.2O+0.2HBr: C, 35.48; H,
3.61; N, 15.51. Found: C, 35.42; H, 3.80; N, 15.30. Step H. A
solution of 2-amino-4-[2-(5-diethylphosphono)furanyl]pyrimidine (1
mmole) in methanol and chloroform was treated with NBS (1.5 mmole)
at 25.degree. C. for 1 h. Extraction and chromatography gave
2-amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]pyrimidine as a
yellow solid. Step I.
2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]pyrimidine was
subjected to Steps F and G of Example 15 followed by Step C of
Example 3 to give
2-amino-5-ethyl-4-[2-(5-phosphono)furanyl]pyrimidine (16.4).
mp>225.degree. C. Anal. calcd. for
C.sub.10H.sub.12N.sub.3O.sub.4P+1.4H.sub.2O+0.2HBr+0.25PhCH.sub.3:
C, 42.30; H, 5.14; N, 12.59. Found: C, 42.74; H, 4.94; N,
12.13.
[0360] The following compounds were prepared according to the above
described procedures or with some minor modifications using
conventional chemistry:
(16.5) 2-[2-(5-Phosphono)furanyl]pyrimidine. mp 194-196.degree. C.
Anal. calcd. for C.sub.8H.sub.7N.sub.2O.sub.4P+0.1H.sub.2O+0.55HBr:
C, 35.27; H, 2.87; N, 10.28. Found: C, 35.26; H, 2.83; N, 9.89.
(16.6) 2-Amino-6-methyl-4-[2-(5-phosphono)furanyl]pyrimidine. mp
238-239.degree. C. Anal. calcd. for
C.sub.9H.sub.10N.sub.3O.sub.4P+0.9HBr: C, 32.96; H, 3.35; N, 12.81.
Found: C, 33.25; H, 3.34; N, 12.46. (16.7)
2-Methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. mp
228-229.degree. C. Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.4PS+0.5H.sub.2O: C, 38.44; H, 3.58; N,
9.96. Found: C, 38.19; H, 3.25; N, 9.66. (16.8)
2-Methyl-4-[2-(5-phosphono)furanyl]pyrimidine. mp 206-212.degree.
C. Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.4P+0.9H.sub.2O+0.25HBr: C, 34.05; H,
3.30; N, 8.82. Found: C, 34.02; H, 3.06: N, 8.75. (16.9)
4,6-Dimethyl-5-bromo-2-[2-(5-phosphono)furanyl]pyrimidine. mp
251-252.degree. C. Anal. calcd. for
C.sub.10H.sub.10BrN.sub.2O.sub.4P: C, 36.06; H, 3.03; N, 8.41.
Found: C, 35.89; H, 2.82; N, 8.11. (16.10)
2-Amino-5-chloro-4-[2-(5-phosphono)furanyl]pyrimidine. Anal. calcd.
for C.sub.8H.sub.7ClN.sub.3O.sub.4P+0.5H.sub.2O: C, 33.76; H, 2.83;
N, 14.76. Found: C, 33.91; H, 2.86; N, 14.20. (16.11)
2-Amino-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine. Anal.
calcd. for C.sub.9H.sub.10N.sub.3O.sub.4PS+HBr: C, 29.36; H, 3.01;
N, 11.41. Found: C, 29.63; H, 3.02; N, 11.27. (16.12)
2-Amino-5-bromo-6-methylthio-4-[2-(5-phosphono)furanyl]pyrimidine.
Anal. calcd. for C.sub.9H.sub.9N.sub.3O.sub.4PSBr+0.8 HBr+0.2 MePh:
C, 27.80; H, 2.56; N, 9.35. Found: C, 27.74; H, 2.40; N, 8.94.
(16.13)
2-Amino-(4-morpholino)-4-[2-(5-phosphono)furanyl]pyrimidine.
Mp>230.degree. C. Anal. calcd. for
C.sub.12H.sub.15N.sub.4O.sub.5P+HBr+0.05 MePh: C, 36.02; H, 4.01;
N, 13.61. Found: C, 35.98; H, 4.04; N, 13.33. (16.14)
6-Amino-4-chloro-2-[2-(5-phosphono)furanyl]pyrimidine.
Mp>230.degree. C. Anal. calcd. for
C.sub.8H.sub.7N.sub.3O.sub.4PCl+0.5H.sub.2O: C, 33.76; H, 2.83; N,
14.76. Found: C, 33.83; H, 2.54; N, 14.48.
Example 17
Preparation of 2-[2-(5-phosphono)furanyl]pyrazines and
2-[2-(5-phosphono)furanyl]triazines
[0361] Step A. The procedures described in Example 16 can also be
applied to the synthesis of 2-[2-(5-phosphono)furanyl]pyrazine and
2-[2-(5-phosphono)furanyl]triazine analogs and in some cases with
minor modifications of these procedures using conventional
chemistry methods.
[0362] The following compounds were prepared accordingly:
(17.1) 2,5-Dimethyl-3-[2-(5-phosphono)furanyl]pyrazine. mp
212-213.degree. C. Anal. calcd. for
C.sub.10H.sub.11N.sub.2O.sub.4P+0.75HBr: C, 38.15; H, 3.76; N,
8.90. Found: C, 38.41; H, 3.93; N, 8.76. (17.2)
2-Chloro-6-[2-(5-phosphono)furanyl]pyrazine. mp 204-205.degree. C.
Anal. calcd. for
C.sub.8H.sub.6ClN.sub.2O.sub.4P+0.3HBr+0.02PhCH.sub.3: C, 34.10; H,
2.27; N, 9.77. Found: C, 34.36; H, 2.07; N, 9.39. (17.3)
2-Amino-3-propyl-6-[2-(5-phosphono)furanyl]pyrazine. mp
227-228.degree. C. Anal. calcd. for
C.sub.11H.sub.14N.sub.3O.sub.4P+0.7HBr: C, 38.87; H, 4.36; N,
12.36. Found: C, 39.19; H, 4.36; N, 11.92. (17.4)
2-Amino-6-[2-(5-phosphono)furanyl]pyrazine. mp 235-236.degree. C.
Anal. calcd. for
C.sub.8H.sub.8N.sub.3O.sub.4P+1.15H.sub.2O+0.03PhCH.sub.3; C,
37.26; H, 4.01; N, 15.88. Found: C, 37.09; H, 3.67; N, 15.51.
(17.5) 2-Amino-3-bromo-6-[2-(5-phosphono)furanyl]pyrazine. Anal.
calcd. for C.sub.8H.sub.7N.sub.3O.sub.4PBr+1HBr: C, 23.97; H, 2.01;
N, 10.48. Found: C, 24.00; H, 2.00; N, 10.13. (17.6)
3-Methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.4PS+0.3H.sub.2O: C, 38.94; H, 3.49; N,
10.09. Found: C, 38.99; H, 3.11; N, 9.67. (17.7)
6-Amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal.
calcd. for C.sub.9H.sub.10N.sub.3O.sub.4PS+1.5H.sub.2O+1.7 HBr+0.25
MePh: C, 27.19; H, 3.54; N, 8.85. Found: C, 27.10; H, 3.85; N,
8.49. (17.8)
6-Amino-5-methylthio-2-[2-(5-phosphono)furanyl]pyrazine. Anal.
calcd. for C.sub.9H.sub.10N.sub.3O.sub.4PS+1.1 HBr+0.05 MePh: C,
29.49; H, 3.04; N, 11.03. Found: C, 29.23; H, 2.79; N, 10.87.
(17.9)
6-Amino-5-methoxycarbonyl-3-chloro-2-[2-(5-phosphono)furanyl]pyrazine.
Anal. calcd. for C.sub.10H.sub.9N.sub.3O.sub.6PCl+0.3 HBr+0.04
MePh: C, 34.15; H, 2.68; N, 11.62. Found: C, 34.20; H, 2.90; N,
11.21. (17.10)
6-Amino-3-methylthio-2-[2-(5-phosphono)furanyl]pyrazine ammonium
salt. Anal. calcd. for C.sub.9H.sub.13N.sub.4O.sub.4PS+0.8 HBr: C,
29.30; H, 3.77; N, 15.18. Found: C, 29.03; H, 3.88; N, 15.08.
(17.11) 2-Amino-4-phenyl-6-[2-(5-phosphono)furanyl]triazine. Anal.
calcd. for C.sub.13H.sub.11N.sub.4O.sub.4P+HBr+0.1 EtOAc: C, 39.45;
H, 3.16; N, 13.73. Found: C, 39.77; H, 3.26; N, 13.48.
Example 18
Preparation of Analogs with X being Methoxycarbonyl
Methylthiocarbonyl, Methylaminocarbonyl and Methylcarbonylamino
Preparations of 4-phosphonomethoxycarbonylthiazoles and
4-phosphonomethoxycarbonyloxazoles
[0363] Step A. A solution of 2-amino-4-ethoxycarbonylthiazole (1
mmole) in 1,4-dioxane (5 mL) was treated with di-tert-butyl
dicarbonate (1.2 mmole), TMEDA (0.1 mmole) and DMAP (0.1 mmole) at
room temperature. After the reaction was stirred for 20 h, it was
evaporated to dryness. The residue was subjected to extraction to
give 2-[N-Boc(amino)]-4-ethoxycarbonyl thiazole as a yellow solid.
Step B. A solution of 2-[N-Boc(amino)]-4-ethoxycarbonylthiazole (1
mmole) in a 2:1 mixture of EtOH:H.sub.2O (10 mL) was treated with
NaOH (3N, 3 mmole) and the reaction was stirred at 60.degree. C.
for 4 h. The reaction was cooled to 0.degree. C. and neutralized to
pH 5 with 3 N HCl, and the resulting solid was collected via
filtration to give 2-[N-Boc(amino)]-4-carboxylthiazole as a white
solid. Step C. A suspension of 2-[N-Boc(amino)]-4-carboxylthiazole
(1 mmole) in CH.sub.2Cl.sub.2 (5 mL) was treated with thionyl
chloride (4 mmole) at room temperature. After stirring for 4 h the
reaction was evaporated to dryness. The residue was dissolved in
CH.sub.2Cl.sub.2 (5 mL) and added to a solution of
diethyl(hydroxymethyl)phosphonate (1.5 mmole) and pyridine (2
mmole) in CH.sub.2Cl.sub.2 (5 mL) at 0.degree. C. The reaction was
warmed to room temperature and stirred for 4 h. The reaction was
quenched with water and the mixture was subjected to extraction to
give 2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole as
a thick yellow oil.
[0364] Alternatively the ester linkage can be formed using a mixed
anhydride method as exemplified in the following procedures:
[0365] A solution of 2-[N-Boc(amino)]-4-carboxylthiazole (1 mmole)
in pyridine (5 mL) was treated with para-toluenesulfonyl chloride
(2 mmole) followed by diethyl (hydroxymethyl)phosphonate (2 mmole)
at room temperature for 4 h. Evaporation, extraction and
chromatography gave
2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole as a
thick yellow oil.
Step D. A solution of
2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1
mmole) and anisole (0.1 mmole) in methylene chloride (5 mL) and
trifluoroacetic acid (5 mL) was stirred at 0.degree. C. for 1 h,
and at room temperature for 1 h. Evaporation, extraction and
chromatography gave
2-amino-4-diethyllphosphonomethoxycarbonylthiazole as a solid. Step
E. 2-Amino-4-diethyllphosphonomethoxycarbonylthiazole was subjected
to Step C of Example 3 to give
2-amino-4-phosphonomethoxycarbonylthiazole (18.1) as a solid.
Mp>240.degree. C. (decomp). Anal. calcd. for
C.sub.5H.sub.7N.sub.2O.sub.5PS: C, 25.22: H, 2.96; N, 11.76. Found:
C, 25.30; H, 2.86; N, 11.77. Step F. A solution of
2-[N-Boc(amino)]-4-diethylphosphonomethoxycarbonylthiazole (1
mmole) in CH.sub.2Cl.sub.2 (5 mL) was treated with bromine (2
mmole) at room, temperature for 4 h. Evaporation and extraction
gave
2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole
as an orange oil which was subjected to Step D of Example 18
followed by Step C of Example 3 to give
2-amino-5-bromo-4-phosphonomethoxycarbonylthiazole (18.2) as a
solid. Mp>230.degree. C. (decomp). Anal. calcd. for
C.sub.5H.sub.6N.sub.2O.sub.5PSBr: C, 18.94; H, 1.91; N, 8.84.
Found: C, 19.08; H, 1.76; N, 8.67. Step G. A solution of
2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole
(1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1
mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5
mmole) and the reaction was stirred at 60.degree. C. for 2 h. The
solvent was removed and the residue taken up in EtOAc and stirred
with 2 mmol NaF in 5 ml water for 1 h. Extraction and
chromatography gave
2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonylthiazole
as a yellow solid. Step H. A suspension of
2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonyl thiazole
(1 mmole) and 10% Pd/C (0.5 mmole) in MeOH (5 mL) was stirred under
an atmosphere of H.sub.2 (balloon) at room temperature for 15 h.
Filtration and evaporation gave
2-[N-Boc(amino)]-5-ethyl-4-diethylphosphonomethoxycarbonylthiazole
as a yellow solid, which was subjected to Step D of Example 18
followed by Step C of Example 3 to give
2-amino-5-ethyl-4-phosphonomethoxycarbonylthiazole (18.3) as a
solid. Mp>230.degree. C. (decomp). Anal. Calcd. for
C.sub.7H.sub.11N.sub.2O.sub.5PS: 31.58; H, 4.16; N, 10.52. Found:
C, 31.80; H, 4.04; N, 10.18. Step I. A solution of
N-[Bis(methylthio)methylene]glycine methyl ester (1 mmole) in
anhydrous THF (2 mL) was added to a solution of t-BuOK (1.4 mmole)
in anhydrous THF (10 mL) at -78.degree. C. and the mixture was
stirred for 30 min. Then a solution of ethyl isothiocyanate (1
mmole) in anhydrous THF (2 mL) was added and the reaction was
stirred at -78.degree. C. for 30 min and at room temperature for 2
h. The reaction was quenched with water. Extraction and
chromatography gave
2-methylthio-5-(N-ethylamino)-4-methoxycarbonylthiazole as a yellow
solid, which was subjected to Step B and C of Example 18 followed
by Step C of Example 3 to give
2-methylthio-5-(N-ethylamino)-4-phosphonomethoxycarbonylthiazole
(18.4) as a solid. Mp>200.degree. C. (decomp). Anal. calcd. for
C.sub.8H.sub.13N.sub.2O.sub.5PS.sub.2+0.1 HBr: C, 29.99; H, 4.12;
N, 8.74. Found: C, 29.71; H, 4.10; N, 8.60. Step J. A solution of 1
mmol of 2-[N-Boc(amino)]-4-thiazolecarboxylate acid chloride (1
mmole) and pyridine (2 mmole) in CH.sub.2Cl.sub.2 (5 mL) was cooled
to -78.degree. C. and H.sub.2S(g) was bubbled through the solution
for 10 min. The reaction was stirred at -78.degree. C. for 30 min
and then warmed to room temperature. The mixture was washed with 3
N HCl. The organic phase was separated, dried and concentrated to
give 2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid as a yellow
solid. Step K. A solution of give
2-[N-Boc(amino)]-4-thiazolethiocarboxylic acid (1 mmole) in THF (5
mL) was cooled to -78.degree. C. and treated with NaH (2 mmole) in
small portions. After 10 min the reaction was treated with a
solution of diethylphosphonomethyl triflate in THF (5 mL). The
reaction was stirred at -78.degree. C. for 1 h, and then quenched
with H.sub.2O. Extraction and chromatography gave
2-[N-Boc(amino)]-4-diethylphosphonomethylthiocarbonylthiazole as a
thick oil, which was subjected to Step D of Example 18 followed by
Step C of Example 3 to give
2-amino-4-phosphonomethylthiocarbonylthiazole (18.5) as a solid.
Mp>230.degree. C. (decomp). Anal. calcd. for
C.sub.5H.sub.7N.sub.2O.sub.4PS.sub.2: C, 23.62; H, 2.78; N, 11.02.
Found: C, 23.77; H, 2.61; N, 10.73.
Preparation of 4-[(N-phosphonomethyl)carbamoyl]thiazole,
3-[N-phosphonomethyl)-carbamoyl]isothiazole and
2-[N-phosphonomethyl)carbamoyl]pyridine
[0366] Step L. A solution of 2-[N-Boc(amino)]-4-thiazolecarboxylic
acid (1 mmole) in DMF (5 mL) was treated with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
1.5 mmole) and 1-hydroxylbenzotriazole hydrate (HOBt, 1.5 mmole)
followed by addition of diethyl aminomethylphosphonate (1.5 mmole)
at room temperature for 24 h. The reaction was subjected to
evaporation, extraction and chromatography to give
2-[N-Boc(amino)]-4-[(N-diethylphosphonomethyl)carbamoyl]thiazole as
a white solid, which was subjected to Step D of Example 18 followed
by Step C of Example 3 to give
2-amino-4-[(N-phosphonomethyl)carbamoyl]thiazole (18.6) as a light
brown solid. Mp>245.degree. C. (decomp). Anal. calcd. for
C.sub.5H.sub.8N.sub.3O.sub.4PS+1.05 HBr: C, 18.64; H, 2.83; N,
13.04. Found: C, 18.78; H, 2.43; N, 12.97.
Preparation of 2-[(N-phosphonoacetyl)amino]thiazole and
2-[(N-phosphonoacetyl)amino]pyridine
[0367] Step M. A solution of 2-amino-4,5-dimethylthiazole
hydrochloride (2 mmole) and diethyl phosphonoacetica acid (1 mmole)
in DMF (5 mL) was treated with EDCI (1.5 mmole), HOBt (1.5 mmole)
and triethylamine (2 mmole) at room temperature for 24 h. The
reaction was subjected to evaporation, extraction and
chromatography to give
2-[(N-diethylphosphonoacetyl)amino]-4,5-dimethylthiazole as a
yellow solid, which was subjected to Step D of Example 18 followed
by Step C of Example 3 to give
4,5-dimethyl-2-[(N-phosphonoacetyl)amino]thiazole (18.7) as a light
brown solid. Mp>250.degree. C. Anal. calcd. for
C.sub.7H.sub.11N.sub.2O.sub.4PS: C, 33.60; H, 4.43; N, 11.20.
Found: C, 33.62; H, 4.29; N, 10.99.
[0368] The following compounds were prepared using some of the
above described procedures or some of the above procedures with
some minor modifications using conventional chemistry:
(18.8) 2-[(N-phosphonomethyl)carbamoyl]pyridine. Anal. calcd. for
C.sub.7H.sub.9N.sub.2O.sub.4P+HBr+0.67H.sub.2O: C, 27.20; H, 3.70;
N, 9.06. Found: C, 27.02; H, 3.71; N, 8.92. (18.9)
2-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for
C.sub.7H.sub.9N.sub.2O.sub.4P+HBr+0.67H.sub.2O: C, 27.20; H, 3.70;
N, 9.06. Found: C, 27.05; H, 3.59; N, 8.86. (18.10)
4-Ethoxycarbonyl-2-[(N-phosphonoacetyl)amino]thiazole. Anal. calcd.
for C.sub.8H.sub.11N.sub.2O.sub.6PS: C, 32.66; H, 3.77; N, 9.52.
Found: C, 32.83; H, 3.58; N, 9.20. (18.11)
2-Amino-5-bromo-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp
232.degree. C. (decomp). Anal. calcd. for
C.sub.5H.sub.7N.sub.3O.sub.4PSBr+0.15HBr+0.1 hexane: C, 19.97; H,
2.56; N, 12.48. Found: C, 19.90; H, 2.29; N, 12.33. (18.12)
2-Amino-5-(2-thienyl)-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp
245.degree. C. (decomp). Anal. calcd. for
C.sub.9H.sub.10N.sub.3O.sub.4PS.sub.2+HBr+0.1 EtOAc: C, 27.60; H,
2.91; N, 10.27. Found: C, 27.20; H, 2.67; N, 9.98. (18.13)
4,5-Dichloro-3-[(N-phosphonomethyl)carbamoyl]isothiazole. Mp
189-191.degree. C. Anal. calcd. for
C.sub.5H.sub.5N.sub.2O.sub.4PSCl.sub.2: C, 20.63; H, 1.73; N, 9.62.
Found: C, 20.43; H, 1.54; N, 9.51. (18.14)
2-Amino-5-bromo-4-{[N-(1-phosphono-1-phenyl)methyl]carbamoyl}thiazole.
Mp>250.degree. C. Anal. calcd. for
C.sub.11H.sub.11N.sub.3O.sub.4PSBr: C, 33.69; H, 2.83; N, 10.71.
Found: C, 33.85; H, 2.63; N, 10.85. (18.15)
2-Amino-5-(2-thienyl)-4-phosphonomethoxycarbonylthiazole.
Mp>230.degree. C. (decomp). Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.5PS.sub.2: C, 33.75; H, 2.83; N, 8.75.
Found: C, 33.40; H, 2.74; N, 8.51. (18.16)
2-Amino-5-benzyl-4-phosphonomethoxycarbonylthiazole.
Mp>230.degree. C. (decomp). Anal. calcd. for
C.sub.12H.sub.13N.sub.2O.sub.5PS: C, 43.91; H, 3.99; N, 8.53.
Found: C, 43.77; H, 4.03; N, 8.25. (18.17)
2-Methylthio-5-methylamino-4-phosphonomethoxycarbonylthiazole.
Anal. calcd. for C.sub.7H.sub.11N.sub.2O.sub.5PS.sub.2+0.2 HBr: C,
26.74; H, 3.59; N, 8.91. Found: C, 26.79; H, 3.89; N, 8.89. (18.18)
2-Amino-5-ethyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp
180.degree. C. (decomp). Anal. calcd. for
C.sub.7H.sub.12N.sub.3O.sub.4PS+HBr+0.4 CH.sub.2Cl.sub.2: C, 23.49;
H, 3.67; N, 11.18. Found: C, 23.73; H, 3.29; N, 11.42. (18.19)
2-Amino-5-isopropyl-4-[(N-phosphonomethyl)carbamoyl]thiazole. Mp
247-250.degree. C. Anal. calcd. for
C.sub.8H.sub.14N.sub.3O.sub.4PS: C, 34.41; H, 5.05; N, 15.05.
Found: C, 34.46; H, 4.80; N, 14.68. (18.20)
2-Amino-5-isopropyl-4-phosphonomethoxycarbonylthiazole.
Mp>230.degree. C. Anal. calcd. for
C.sub.8H.sub.13N.sub.2O.sub.5PS: C, 34.29; H, 4.68; N, 10.00.
Found: C, 33.97; H, 4.49; N, 9.70. (18.21)
2-Amino-5-phenyl-4-phosphonomethoxycarbonylthiazole.
Mp>230.degree. C. Anal. calcd. for
C.sub.11H.sub.11N.sub.2O.sub.5PS: C, 42.04; H, 3.53; N, 8.91.
Found: C, 42.04; H, 3.40; N, 8.72. (18.22)
2-Amino-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for
C.sub.5H.sub.7N.sub.2O.sub.6P+0.09-HBr: C, 26.18; H, 3.12; N,
12.21. Found: C, 26.29; H, 3.04; N, 11.90. (18.23)
2-Amino-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd. for
C.sub.7H.sub.10N.sub.3O.sub.4P+1.1 HBr+0.25 MeOH: C, 26.54; H,
3.72; N, 12.80. Found: C, 26.79; H, 3.63; N, 12.44. (18.24)
2-Amino-5-methyl-4-[(N-phosphonomethyl)carbamoyl]thiazole.
Mp>250.degree. C. Anal. calcd. for
C.sub.6H.sub.10N.sub.3O.sub.4PS+0.06 EtOAc: C, 29.22; H, 4.12; N,
16.38. Found: C, 29.03; H, 3.84; N, 16.01. (18.25)
2-Amino-3-bromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal. calcd.
for C.sub.7H.sub.9N.sub.3O.sub.4PBr+1.25 HBr+0.8 EtOAc: C, 25.43;
H, 3.48; N, 8.72. Found: C, 25.58; H, 3.71; N, 8.56. (18.26)
2-Amino-3,5-dibromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal.
calcd. for C.sub.7H.sub.8N.sub.3O.sub.4PBr.sub.2+HBr+0.5 EtOAc: C,
21.03; H, 2.55; N, 8.18. Found: C, 21.28; H, 2.55; N, 7.91. (18.27)
2-Amino-5-methyl-4-phosphonomethoxycarbonylthiazole. Mp 230.degree.
C. (decomp). Anal. calcd. for C.sub.6H.sub.9N.sub.2O.sub.5PS: C,
28.58; H, 3.60; N, 11.11. Found: C, 28.38; H, 3.49; N, 11.10.
(18.28) 2-Amino-3,5-diethyl-6-[(N-phosphonoacetyl)amino]pyridine.
MS calcd. for C.sub.11H.sub.18N.sub.3O.sub.4P+H: 288, found 288.
(18.29)
2-Amino-3,5-dibromo-6-{[N-(2,2-dibromo-2-phosphono)acetyl]amino}pyridine.
Anal. calcd. for C.sub.7H.sub.6N.sub.3O.sub.4PBr.sub.4+0.5
HBr+EtOAc: C, 19.56; H, 2.16; N, 6.22. Found: C, 19.26; H, 2.29; N,
5.91. (18.30)
2-Amino-5-isopropyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd.
for C.sub.8H.sub.13N.sub.2O.sub.6P+0.2 HBr: C, 34.27; H, 4.75; N,
9.99. Found: C, 34.47; H, 4.84; N, 9.83. (18.31)
2-Amino-5-[1-(2-cyclohexylmethyl)ethynyl]-4-phosphonomethoxycarbonylthiaz-
ole. Mp 230.degree. C. (decomp). Anal. calcd. for
C.sub.14H.sub.19N.sub.2O.sub.5PS+0.1 HBr: C, 45.89; H, 5.25; N,
7.64. Found: C, 45.85; H, 4.96; N, 7.44. (18.32)
2-Amino-5-[1-(4-cyano)butynyl]-4-phosphonomethoxycarbonylthiazole.
Mp 230.degree. C. (decomp). Anal. calcd. for
C.sub.10H.sub.10N.sub.3O.sub.5PS+0.25 HBr: C, 35.80; H, 3.08; N,
12.53. Found: C, 35.92; H, 2.99; N, 12.20. (18.33)
2-Amino-5-methyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd.
for C.sub.6H.sub.9N.sub.2O.sub.6P+0.15 HBr: C, 29.03; H, 3.71; N,
11.28. Found: C, 28.98; H, 3.66; N, 11.21. (18.34)
2-Amino-5-[1-(4-cyano)butyl]-4-phosphonomethoxycarbonylthiazole. Mp
230.degree. C. (decomp). Anal. calcd. for
C.sub.10H.sub.14N.sub.3O.sub.5PS: C, 37.62; H, 4.42; N, 13.16.
Found: C, 37.23; H, 4.18; N, 12.79. (18.35)
2-Amino-5-pentyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd.
for C.sub.10H.sub.17N.sub.2O.sub.6P: C, 41.10; H, 5.86; N, 9.59.
Found: C, 41.16; H, 5.75; N, 9.50. (18.36)
2-[N-Boc(amino)]-4-[(2-phosphono)ethoxycarbonyl]thiazole. Anal.
calcd. for C.sub.11H.sub.17N.sub.2O.sub.7PS: C, 37.50; H, 4.86; N,
7.95. Found: C, 37.10; H, 4.59; N, 7.84. (18.37)
2-Amino-4-[(2-phosphono)ethoxycarbonyl]thiazole hydrobromide. Anal.
calcd. for C.sub.6H.sub.9N.sub.2O.sub.5PS+HBr: C, 21.63; H, 3.03;
N, 8.41. Found: C, 22.01; H, 2.99; N, 8.15. (18.38)
2-Amino-5-butyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd. for
C.sub.9H.sub.15N.sub.2O.sub.6P: C, 38.86; H, 5.43; N, 10.07. Found:
C, 38.59; H, 5.43; N, 9.96. (18.39)
2-Amino-5-[1-(1-oxo-2,2-dimethyl)propyl]-4-phosphonomethoxycarbonylthiazo-
le. Anal. Calcd. for C.sub.10H.sub.15N.sub.2O.sub.6PS: C, 37.27; H,
4.69; N, 8.69. Found: C, 37.03; H, 4.69; N, 8.39. (18.40)
2-Amino-5-propyl-4-phosphonomethoxycarbonyloxazole. Anal. calcd.
for C.sub.8H.sub.13N.sub.2O.sub.6P+0.35 EtOAc+0.05 HBr: C, 37.75;
H, 5.34; N, 9.37. Found: C, 37.69; H, 5.21; N, 9.03. (18.41)
2-Amino-5-propyl-4-phosphonomethoxycarbonylthiazole. Mp 134.degree.
C. (decomp). Anal. calcd. for C.sub.8H.sub.13N.sub.2O.sub.5PS: C,
34.29; H, 4.68; N, 10.00. Found: C, 33.90; H, 4.30; N, 9.61.
(18.42) 2-Amino-5-pentyl-4-phosphonomethoxycarbonylthiazole. Mp
130.degree. C. (decomp). Anal. calcd. for
C.sub.10H.sub.17N.sub.2O.sub.5PS: C, 38.96; H, 5.56; N, 9.09.
Found: C, 38.69; H, 5.25; N, 8.85. (18.43)
2-Amino-5-bromo-4-phosphonomethylthiocarbonylthiazole. Mp
230.degree. C. (decomp). Anal. calcd. for
C.sub.5H.sub.6N.sub.2O.sub.5PS.sub.2Br: C, 18.03; H, 1.82; N, 8.41.
Found: C, 18.40; H, 1.93; N, 8.18. (18.44)
2-Amino-5-(2-furanyl)-4-phosphonomethoxycarbonylthiazole. Mp
230.degree. C. (decomp). Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.6PS: C, 35.53; H, 2.98; N, 9.21. Found:
C, 35.78; H, 3.05; N, 8.11. (18.45)
2-Amino-5-ethyl-4-phosphonomethoxycarbonyloxazole. Mp 141.degree.
C. (decomp). Anal. calcd. for C.sub.7H.sub.11N.sub.2O.sub.6P: C,
33.61; H, 4.43; N, 11.20. Found: C, 33.79; H, 4.47; N, 11.09.
(18.46) 5-Methyl-4-[(N-phosphonomethyl)carbamoyl]imidazole. Anal.
calcd. for C.sub.6H.sub.10N.sub.3O.sub.4P: C, 32.89; H, 4.60; N,
19.18. Found; C, 33.04; H, 4.65; N, 18.84.
Example 19
Preparation of 3-[2-(5-phosphono)furanyl]pyrazoles
[0369] Step A. A solution of diethyl
5-(2-isobutyl-3-N,N-dimethylamino)acryloyl-2-furanphosphonate (1
mmole, prepared according to Step A of Example 17) in ethanol was
treated with hydrazine (1.2 mmole) 80.degree. C. for 12 h.
Evaporation and chromatography gave
4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole. Step B.
4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected
to Step C of Example 3 to give
4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole (19.1). mp
210-215.degree. C. Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.4P: C, 48.89; H, 5.60; N, 10.37.
Found: C, 48.67; H, 5.55; N, 10.20. Step C.
4-Isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole was subjected
to Step A of Example 11 to give
1-methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole. Step
D. 1-Methyl-4-isobutyl-3-[2-(5-diethylphosphono)furanyl]pyrazole
was subjected to Step C of Example 3 to give
1-methyl-4-isobutyl-3-[2-(5-phosphono)furanyl]pyrazole (19.2).
Anal. calcd. for
Cl.sub.2H.sub.17N.sub.2O.sub.4P+0.85HBr+0.75H.sub.2O: C, 39.32; H,
5.32; N, 7.64.
[0370] Found: C, 39.59; H, 5.30; N, 7.47.
Example 20
Preparation of 3-[2-(5-phosphono)furanyl]isoxazoles
[0371] Step A. A solution of 5-diethylphosphono-2-furaldehyde (1
mmole) in ethanol was treated with hydroxylamine (1.1 mmole) and
sodium acetate (2.2 mmole) at 25.degree. C. for 12 h. Extraction
and chromatography gave 5-diethylphosphono-2-furaldehyde oxime.
Step B. A solution of 5-diethylphosphono-2-furaldehyde oxime (1
mmole) in DMF was treated with N-chlorosuccinimide (1.1 mmole) at
25.degree. C. for 12 h. Extraction gave
5-diethylphosphono-2-chlorooximidofuran. Step C. A solution of
5-diethylphosphono-2-chlorooximidofuran (1 mmole) and ethyl
propiolate (5 mmole) in diethyl ether was treated with
triethylamine (2 mmole) at 25.degree. C. for 12 h. Extraction and
chromatography gave
5-ethoxycarbonyl-3-{2-(5-diethylphosphono)furanyl]isoxazole. Step
D. 5-Ethoxycarbonyl-3-{2-(5-diethylphosphono)furanyl]isoxazole was
subjected to Step A of Example 9 followed by Step C of Example 3 to
give 5-carbamoyl-3-[2-(5-phosphono)furanyl]isoxazole (20.1). mp
221-225.degree. C. Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.6P+0.25EtOH: C, 37.86; H, 3.18; N,
10.39. Found: C, 37.90; H, 3.02; N, 10.05.
[0372] The following compound was prepared according to this
procedure:
(20.2)
5-Ethoxycarbonyl-4-methyl-3-[2-(5-phosphono)furanyl]isoxazole. mp
150-152.degree. C. Anal. calcd. for
C.sub.11H.sub.12NO.sub.7P+0.25H.sub.2O+0.15HBr: C, 41.57; H, 4.01;
N, 4.41. Found: C, 41.57; H, 4.20; N, 4.54. (20.3)
4,5-Bis(ethoxycarbonyl)-3-[2-(5-phosphono)furanyl]isoxazole. Anal.
calcd for C.sub.13H.sub.14NO.sub.9P: C, 43.47; H, 3.93; N, 3.90.
Found: C, 43.26; H, 3.92; N, 3.97. (20.4)
5-Amino-4-ethoxycarbonyl-3-[2-(5-phosphono)furanyl]isoxazole. mp
190.degree. C. (decomp). Anal. calcd for
C.sub.10H.sub.11N.sub.2O.sub.7P+0.25HBr: C, 37.25; H, 3.52; N,
8.69. Found: C, 37.56; H, 3.50; N, 8.85. (20.5)
4,5-bis(carbamoyl)-3-[2-(5-phosphono)furanyl]isoxazole.
mp>220.degree. C. Anal. calcd for C.sub.9H.sub.8N.sub.3O.sub.7P:
C, 35.90; H, 2.68; N, 13.95. Found: C, 35.67; H, 2.55; N, 13.62.
(20.6)
4-Ethoxycarbonyl-5-trifluoromethyl-3-[2-(5-phosphono)furanyl]isoxazole.
Anal. calcd for C.sub.11H.sub.9F.sub.3NO.sub.7P+0.25HBr: C, 35.20;
H, 2.48; N, 3.73. Found: C, 35.25; H, 2.34; N, 3.98. (20.7)
5-Amino-4-(2-furyl)-3-[2-(5-phosphono)furanyl]isoxazole.
mp>220.degree. C. Anal. calcd for
C.sub.12H.sub.9N.sub.2O.sub.7P+0.1AcOEt: C, 44.73; H, 2.97; N,
8.41. Found: C, 45.10; H, 2.58; N, 8.73. (20.8)
4-Amino-5-cyano-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd
for C.sub.8H.sub.6N.sub.3O.sub.5P+0.1H.sub.2O+0.2HBr: C, 35.18; H,
2.36; N, 15.39. Found: C, 35.34; H, 2.50; N, 15.08. (20.9)
4-Cyano-5-phenyl-3-[2-(5-phosphono)furanyl]isoxazole. Anal. calcd
for C.sub.14H.sub.9N.sub.2O.sub.5P+0.15HBr: C, 51.21; H, 2.81; N,
8.53. Found: C, 51.24; H, 3.09; N, 8.33.
Example 21
Preparation of 2-[2-(5-phosphono)furanyl]thiazoles
[0373] Step A. Diethyl 5-tributylstannyl-2-furanphosphonate (14)
and 2-bromo-4-ethoxycarbonylthiazole was subjected to Step A of
Example 6 to give
4-ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole. Step B.
4-Ethoxycarbonyl-2-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step A of Example 9 followed by Step C of Example 3 to
give 4-carbamoyl-2-[2-(5-phosphono)furanyl]thiazole (21.1). mp
239-240.degree. C. Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.5PS+0.2H.sub.2O: C, 34.59; H, 2.68; N,
10.08. Found: C, 34.65; H, 2.69; N, 9.84.
Example 22
Preparation of 4-(3,3-difluoro-3-phosphono-1-propyl)thiazoles
[0374] Step A. A solution of
3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene
chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5
equiv. wt/wt) and pyridinium chlorochromate (1.5 mmole) at
0.degree. C. The resulting mixture was stirred at room temperature
for 2 h, and diluted with diethyl ether (7 mL) and stirred at room
temperature for another 30 min. Filtration, evaporation and
chromatography gave 3-(tert-butyldiphenylsilyloxy)-1-propanal as a
clear oil. Step B. A solution of LDA (1.06 mmole) in THF was
treated with a solution of diethyl difluoromethylphosphonate (1
mmole) at -78.degree. C. for 45 min. The reaction was then treated
with a THF solution of 3-(tert-butyldiphenylsilyloxy)-1-propanal
(1.07 mmole) and the resulting solution was stirred at -78.degree.
C. for another 4 h. The reaction was quenched with phenyl
chlorothioformate (2.14 mmole), and the reaction mixture was
subjected to extraction and chromatography to give diethyl
4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutyl-
phosphonate as a clear oil. Step C. A solution of diethyl
4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutyl-
phosphonate (1 mmole) in toluene (1 mL) was treated with
tri-n-butyltin hydride (1.5 mmole) and AIBN (0.1 mmole), and the
resulting reaction mixture was heated to reflux for 2 h.
Evaporation and chromatography gave diethyl
4-(tert-butyldiphenylsilyloxy)-272-difluorobutylphosphonate as a
clear oil. Step D. A solution of diethyl
4-(tert-butyldiphenylsilyloxy)-2,2-difluorobutylphosphonate (1
mmole) in methanol (1 mL) was treated with hydrochloric acid (4 N,
4 mmole) at 0.degree. C., and the resulting reaction was stirred at
room temperature for 2 h. Evaporation and chromatography gave
diethyl 4-hydroxy-2,2-difluorobutylphosphonate as a clear oil. Step
E. A solution of gave diethyl
4-hydroxy-2,2-difluorobutylphosphonate (1 mmole) in acetone (10 mL)
was treated with Jones's reagent (10 mmole) at 0.degree. C. for 30
min. The reaction was quenched with 2-propanol (10 mL), and the
resulting mixture was filtered through a Celite pad. Evaporation of
the filtrate followed by extraction gave diethyl
3-carboxyl-2,3-difluoropropylphosphonate as an oil. Step F. A
solution of diethyl 3-carboxyl-2,3-difluoropropylphosphonate (1
mmole) in thionyl chloride (3 mL) was heated to reflux for 2 h. The
reaction was evaporated to dryness, and the residue was dissolved
in diethyl ether (1 mL) was treated with an etheral solution of
diazomethane (10 mmole) at 0.degree. C. for 30 min. A solution of
HBr in acetic acid (30%, 1 mL) was added to the reaction, and the
resulting solution was stirred at room temperature for 1 h. The
reaction was evaporated to dryness and the residue was dissolved in
THF-EtOH (1:1, 5 mL) and treated with thiourea (1 mmole). The
resulting reaction mixture was heated to 75.degree. C. for 1 h.
Evaporation followed by extraction and chromatography gave
2-amino-4-[1-(3-diethylphosphono-3,3-difluoro)propyl]thiazole as a
solid, which was subjected to Step C of Example 3 to give gave
2-amino-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazole (22.1) as a
solid. Anal. calcd. for C.sub.6H.sub.9N.sub.2O.sub.3PSF.sub.2+HBr:
C, 21.25; H, 2.97; N, 8.26. Found: C, 21.24; H, 3.25; N, 8.21.
[0375] The following compound was prepared in a similar manner:
2-Amino-5-methylthio-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazole
(22.2). MS m/e 305 (M+H).
Example 23
Preparation of 2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole
and 2-phosphonomethylthiopyridine
[0376] Step A. A solution of 2-methylthio-1,3,4-thiadiazole-5-thiol
(1 mmole) in THF (5 mL) was treated with sodium hydride (60%, 1.1
mmole) at 0.degree. C. and the resulting mixture was stirred at
room temperature for 30 min. The reaction was then cooled to
0.degree. C. and treated with diethylphosphonomethyl
trifluoromethanesulfonate (1.1 mmole). After stirring at room
temperature for 12 h, the reaction was quenched with saturated
ammonium chloride. Extraction and chromatography gave
2-methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole as an
oil. Step B.
2-Methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole was
subjected to Step C of Example 3 to give
2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole (23.1) as a
yellow solid. Anal. calcd. for
C.sub.4H.sub.7N.sub.2O.sub.3PS.sub.3+0.2 HBr: C, 17.50; H, 2.64; N,
10.21. Found: C, 17.64; H, 2.56; N, 10.00.
[0377] Alternatively, phosphonomethylthio substituted
heteroaromatics are made using the following method as exemplified
by the synthesis of 2-phosphonomethylthiopyridine:
Step C. A solution of 2,2'-dipyridyl disulfide (1 mmole) in THF was
treated with tri-n-butylphosphine (1 mmole) and diethyl
hydroxymethylphosphonate at 0.degree. C. The resulting reaction
solution was stirred at room temperature for 18 h. Extraction and
chromatography gave 2-diethylphosphonomethylthiopyridine as a
yellow oil. Step D. 2-Diethylphosphonomethylthiopyridine was
subjected to Step C of Example 3 to give
2-phosphonomethylthiopyridine (23.2) as a yellow solid. Anal.
calcd. for C.sub.6H.sub.8NO.sub.3PS+0.62 HBr: C, 28.22; H, 3.40; N,
5.49. Found: C, 28.48; H, 3.75; N, 5.14.
Example 24
Preparation of 2-[(2-phosphono)ethynyl]pyridine
[0378] Step A. A solution of 2-ethynylpyridine (1 mmole) in THF (5
mL) was treated with LDA (1.2 mmole) at 0.degree. C. for 40 min.
Diethyl chlorophosphate (1.2 mmole) was added to the reaction and
the resulting reaction solution was stirred at room temperature for
16 h. The reaction was quenched with saturated ammonium chloride
followed by extraction and chromatography to give
2-[(2-diethylphosphono)ethynyl]pyridine as a yellow oil. Step B.
2-[(2-Diethylphosphono)ethynyl]pyridine was subjected to Step C of
Example 3 to give 2-[1-(2-phosphono)ethynyl]pyridine (24.1) as a
brown solid. Mp 160.degree. C. (decomp). MS m/e 184 (M+H).
Example 25
Preparation of 5-[2-(5-phosphono)furanyl]tetrazole
[0379] Step A. To a mixture of tetrazole (1 mmole) and powdered
K.sub.2CO.sub.3 (1.5 mmole) in 1 mL DMF cooled to 0.degree. C. was
added benzyl chloromethyl ether (1.2 mmole) and the resulting
mixture stirred for 30 min at 0.degree. C. and then for 16 h at rt.
The mixture was diluted with water and ether. Extraction and
chromatography provided 2-benzyloxymethyltetrazole as a colorless
oil. Step B. To a solution of 2-benzyloxymethyltetrazole (1 mmole)
and TMEDA (2 mmole) in 3 mL diethyl ether at -78.degree. C. was
added n-BuLi in hexanes (1 mmole). This was let stir for 5 min at
-78.degree. C. and then it was added to a precooled (-78.degree.
C.) solution of (n-Bu).sub.3SnCl (1 mmole) in 2 mL of diethyl
ether. After stirring at -78.degree. C. for 30 min it was diluted
with water and diethyl ether. Extraction and chromatography
provided 2-benzyloxymethyl-5-(tributylstannyl)tetrazole as a
colorless oil. Step C. A mixture of 5-iodo-2-diethylphosphonofuran
(1 mmole), 2-benzyloxymethyl-5-(tributylstannyl)tetrazole (1.05
nmole), tetrakis(triphenylphosphine) palladium(0) (0.03 mmole) and
copper(I) iodide (0.07 mmole) in 3 mL of toluene was refluxed at
1110.degree. C. for 20 h. Evaporation and chromatography provided
2-benzyloxymethyl-5-[2-(5-diethylphosphono)furanyl]tetrazole as an
oil. Step D. A mixture of
2-benzyloxymethyl-5-[2-(5-diethylphosphono)furanyl]tetrazole (1
mmole) and 6 M HCl (1 mL) in 10 mL ethanol was heated at 70.degree.
C. for 20 h and then the solvent concentrated by evaporation, made
basic with 1 N NaOH and extracted with EtOAc. The aqueous layer was
made acidic and extracted with EtOAc. This EtOAc extract was
evaporated to provide 5-[2-(5-diethylphosphono)furanyl]tetrazole as
a solid, which was subjected to Step C of Example 3 to give
5-[2-(5-phosphono)furanyl]tetrazole (25.1) as a solid: mp
186-188.degree. C. Anal. calcd. for
C.sub.5H.sub.5N.sub.4O.sub.4P+1.5H.sub.2O: C, 24.70; H, 3.32; N,
23.05. Found: C, 24.57; H, 2.57; N, 23.05.
Step E.
[0380] Step 1. A mixture of
5-[2-(5-diethylphosphono)furanyl]tetrazole (1 mmole),
1-iodo-2-methylpropane (2 mmole) and powdered K.sub.2CO.sub.3 (2
mmole) in 5 mL DMF was stirred at 80.degree. C. for 48 h and then
diluted with CH.sub.2Cl.sub.2 and water and the layers separated.
The CH.sub.2O.sub.2 layer was evaporated and combined with the
product of the following reaction for chromatography. Step 2. The
aqueous layer of Step 1 was made acidic and extracted with EtOAc.
This extract was evaporated and the residue heated at 80.degree. C.
in 2 mL of SOCl.sub.2 for 3 h and then the solvent evaporated. The
residue was dissolved in 5 mL CH.sub.2Cl.sub.2 and 0.3 mL NEt.sub.3
and 0.5 mL of EtOH was added. After stirring for 1 h at rt the
mixture was diluted with CH.sub.2Cl.sub.2 and water. This organic
extract was combined with that kept from Step 1 and chromatography
provided 1-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole and
2-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole each as an
oil. Step 3. 1-Isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole
was subjected to Step C of Example 3 to give
1-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole (25.2) as a solid:
mp 200-202.degree. C. Anal. calcd. for
C.sub.9H.sub.13N.sub.4O.sub.4P: C, 39.71; H, 4.81; N, 20.58. Found:
C, 39.64; H, 4.63; N, 20.21. Step F. A mixture of
2-isobutyl-5-[2-(5-diethylphosphono)furanyl]tetrazole (1 mmole) and
TMSBr (10 mmole) in 10 mL of CH.sub.2Cl.sub.2 was stirred at room
temperature for 16 h. The solvent was evaporated and the residue
dissolved in 10:1 CH.sub.3CN:water, the solvent evaporated and the
residue precipitated from acetone by addition of dicyclohexylamine
(2 mmole) to provide 2-isobutyl-5-[2-(5-phosphono)furanyl]tetrazole
N,N-dicyclohexyl ammonium salt. (25.3) as a solid: mp
226-228.degree. C. Anal. calcd. for
C.sub.9H.sub.13N.sub.4O.sub.4P+C.sub.12H.sub.23N: C, 55.62; H,
8.00; N, 15.44. Found: C, 55.55; H, 8.03; N, 15.07.
Example 26
High Throughput Synthesis of Various 2-(5-phosphono)furanyl
Substituted Heteroaromatic Compounds
[0381] Step A. Various 2-(5-diethylphosphono)furanyl substituted
heteroaromatic compounds were prepared in a similar manner as Step
B of Example 15, and some of these compounds were used for the high
throughput synthesis of compounds listed in Table 33.1 and Table
33.2. Step B. A mixture of
2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and
TMSBr (0.1 mL) in CH.sub.2Cl.sub.2 (0.5 mL) was stirred at room
temperature for 16 h and then evaporated and diluted with 0.5 mL of
9:1 CH.sub.3CN:water. Evaporation provided
2-chloro-6-[2-(5-phosphono)furanyl]pyridine. Step C. A mixture of
2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmole) and
a solution of freshly prepared sodium propoxide in propanol (0.25
M, 0.4 mL) was let sit at 85.degree. C. for 14 h. The reaction
mixture was evaporated and the residue was subjected to Step B of
Example 33 to give 2-propyloxy-6-[2-(5-phosphono)furanyl]pyridine.
Step D. A mixture of
2-chloro-6-[2-(5-diethylphosphono)furanyl]pyridine (0.01 mmol) and
1-methylpiperazine (0.2 mL) in ethylene glycol (0.2 mL) was heated
at 145.degree. C. for 24 h. The mixture was further diluted with
0.5 mL of CH.sub.3CN and 0.1 mL of water and then 150 mg of Dowex 1
2-100 formate resin was added. After stirring this mixture 30 min
it was filtered and the resin washed with DMF (2.times.10 mL),
CH.sub.3CN (2.times.10 mL) and then 9:1 CH.sub.3CN:water
(1.times.10 mL). Finally the resin was stirred with 9:1 TFA:water
for 30 min, filtered and the filtrate evaporated. The residue
obtained subjected to Step B of example to give
2-[1-(4-methyl)piperazinyl]-6-[2-(5-phosphono)furanyl]pyridine.
Step E. A mixture of
3-chloro-5-[2-(5-diethylphosphono)furanyl]pyrazine (0.01 mmole),
5-tributylstannylthiophene (0.04 mmole), Pd(PPh.sub.3).sub.4 (0.001
mmole) and CuI (0.002 mmole) in dioxane (0.5 mL) was heated at
85.degree. C. for 16 h then the solvent was evaporated. The
resulting residue and TMSBr (0.1 mL) in 0.5 mL CH.sub.2Cl.sub.2 was
stirred at rt for 16 h and then evaporated and diluted with 0.5 mL
of 9:1 CH.sub.3CN:water. To this solution 150 mg of Dowex 1 2-100
formate resin was added and after stirring 30 min it was filtered
and the resin washed with DMF (2.times.10 mL), CH.sub.3CN
(2.times.10 mL) and then 9:1 CH.sub.3CN:water (1.times.10 mL).
Finally the resin was stirred with 9:1 TFA:water for 30 min,
filtered and the filtrate evaporated to give
3-(2-thienyl)-5-[2-(5-phosphono)furanyl]pyrazine. Step F. A mixture
of 3-chloro-5-[2-(5-diethylphosphono)furanyl]pyrazine (0.01 mmole),
1-hexyne (0.04 mmole), diisopropylethylamine (0.1 mmole),
Pd(PPh.sub.3).sub.4 (0.001 mmole) and CuI (0.002 mmole) in dioxane
(0.5 mL) was heated at 85.degree. C. for 16 h then the solvent was
evaporated. The resulting residue was subjected to Step B to give
3-(1-hexyn-1-yl)-5-[2-(5-phosphono)furanyl]pyrazine.
Preparation of the Carboxymethylphosphonate Resin
[0382] Step G. A solution of trimethylphosphonoacetate (30.9 mmol),
2-(trimethylsiyl)ethanol (10.4 mmol) and DMAP (3.1 mmol) in toluene
(25 mL) was refluxed for 48 h under N.sub.2. After cooling, the
solution was diluted with EtOAc and washed with 1N HCl followed by
water. The organic solution was dried over sodium sulfate and
concentrated under vacuum to give an oil. The residue was treated
with LiI (10.4 mmol) in 2-butanone (30 mL), and refluxed overnight
under N.sub.2. The solution was diluted with EtOAc, washed with 1N
HCl, dried over Na.sub.2SO.sub.4 and concentrated under vacuum to
afford the SEM protected carboxy monomethylphosphonate as a
colorless oil. Step H. Hydroxymethylpolystyrene (2.35 mmol) was
prepared for coupling by combining with anhydrous THF (40 mL),
gently shaking for 20 min. and then removing the excess solvent by
cannula. This procedure was repeated 3 times. The swollen resin was
then suspended in THF (40 mL) and DIPEA (21.2 mmol). To this
mixture was added, by cannula, a solution of the SEM protected
carboxy monomethylphosphonate (prepared in Step G) (7.1 mmol), DIAD
(7.1 mmol) and tris(4-chlorophenyl)phosphine (7.1 mmol) in THF (15
mL) which had been stirred for 15 min. prior to addition. After
shaking the mixture overnight under a blanket of N.sub.2, the resin
was filtered, rinsed with THF (3.times.40 mL), DMF (3.times.40 mL),
and THF again (3.times.40 mL) before drying under vacuum to afford
3.8 g of the coupled phosphonate resin. Step I. To coupled
phosphonate resin (2.41 mmol) in THF (100 mL) was added 1 M TBAF in
THF solution (12 mL). The mixture was shaken overnight before being
filtered and the resin rinsed with THF (3.times.40 mL) to afford
the desired carboxymethylphosphonate resin as the
tetrabutylammonium salt.
Coupling of the Carboxymethylphosphonate Resin to a Heteroaromatic
Amine
[0383] Step J. In a 2 mL well, a heteroaromatic amine (0.14 mmol),
resin (0.014 mmol), PyBOP (0.14 mmol) and TEA (0.36 mmol) in DMF
(1.45 mL) were combined and shaken for 48 h at room temperature.
The treated resin was then filtered, washed with DMF (3.times.) and
CH.sub.2Cl.sub.2 (3.times.). The isolated resin was resuspended in
CH.sub.2Cl.sub.2 (900 .mu.L), combined with TMSBr (100 .mu.L) and
mixed for 6 h. The mixture was filtered, the resin washed with
anhydrous CH.sub.2Cl.sub.2 (500 .mu.L) and the filtrate
concentrated under vacuum. To the isolated residue was added a
solution of CH.sub.3CN/H.sub.2O (9:1, 300 .mu.L). After shaking for
30 min. the solvents were removed to provide the desired
[{N-(phosphono)acetyl]amino} substituted heteroaromatic analogs.
Compounds 26.97-26.119 and 26.146-26.164 were synthesized according
to these procedures and they are listed in Table 33.1 and Table
33.2.
Preparation of the Aminomethylphosphonate Resin
[0384] Step K. To a solution of dimethyl
phthalimidomethylphosphonate (37 mmole) in 2-butanone (150 mL) was
added LiI (38.9 mmol). After refluxing overnight under N.sub.2, the
solution was diluted with EtOAc, washed with 1N HCl, dried over
MgSO.sub.4 and concentrated under vacuum to afford monomethyl
phthalimidomethylphosphonate as a white solid. Step L. As described
above in Step H, monomethyl phthalimidomethyl-phosphonate was
coupled to hydroxymethylpolystyrene to give the resin-coupled
phthalimidomethylphosphonate monomethyl ester. Step M. To the
resin-coupled phthalimidomethylphosphonate monomethyl ester (6.8
mmol) in DMF (7 mL) was added anhydrous hydrazine (3 mL). After
shaking at room temperature for 24 h the resin was filtered, rinsed
with DMF (3.times.10 mL), CH.sub.2Cl.sub.2 (3.times.10 mL) and then
dried under vacuum to afford 832 mg the desired resin-coupled
aminomethylphosphonate monomethyl ester.
Coupling of Various Heteroaromatic Carboxylic Acids to the
Resin-Coupled Aminomethylphosphonate Monomethyl Ester.
[0385] Step N. In a 2 mL well, a heteroaromatic carboxylic acid
(0.2 mmol), resin (0.02 mmol), EDC (0.2 mmol) and HOBT (0.2 mmol)
in DMF (0.5 mL) were combined and shaken for 24 h at room
temperature. The treated resin was then filtered, washed with DMF
(3.times.) and CH.sub.2Cl.sub.2 (3.times.). The isolated resin was
resuspended in CH.sub.2Cl.sub.2 (500 .mu.L), combined with TMSBr
(50 .mu.L) and mixed for 6 h. The mixture was filtered, the resin
washed with anhydrous CH.sub.2Cl.sub.2 (500 .mu.L) and the filtrate
concentrated under vacuum. To the isolated residue was added a
solution of CH.sub.3CN/H.sub.2O (9:1, 300 .mu.L). After shaking for
30 min the solvents were evaporated to provide the desired
(N-phosphonomethyl)carbamoyl substituted heteroaromatic analogs.
Compounds 26.120-26.145 were synthesized according to these
procedures and they are listed in Table 33.2.
[0386] The following compounds were prepared according to some or
all of the above described procedures. These compounds were
characterized by HPLC (as described below) and mass spectroscopy
(APCI negative ion), and these characterization data are listed in
Table 33.1 and Table 33.2.
[0387] HPLC was performed using a YMC ODS-Aq, Aq-303-5, 250 4.6 mm
ID, S-5 .mu.m, 120 A column with the UV detector set at 280 nm.
HPLC Elution Program: 1.5 mL/min flow rate
TABLE-US-00020 Time (min) % Acetonitrile (A) % Buffered.sup.a (B) 0
10 90 7.5 90 10 12.4 90 10 12.5 10 90 15 10 90 .sup.aBuffer =
95:5:0.1 water:methanol:acetic acid
TABLE-US-00021 TABLE 26.1 ##STR00052## syn- thetic HPLC example Rt
M-1 number A B X Y' (min.) found 26.146 H Br NHC(O)CH.sub.2 S 6.58
299/ 301 26.147 H Ph NHC(O)CH.sub.2 S 6.57 297 26.148 Ph H
NHC(O)CH.sub.2 S 6.06 297 26.149 Ph Et NHC(O)CH.sub.2 O 309 26.150
H H NHC(O)CH.sub.2 S 4.22 221 26.151 adaman- Me NHC(O)CH.sub.2 S
6.59 369 tyl 26.152 Bu-t Br NHC(O)CH.sub.2 S 6.62 355/ 357 26.153 H
Ph(-4-Br) NHC(O)CH.sub.2 S 6.62 375/ 377 ##STR00053## syn- thetic
HPLC example Rt M-1 number A* B* X Y' (min.) found 26.154 H H
NHC(O)CH.sub.2 O 6.68 205 26.155 null NH.sub.2 NHC(O)CH.sub.2 O 6.6
221 26.156 NHMe null NHC(O)CH.sub.2 S 3.82 251 26.157 Me H
NHC(O)CH.sub.2 NH 26.158 H H NHC(O)CH.sub.2 NH 26.159 OH H
NHC(O)CH.sub.2 NH 26.160 Bu-t H NHC(O)CH.sub.2 O 6.62 261 26.161
null 3-pyridyl NHC(O)CH.sub.2 O 6.58 283 26.162 CH.sub.2- null
NHC(O)CH.sub.2 O Ph-(2,6- dichloro) 26.163 Br null furan-2,5-diyl
NH 4.46 292/ 294 26.164 Br null furan-2,5-diyl S 5.96 309/ 311
*when A or B is null, then the corresponding G is N.
TABLE-US-00022 TABLE 26.2 ##STR00054## synthetic HPLC example Rt
M-1 number A* B* X D* E* (min.) found 26.1 NH.sub.2 Cl
furan-2,5-diyl Me null 11.06 288 26.2 H OC(O)(Ph- furan-2,5-diyl H
H 3.99 413 2,6- dichloro) 26.3 OMe H furan-2,5-diyl CH.sub.2OH H
8.34 284 26.4 OMe H furan-2,5-diyl C(O)NH.sub.2 H 8.23 297 26.5 OMe
H furan-2,5-diyl CO.sub.2H H 9.54 298 26.6 OH H furan-2,5-diyl
CF.sub.3 C(O)NH.sub.2 3.91 351 26.7 OMe H furan-2,5-diyl CF.sub.3
C(O)NH.sub.2 9.14 365 26.8 null H furan-2,5-diyl H OMe 9.72 255
26.9 null H furan-2,5-diyl H OH 4.52 241 26.10 OH H furan-2,5-diyl
Me null 3.79 255 26.11 OMe H furan-2,5-diyl Me null 6.44 269 26.12
NH.sub.2 null furan-2,5-diyl OH H 3.96 256 26.13 NH.sub.2 null
furan-2,5-diyl OMe H 8.02 270 26.14 H OMe furan-2,5-diyl null H
7.22 255 26.15 H OH furan-2,5-diyl null H 4.82 241 26.16 OMe H
furan-2.5-diyl null H 7.48 255 26.17 OEt H furan-2.5-diyl H H 9.72
268 26.18 OEt H furan-2,5-diyl CH.sub.2OH H 5.26 298 26.19 null H
furan-2,5-diyl Me OEt 7.80 283 26.20 null H furan-2,5-diyl Me OH
3.80 255 26.21 OH H furan-2,5-diyl Me null 3.77 255 26.22 OEt H
furan-2,5-diyl Me null 7.33 283 26.23 NH.sub.2 null furan-2,5-diyl
OH H 3.94 256 26.24 NH.sub.2 null furan-2,5-diyl OEt H 5.66 284
26.25 NH.sub.2 H furan-2,5-diyl OEt null 5.90 284 26.26 NH.sub.2 H
furan-2,5-diyl OH null 3.78 256 26.27 H OEt furan-2,5-diyl null H
9.74 269 26.28 H OH furan-2,5-diyl null H 4.81 241 26.29 OEt H
furan-2,5-diyl null H 9.78 269 26.30 Br H furan-2,5-diyl H NO.sub.2
7.78 347/349 26.31 Cl H furan-2,5 -diyl H C(O)OEt 9.69 330 26.32 Br
H furan-2,5-diyl H C(O)OEt 9.69 374/376 26.33 Cl H furan-2,5-diyl
Me C(O)NH.sub.2 3.72 315 26.34 Cl CF.sub.3 furan-2,5-diyl H
CF.sub.3 9.04 394 26.35 Cl H furan-2,5-diyl NH.sub.2 H 4.89 273
26.36 Cl H furan-2,5-diyl CN H 7.93 283 26.37 Cl H furan-2,5-diyl
CH.sub.2OH H 5.38 288 26.38 Cl H furan-2,5-diyl C(O)NH.sub.2 H 5.57
301 26.39 Cl H furan-2,5-diyl C(O)OEt H 8.54 330 26.40 Cl 1-
furan-2,5-diyl H H 8.91 398 triazinyl- (3-amino- 5-methyl- thio)
26.41 Cl H furan-2,5-diyl Me CN 8.22 297 26.42 Cl H furan-2,5-diyl
CF.sub.3 NH.sub.2 8.60 341 26.43 Cl H furan-2,5-diyl CF.sub.3 CN
8.66 351 26.44 null CH.sub.3 furan-2,5-diyl Me Br 9.25 331/333
26.45 null CH.sub.3 furan-2,5-diyl Me Cl 9.25 287 26.46 Br CH.sub.3
furan-2,5-diyl H null 5.62 317/319 26.47 Br Br furan-2,5-diyl H
null 3.54 381/ 383/ 385 26.48 Br H furan-2,5-diyl Me null 5.55
317/319 26.49 H NH.sub.2 furan-2,5-diyl Br null 4.78 318/320 26.50
Br Cl furan-2,5-diyl Br null 8.38 417/419 26.51 SMe Ph
furan-2,5-diyl Br null 9.26 425/427 26.52 NH.sub.2 H furan-2,5-diyl
Br null 4.87 318/320 26.53 NH.sub.2 H furan-2,5-diyl OH null 3.70
256 26.54 Br H furan-2,5-diyl Br null 9.64 381/ 383/385 26.55 Br H
furan-2,5-diyl Cl null 9.64 337/339 26.56 H Br furan-2,5-diyl null
H 5.08 303/305 26.57 NH.sub.2 Cl furan-2,5-diyl null C(O)OMe 3.34
332 26.58 OPr-n H furan-2,5-diyl Me null 8.14 297 26.59 H OPr-n
furan-2,5-diyl null H 8.45 283 26.60 H O(CH.sub.2).sub.2-OEt
furan-2,5-diyl null H 7.82 313 26.61 NH.sub.2 null furan-2,5-diyl
OH H 3.97 256 26.62 NH.sub.2 null furan-2,5-diyl OPr-n H 7.84 298
26.63 OPr-n H furan-2,5-diyl CH.sub.2OH H 4.36 312 26.64 OBu-n H
furan-2,5-diyl CH.sub.2OH H 8.58 326 26.65 O--(CH.sub.2).sub.2-OEt
H furan-2,5-diyl CH.sub.2OH H 4.13 342 26.66 NH.sub.2 H
furan-2,5-diyl OPr-n null 7.96 298 26.67 NH.sub.2 H furan-2,5-diyl
OBu-n null 3.86 312 26.68 H OBu-i furan-2,5-diyl null H 8.80 297
26.69 H O(CH.sub.2).sub.2-OEt furan-2,5-diyl null H 7.14 299 26.70
H O(CH.sub.2).sub.2--NMe.sub.2 furan-2,5-diyl null H 4.57 312 26.71
NH.sub.2 null furan-2,5-diyl OBu-i H 8.06 312 26.72 NH.sub.2 null
furan-2,5-diyl O(CH.sub.2).sub.2OMe H 4.84 314 26.73 NH.sub.2 H
furan-2,5-diyl OBu-i null 8.70 312 26.74 Br H furan-2,5-diyl
C(O)NH.sub.2 H 7.68 346/348 26.75 NH.sub.2 null furan-2,5-diyl Cl H
4.77 274 26.76 NH--(CH.sub.2).sub.2--OH H furan-2,5-diyl Me null
4.56 298 26.77 H NH(CH.sub.2).sub.2OH furan-2,5-diyl null H 4.55
284 26.78 NH.sub.2 null furan-2,5-diyl NH--(CH).sub.2OH H 4.58 299
26.79 NH--(CH.sub.2).sub.2--OH H furan-2,5-diyl NH.sub.2 null 4.58
299 26.80 NH--(CH.sub.2).sub.2--OH H furan-2,5-diyl CH.sub.2OH H
4.44 313 26.81 NH.sub.2 H furan-2,5-diyl NH--(CH.sub.2).sub.2OH
null 4.33 299 26.82 NH--CH--CH--(OH)-Me H furan-2,5-diyl CH null
4.65 312 26.83 NH.sub.2 null furan-2,5-diyl NHCH.sub.2--CH(OH)-Me H
4.63 313 26.84 NH--CH.sub.2--CH--(OH)-Me H furan-2,5-diyl NH.sub.2
null 4.63 313 26.85 NH--CH.sub.2--CH--(OH)-Me H furan-2,5-diyl
CH.sub.2OH H 4.52 327 26.86 NH.sub.2 H furan-2,5-diyl
NHCH.sub.2--CH(OH)-Me null 4.65 313 26.87 NH--(CH.sub.2).sub.3--OH
H furan-2,5-diyl Me null 4.62 312 26.88 NH.sub.2 null
furan-2,5-diy1 NH--(CH.sub.2).sub.3OH H 4.48 313 26.89
NH--(CH.sub.2).sub.3--OH H furan-2,5-diyl NH.sub.2 null 4.48 313
26.90 NH.sub.2 NH--(CH.sub.2).sub.3OH furan-2,5-diyl null
C(O)NH--(CH.sub.2).sub.3OH 4.76 414 26.91 H 4- furan-2,5-diyl null
H 6.46 310 morpho- linyl 26.92 4- H furan-2,5-diyl Me null 6.53 324
morpho- linyl 26.93 NH.sub.2 null furan-2,5-diyl 4-morpho- H 6.15
325 linyl 26.94 4- H furan-2,5-diyl NH.sub.2 null 4.84 325 morpho-
linyl 26.95 NH.sub.2 4 -morpho- furan-2,5-diyl null C(O)-(4- 7.47
438 linyl morpho- linyl) 26.96 NH.sub.2 H furan-2,5-diyl 4-morph-
null 5.30 325 olinyl 26.97 Me H NHC(O)CH.sub.2 H H 6.58 229 26.98 H
Me NHC(O)CH.sub.2 H H 6.60 229 26.99 NH.sub.2 H NHC(O)CH.sub.2 H Cl
6.63 264 26.100 NH.sub.2 Cl NHC(O)CH.sub.2 H H 6.63 264 26.101 H OH
NHC(O)CH.sub.2 H H 6.54 231 26.102 Me H NHC(O)CH.sub.2 Me H 6.59
243 26.103 H H NHC(O)CH.sub.2 H Cl 7.02 249 26.104 H H
NHC(O)CH.sub.2 H Br 8.01 293/295 26.105 Me H NHC(O)CH.sub.2 H Br
6.64 307/309 26.106 H H NHC(O)CH.sub.2 H H 6.72 215 26.107 H H
NHC(O)CH.sub.2 H Me 6.54 229 26.108 H H NHC(O)CH.sub.2 Me H 6.53
229 26.109 Me Cl NHC(O)CH.sub.2 Me null 3.93 279 26.110 Cl H
NHC(O)CH.sub.2 null H 4.20 251 26.111 H Br NHC(O)CH.sub.2 H Me 6.44
307/309 26.112 NH.sub.2 H NHC(O)CH.sub.2 NH-(Ph- null 4.42 401/403
4-Br) 26.113 NH.sub.2 Bn NHC(O)CH.sub.2 H Bn 6.49 410 26.114 H H
NHC(O)CH.sub.2 Et H 6.57 243 26.115 Me Et NHC(O)CH.sub.2 H H 6.54
257 26.116 Me H NHC(O)CH.sub.2 H Br 6.55 307/309 26.117 H Br
NHC(O)CH.sub.2 H Me 6.51 307/309 26.118 H Me NHC(O)CH.sub.2 H Br
6.52 307/309 26.119 Me Br NHC(O)CH.sub.2 H Br 6.19 385/ 387/ 389
26.120 H H C(O)NHCH.sub.2 H H 3.74 215 26.121 Me H C(O)NHCH.sub.2 H
H 229 26.122 OH H C(O)NHCH.sub.2 H H 3.72 231 26.123 Br H
C(O)NHCH.sub.2 H H 5.02 293/295 26.124 Cl H C(O)NHCH.sub.2 H H 4.60
249/251 26.125 H H C(O)NHCH.sub.2 Cl H 5.18 249/251 26.126 H Br
C(O)NHCH.sub.2 OH H 3.60 310/312 26.127 H H C(O)NHCH.sub.2 null H
3.70 216 26.128 H H C(O)NHCH.sub.2 NO.sub.2 H 5.00 260 26.129 H H
C(O)NHCH.sub.2 H Bu-n 8.35 271 26.130 H OPr-n C(O)NHCH.sub.2 H H
7.46 273 26.131 Cl Cl C(O)NHCH.sub.2 H H 4.23 283/ 285/ 287 26.132
Cl CF.sub.3 C(O)NHCH.sub.2 H H 8.05 317/319 26.133 H Cl
C(O)NHCH.sub.2 H CF.sub.3 6.49 317/319 26.134 H Cl C(O)NHCH.sub.2
Cl Cl 7.20 318/ 320/ 322 26.135 H C(O)Ph C(O)NHCH.sub.2 H H 7.00
319 26.136 H OEt C(O)NHCH.sub.2 H CF.sub.3 6.65 327 26.137 SMe Cl
C(O)NHCH.sub.2 H null 5.82 296/298 26.138 SMe Br C(O)NHCH.sub.2 H
null 5.40 340/342 26.139 H O(Ph-3- C(O)NHCH.sub.2 null H 376
CF.sub.3) 26.140 H H C(O)NHCH.sub.2 null Me 3.75 230 26.141 H Me
C(O)NHCH.sub.2 H H 4.96 229 26.142 Cl Cl C(O)NHCH.sub.2 Cl Cl 9.18
351/ 353/ 355/357 26.143 H F C(O)NHCH.sub.2 OH null 250 26.144 Me F
C(O)NHCH.sub.2 OH null 264 26.145 OH F C(O)NHCH.sub.2 OH null 3.93
266 *When A, B, D or E is null, then the corresponding G' is N.
Section 2
Synthesis of Compounds of Formula X
Example 27
Preparation of
2-amino-4-phosphonomethyloxy-6-bromobenzothiazole
[0388] Step A. A solution of AlCl.sub.3 (5 mmole) in EtSH (10 mL)
was cooled to 0.degree. C. and treated with
2-amino-4-methoxybenzothiazole (1 mmole). The mixture was stirred
at 0-5.degree. C. for 2 h. Evaporation and extraction gave
2-amino-4-hydroxybenzothiazole as white solid. Step B. A mixture of
2-amino-4-hydroxybenzothiazole (1 mmole) and NaH (1.3 mmole) in DMF
(5 mL) was stirred at 0.degree. C. for 10 min, and then treated
with diethylphosphonomethyl trifluoromethylsulfonate (1.2 mmole).
After being stirred at room temperature for 8 h. the reaction was
subjected to extraction and chromatography to give
2-amino-4-diethylphosphonomethyloxybenzothiazole as an oil. Step C.
A solution of 2-amino-4-(diethylphosphonomethyloxy)benzothiazole (1
mmole) in AcOH (6 mL) was cooled to 10.degree. C. and treated with
bromine (1.5 mmole) in AcOH (2 mL). After 5 min the mixture was
stirred at room temperature for 2.5 h. The yellow precipitate was
collected via filtration and washed with CH.sub.2Cl.sub.2 to give
2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole. Step D. A
solution of
2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmole)
in CH.sub.2Cl.sub.2 (4 mL) was treated with TMSBr (10 mmole) at
0.degree. C. After stirred for 8 h at room temperature the reaction
was evaporated to dryness and the residue was taken into water (5
mL). The resulting precipitate was collected via filtration and
washed with water to give
2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (27.1) as white
solid. mp>220.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.8N.sub.2O.sub.4PSBr: C, 28.34; H, 2.38; N, 8.26.
Found: C, 28.32; H, 2.24; N, 8.06,
[0389] Similarly, the following compounds were prepared according
to the above described procedures:
(27.2) 2-Amino-4-phosphonomethyloxybenzothiozole. mp>250.degree.
C. Anal. calcd. for C.sub.8H.sub.9N.sub.2O.sub.4PS+0.4H.sub.2O: C,
35.93; H, 3.69; N, 10.48. Found: C, 35.90; H, 3.37; N, 10.37.
Example 28
Preparation of
2-amino-4-phosphonomethyloxy-6-bromo-7-chlorobenzothiazole
[0390] Step A. A solution of
1-(2-methoxy-5-chlorophenyl)-2-thiourea (1 mmole) in chloroform (10
mL) was cooled to 10.degree. C. and treated with bromine (2.2
mmole) in chloroform (10 mL). The reaction was stirred at
10.degree. C. for 20 min and at room temperature for 0.5 h. The
resulting suspension was heated at reflux for 0.5 h. The
precipitate was collected via filtration (washed with
CH.sub.2Cl.sub.2) to give 2-amino-4-methoxy-7-chlorobenzothiazole
which was subjected to Steps A, B, C and D of Example 27 to give
2-amino-4-phosphonomethoxy-6-bromo-7-chloro benzothiazole (28.1).
mp>220.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.4PSClBr: C, 25.72; H, 1.89; N, 7.50.
Found: C, 25.66; H, 1.67; N, 7.23.
[0391] Similarly, the following compounds were prepared according
to the above described procedures:
(28.2) 2-Amino-4-phosphonomethoxy-6-bromo-7-methyl benzothiazole.
mp>220.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.10N.sub.2O.sub.4PSBr: C, 30.61; H, 2.85; N, 7.93
Found: 030.25; H, 2.50; N, 7.77. (28.3)
2-Amino-4-phosphonomethoxy-7-methylbenzothiazole. mp>220.degree.
C. (dec.). Anal: calcd. for C.sub.9H.sub.11N.sub.2O.sub.4PS+1.0
H.sub.2O: C, 36.99; H, 4.48; N, 9.59. Found: C, 36.73; H, 4.23; N,
9.38. (28.4) 2-Amino-4-phosphonomethoxy-7-chlorobenzothiazole.
mp>220.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.8N.sub.2O.sub.4PSCl+0.1H.sub.2O: C, 32.41; H, 2.79; N,
9.45. Found: C, 32.21; H, 2.74; N, 9.22.
Example 29
Preparation of
2-Amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
[0392] Step A. 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalene was
subjected to Step B of Example 27 to give
3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthlene.
Step B. A solution of KSCN (16 mmole) and CuSO.sub.4 (7.7 mmole) in
MeOH (10 mL) was treated with a solution of
3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthalene
(1 mmole) in MeOH (5 mL) at room temperature. The mixture was
heated at reflux for 2 h. Filtration, extraction and chromatography
provided
2-amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiaz-
ole as light brown solid. Step C.
2-Amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiaz-
ole was subjected to Step D of Example 27 to give
2-Amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(29.1). mp>220.degree. C. (dec.). Anal. calcd. for
Cl.sub.2H.sub.15N.sub.2O.sub.4PS+0.5H.sub.2O: C, 45.86; H, 4.81; N,
8.91 Found: C, 44.68; H, 4.77; N, 8.73.
[0393] The following compounds were also prepared according to
above procedures:
(29.2) 2-Amino-4-phosphonomethoxy-[1,2-d]naphthothiazole.
mp>240.degree. C. (dec.). Anal. calcd. for
C.sub.12H.sub.11N.sub.2O.sub.4PS+0.2HBr: C, 44.15; H, 3.46; N,
8.58. Found: C, 44.13; H, 3.46; N, 8.59. (29.3)
2-Amino-5,7-dimethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole.
mp>240.degree. C. (dec.). Anal. calcd. for
C.sub.11H.sub.12N.sub.3O.sub.4PS.sub.2+0.2CH.sub.2Cl.sub.2: C,
37.13; H, 3.45; N, 11.60. Found: C, 37.03; H, 3.25; N, 11.65.
(29.4) Starting with 2-hydroxy-5-phenyl aniline and using the same
reaction sequence as above gave
2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.11H.sub.12N.sub.3O.sub.4PS.sub.2+0.2H.sub.2O: C, 45.38; H,
3.15; N, 10.58. Found: C, 45.25; H, 3.21; N, 10.53. (29.5) Starting
with 2-hydroxy-3,5-dichloro-4-methyl aniline and using the same
reaction sequence as above (except the cyclization step was done
using B.sub.2, AcOH method i.e. Step A of Example 33) gave
2-Amino-5,7-dichloro-6-methyl-4-phosphonomethoxybenzothiazole.
mp.>230.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.4PSCl.sub.2: C, 31.50; H, 2.64; N, 8.16.
Found: C, 31.61; H, 2.66; N, 8.08. (29.6) Starting with
2-hydroxy-4-methoxycarbonyl aniline and using the same reaction
sequence as above gave
2-Amino-4-phosphonomethoxy-6-carboxybenzothiazole.
mp.>230.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.9N.sub.2O.sub.6PS: C, 35.53; H, 2.98; N, 9.21. Found:
C, 35.56; H, 3.26; N, 9.03.
Example 30
Preparation of
2-Amino-7-methoxy-6-thiocyanato-4-phosphonomethoxy-benzothiazole
[0394] Step A. 2-Hydroxy-5-methoxynitrobenzene was subjected to
Step B of Example 27 to give
2-diethylphosphonomethyloxy-5-methoxynitrobenzene. Step B. A
solution of SnCl.sub.2 (4 mmole) in freshly prepared methonolic HCl
(10 mL) was added to a cold (0.degree. C.) solution of
2-diethylphosphonomethyloxy-5-methoxynitrobenzene (1 mmole) in MeOH
(5 mL). The mixture was warmed to room temperature and stirred for
3 h. Evaporation, extraction and chromatography provided
2-diethylphosphonomethyloxy-5-methoxyaniline. Step C.
2-Diethylphosphonomethyloxy-5-methoxyaniline was subjected to Step
B of Example 29 to give
2-amino-4-diethylphosphonomethyloxy-6-thiocyano-7-methoxybenzothiazole,
which was subjected to Step D of Example 27 to give
2-amino-7-methoxy-6-thiocyanato-4-phosphonomethoxybenzothiazole
(30.1). mp>170.degree. C. (dec.). Anal.calcd. for
C.sub.10H.sub.10N.sub.3O.sub.5PS.sub.2: C, 34.58; H, 2.90; N,
12.10. Found: C, 34.23; H, 2.68; N, 11.77.
[0395] Similarly, the following compounds were prepared according
to above procedures:
(30.2) 2-Amino-5,6-difluoro-4-phosphonomethoxybenzothiazole.
mp>240.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.4PSF.sub.2: C, 32.44; H, 2.38; N, 9.46.
Found: C, 32.30; H, 2.26; N, 9.17. (30.3)
2-Amino-5-fluoro-7-bromo-4-phosphonomethoxybenzothiazole.
mp>190.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.4PSBrF: C, 26.91; H, 1.98; N, 7.84.
Found: C, 27.25; H, 1.92; N, 7.54. (30.4)
2-Amino-7-ethoxycarbonyl-4-phosphonomethoxybenzothiazole.
mp>240.degree. C. (dec.). Anal. calcd. for
C.sub.11H.sub.13N.sub.2O.sub.6PS+0.2HBr+0.1DMF: C, 38.15; H, 3.94;
N, 8.27. Found: C, 38.51; H, 3.57; N, 8.66.
Example 31
Preparation of 2-Amino-7-bromo-6-thiocyanato-4-phosphonomethoxy
benzothiazole
[0396] Step A. A solution of 2-fluoro-5-bromonitrobenzene (1 mmole)
in DMF (5 mL) was cooled to 0.degree. C., and treated with a
solution of freshly prepared sodium salt of
diethylhydroxymethylphosphonate (1.2 mmole) in DMF (5 mL). The
mixture was stirred at room, temperature for 16 h. Evaporation,
extraction and chromatography provided
2-diethylphosphonomethyloxy-5-bromonitrobenzene. Step B.
2-Diethylphosphonomethyloxy-5-bromonitrobenzene was subjected to
Step B of Example 30, Step B of Example 29, and Step D of Example
27 to give
2-amino-7-bromo-6-thiocyanato-4-phosphonomethoxybenzothiazole
(31.1). mp>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.7N.sub.3O.sub.4PS.sub.2 Br: C, 27.29; H, 1.78; N,
10.61. Found: C, 26.90; H, 1.58; N, 10.54.
[0397] Similarly, the following compounds were prepared according
to above procedures:
(31.2)
2-Amino-7-fluoro-6-thiocyanato-4-phosphonoinethoxybenzothiazole.
mp>136.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.7N.sub.3O.sub.4 PFS.sub.2+0.3HBr: C, 30.07; H, 2.05;
N, 11.69. Found: C, 30.27; H, 2.01; N, 11:38. (31.3) Starting with
2-fluoro-4-chloro nitrobenzene and using the same reaction sequence
as above gave 2-Amino-6-chloro-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.8N.sub.2O.sub.4PSCl: C, 32.61; H, 2.74; N, 9.51.
Found: C, 32.27; H, 2.67; N, 9.18. (31.4) Starting with
2-fluoro-4,5-dichloro nitrobenzene and using the same reaction
sequence as above gave
2-Amino-6,7-dichloro-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.8H.sub.7N.sub.2O.sub.4PSCl.sub.2: C, 29.20; H, 2.14; N, 8.51.
Found: C, 29.11; H, 2.11; N, 8.36.
Example 32
Preparation of
2-Amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethoxy
benzothiazole
[0398] Step A. 2-Chloro-5-formylnitrobenzene was subjected to Step
A of Example 31 to give
2-diethylphosphonomethyloxy-5-formylnitrobenzene. Step B. A
solution of 2-diethylphosphonomethyloxy-5-formylnitrobenzene (1
mmole) in methanol (5 mL) was treated with 10% palladium on carbon
(0.05 mmole) under 1 atmosphere of hydrogen at room temperature for
12 h. Filtration followed by evaporation gave
2-diethylphosphonomethyloxy-5-hydroxymethylaniline which was
subjected to Step B of Example 29 followed by Step D of Example 27
to give
2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole
(32.1). mp 181-184.degree. C. Anal. calcd. for
C.sub.10H.sub.10N.sub.3O.sub.5PS.sub.2+0.35H.sub.2O: C, 33.97;
11:3.05; N, 11.88. Found: C, 33.76; 11:2.66; N, 11.61.
[0399] A similar procedure was used to prepare the following
compounds:
(32.2) Starting with 2-fluoro-4-methyl nitrobenzene and using the
same reaction sequence as above gave
2-Amino-6-methyl-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.11N.sub.2O.sub.4PS+0.2 CH.sub.2Cl.sub.2: C, 37.94; H,
3.95; N, 9.62. Found: C, 38.16; H, 4.18; N, 9.39. (32.3) Starting
with 2-chloro-5-cyano nitrobenzene and using the same reaction
sequence as above gave
2-Amino-7-cyano-4-phosphonomethoxybenzothiazole. mp.>250.degree.
C. (dec.). Anal. calcd. for
C.sub.9H.sub.8N.sub.3O.sub.4PS+0.9H.sub.2O: C, 35.86; H, 3.28; N,
13.94. Found: C, 35.07; H, 2.88; N, 13.58.
Example 33
Preparation of
2-Amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole
[0400] Step A. A solution of
2-diethylphosphonomethyloxy-4-bromo-5-fluoroaniline (1 mmole,
prepared as in Example 4, Step B) and KSCN (2 mmole) in AcOH (8 mL)
was cooled to 10.degree. C., and treated with a solution of bromine
(2 mmole) in AcOH (5 mL). After being stirred at room temperature
for 0.5 h, the reaction mixture was evaporated to dryness and the
residue was purified by chromatography to provide
2-amino-7-fluorol-6-bromo-4-diethylphosphonomethyloxybenzothiazole
which was subjected to Step D of Example 27 to give
2-amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole (33.1).
Anal. calcd. for C.sub.8H.sub.7N.sub.2O.sub.4PSBrF+0.1HBr: 0:26.31;
11:1.96; N, 7.67. Found: 0:25.96; 11:1.94; N, 7.37.
Example 34
Preparation of
2-Amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole
[0401] Step A. A solution of
2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared
as in Example 31, Step A from 2-fluoro-5-bromonitrobenzene) in DMF
(5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and
palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the
mixture was heated at 60.degree. C. under nitrogen for 6 h.
Evaporation and chromatography gave
2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was
subjected to Step B of Example 31, Step B of Example 29, and Step D
of Example 27 to give
2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (34.1).
mp>167.degree. C. (dec.). Anal. calcd. for
C.sub.11H.sub.12N.sub.3O.sub.4PS.sub.2: C, 38.26; H, 3.50; N,
12.17. Found: C, 37.87; H, 3.47; N, 11.93.
[0402] A similar procedure was used to prepare the following
compounds:
(34.2)
2-Amino-7-propyl-6-thiocyanato-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.12H.sub.14N.sub.3O.sub.4PS.sub.2: C, 40.11; H, 3.93; N,
11.69. Found: C, 39.72; H, 3.82; N, 11.50. Using allyl tributyltin.
(34.3)
2-Amino-7-(2-furyl)-6-thiocyanato-4-phosphonomethoxybenzothiazole.
Anal. calcd. for C.sub.14H.sub.11N.sub.3O.sub.5BrPS.sub.2+0.6 MeOH:
C, 33.79; H, 2.79; N, 8.69. Found: C, 34.10; H, 2.83; N, 8.35.
Using 2-furanyl tlibutyltin. (34.4)
2-Amino-6-thiocyanato-7-(2-thienyl)-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.13H.sub.10N.sub.3O.sub.4PS.sub.3: C, 39.09; H, 2.52; N,
10.52. Found: C, 38.91; H, 2.41; N, 10.34. Using 2-thienyl
tributyltin. (34.5) 2,5-Difluoro-4-bromo nitrobenzene was treated
the same way to give
2-Amino-6-ethyl-7-fluoro-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.10H.sub.12N.sub.2O.sub.4PSF: C, 39.22; H, 3.95; N, 9.15.
Found: C, 38.83; H, 3.55; N, 9.02. (34.6) 2,5-Difluoro-4-bromo
nitrobenzene was treated with 2-thienyl tributyltin in the second
step to give
2-Amino-7-fluoro-6-[2-(5-thiocyanato)thienyl]-4-phosphonomethoxybenzothia-
zole. mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.13H.sub.9N.sub.3O.sub.4PS.sub.3F+0.6H.sub.2O: C, 36.46; H,
2.40; N, 9.81. Found: C, 36.16; H, 2.10; N, 9.68.
Example 35
Preparation of
2-Amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxy
Benzothiazole
[0403] Step A. A suspension of
2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmole, prepared
as in Step A of Example 33) and Pd(OAc).sub.2 (0.1 mmole) in ether
(8 mL) was treated with a solution of diazomethane (generated from
3.0 g of 1-methyl-3-nitro-1-nitrosoguanidine) in ether at 0.degree.
C. After being stirred at room temperature for 20 h the reaction
was evaporated to dryness and the residue was chromatographed to
give 2-diethylphosphonomethyloxy-5-cyclopropylnitrobenzene which
was subjected to Step B of Example 30, Step B of Example 29, and
Step D of Example 27 to give
2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxybenzothiazo-
le hydrogen bromide (35.1). Anal. calcd. for
C.sub.12H.sub.13N.sub.3O.sub.4PS.sub.2Br+0.1HBr: C, 27.76; H, 2.72;
N, 8.09. Found: C, 27.54; H, 3.05; N, 7.83.
Example 36
Preparation of 2-Amino-4-phosphonomethoxy-6-chloro-7-methyl
Benzothiazole
[0404] Step A. 2-Methoxy-4-chloro-5-methylaniline was subjected to
Steps A and B of Example 27, Step B of Example 29, and Step D of
Example 27 to give 2-amino-4-phosphonomethoxy-6-chloro-7-methyl
benzothiazole (36.1). mp>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.10N.sub.2O.sub.4PS.sub.2Cl+0.3H.sub.2O+0.4 HBr: C,
31.20; H, 3.20; N, 8.09. Found: C, 31.37; H, 2.87; N, 7.89.
[0405] Similarly, the following compounds were prepared according
to above procedures:
(36.2)
2-Amino-7-phenyl-6-thiocyanato-4-phosphonomethoxybenzothiazole.
mp>250.degree. C. (dec.). Anal. calcd. for
C.sub.15H.sub.12N.sub.3O.sub.4PS.sub.2+0.2H.sub.2O: C, 45.38; H,
3.15; N, 10.58. Found: C, 45.25; H, 3.21; N, 10.53.
Example 37
Preparation of
2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e
[0406] Step A. A solution of
2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e (1 mmole) in CH.sub.3CN (4 mL) was cooled to 0.degree. C., and
treated with CuBr.sub.2 (1.2 mmole) followed by isoamylnitrite (1.5
mmole) in a dropwise fashion. The resulting dark mixture was
stirred for 3.5 h. Evaporation and chromatography gave
2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e as an oil. Step B.
2-Bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e was subjected to Step D of Example 27 to give
2-bromo-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(37.1) as a solid. Mp 220-230.degree. C. Anal. calcd. for
C.sub.12H.sub.13NO.sub.4PSBr: C, 38.11; H, 3.46; N, 3.70. Found: C,
37.75; H, 3.26; N, 3.69. (37.2) The same procedure was used to
react 2-amino-4-diethylphosphonomethoxy-6-chloro-7-methyl
benzothiazole with CuCl.sub.2 to give
2-Chloro-4-phosphonomethoxy-6-chloro-7-methyl benzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.8NO.sub.4PSCl.sub.2+0.7 HBr: C, 28.10; H, 2.28; N,
3.64. Found: C, 28.23; H, 2.20; N, 3.79.
Example 38
Preparation of
4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
[0407] Step A. A solution of isoamylnitrite (1.5 mmole) in DMF (1
mL) at 65.degree. C. was treated with
2-amino-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e (1 mmole) in DMF (3 mL). After 30 min, the cooled reaction
solution was subjected to evaporation and chromatography to provide
4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
as an oil, which was subjected to Step D of Example 27 to give
4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (38.1)
as a solid. Mp 215-220.degree. C. Anal. calcd. for
C.sub.12H.sub.14NO.sub.4PS+1.3HBr: C, 35.63; H, 3.81; N, 3.46.
Found: C, 35.53; H, 3.46; N, 3.40. (38.2) The same reaction
sequence was used to transform
2-amino-4-diethylphosphonomethoxy-6-chloro-7-methyl benzothiazole
to 4-Phosphonomethoxy-6-chloro-7-methyl benzothiazole. mp.
195-198.degree. C. Anal. calcd. for
C.sub.9H.sub.9NO.sub.4PSCl+0.5H.sub.2O: C, 35.71; H, 3.33; N, 4.63.
Found: C, 35.49; H, 3.19; N, 4.65.
Example 39
Preparation of 2-Amino-4-phosphonomethythio Benzothiazole
[0408] Step A. 2-Diethylphosphonomethylthioaniline, prepared
according to Step B of Example 27, was subjected to Step B of
Example 29 to give
2-amino-4-diethylphosphonomethylhio-benzothiazole. Step B.
2-Amino-4-diethylphosphonomethylhiobenzothiazole was subjected to
Step D of Example 34 to give
2-amino-4-phosphonomethythiobenzothiazole (39.1) as a foam. Anal.
calcd. for C.sub.8H.sub.10N.sub.2O.sub.3PS.sub.2+0.4H.sub.2O: C,
35.63; H, 3.81; N, 3.46. Found: C, 35.53; H, 3.46; N, 3.40.
Example 40
Preparation of 2-Amino-7-hexyl-6-thiocyano-4-phosphonomethoxy
Benzothiazole
[0409] Step A. A solution of 1 mmole of
2-diethylphosphonomethoxy-5-bromonitrobenzene (prepared as in
Example 30, step A) in diethyl amine (5 mL) was treated with
1-hexyne (1.2 mmole), CuI (0.1 mmole) and palladium
bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was
heated at 60.degree. C. under nitrogen for 14 h. Evaporation and
chromatography gave 2-diethylphosphonomethoxy-5-(1-hexyn) benzene
as an oil, which was subjected to Step B of Example 32, Step B of
Example 29, and Step D of Example 27 to give
2-amino-7-hexyl-6-thiocyano-4-phosphonomethoxybenzothiazole. (40.1)
2-Amino-6-thiocyanato-7-(n-hexyl)-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.15H.sub.20N.sub.3O.sub.4PS.sub.2: C, 44.88; H, 5.02; N,
10.47. Found: C, 44.54; H, 4.75; N, 10.37.
[0410] Similarly, the following compounds were prepared:
(40.2) A solution of 1 mmole of
2-diethylphosphonomethoxy-5-bromonitrobenzene (prepared as in
Example 30, step A) was subjected to Step C of Example 27, followed
a similar sequence as compound 40.1 to give
2-Amino-6-methyl-7-(n-hexyl)-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.15H.sub.23N.sub.2O.sub.4PS+0.25HBr: C, 47.58; H, 6.19; N,
7.40. Found: C, 47.40; H, 6.07; N, 7.54.
Example 41
Preparation of
2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole
[0411] Step A. A solution of 2-chloro-4-floro-5-methylnitrobenzene
(1 mmole) in DMF (5 mL) was treated with fresh sodium methoxy (1.1
mmole), and the mixture was stirred for 6 h. Evaporation and
chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene. Step
B. 2-chloro-4-methoxy-5-methylnitrobenzene was subjected to Step A
of Example 31, Step B of Example 32, Step A of Example 33, and Step
D of Example 27 to give
2-Amino-6-methoxy-7-methyl-4-phosphonomethoxybenzothiazole 41.1.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.10H.sub.13N.sub.2O.sub.4PS: C, 39.48; H, 4.31; N, 9.21.
Found: C, 39.39; H, 4.17; N, 8.98.
[0412] Similarly, the following compounds were prepared:
(41.2)
2-Amino-7-methyl-6-methylthio-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.10H.sub.13N.sub.2O.sub.4PS.sub.2+0.45 HBr: C, 33.67; H, 3.80;
N, 7.85. Found: C, 33.62; H, 3.86; N, 7.76. (41.3)
2-Amino-6-ethoxy-7-methyl-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.5PS: C, 41.51; H, 4.75; N, 8.80.
Found: C, 41.80; H, 4.59; N, 8.95. (41.4)
2-Amino-6-isobutoxy-7-methyl-4-phosphonomethoxybenzothiazole.
[0413] mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.13H.sub.19N.sub.2O.sub.5PS+0.15 HBr: C, 43.56; H, 5.38; N,
7.81. Found: C, 43.59; H, 5.38; N, 7.86.
Example 42
Preparation of 2-Amino-6-ethyl-4-phosphonomethoxybenzothiazole
[0414] Step A. To a solution of 1 mmol of 3-bromo chlorobenzene in
2 mL of con. H.sub.2SO.sub.4 was added 1.5 mmol of 79% HNO.sub.3 at
-10.degree. C. After it was stirred for 30 min. the mixture was
poured onto ice/water mixture. The yellow precipitate was filtered
and dried to give a mixture of 2-chloro-4-bromo nitrobenzene
(desired) and 4-chloro-2-bromo nitrobenzene. Step B.
2-Chloro-4-bromo nitrobenzene was subjected to Step A of Example
34, Step B of Example 32, Step B of Example 29, and Step D of
Example 27 to give 2-Amino-6-ethyl-4-phosphonomethoxybenzothiazole
(42.1) mp.>220.degree. C. (dec.). Anal. calcd. for
C.sub.10H.sub.13N.sub.2O.sub.4PS+0.3 HBr: C, 38.43; H, 4.29; N,
8.96. Found: C, 38.35; H, 4.44; N, 8.75.
[0415] Similarly, the following compound was prepared:
(42.2) 2-Amino-6-propyl-4-phosphonomethoxybenzothiazole.
mp.>220.degree. C. (dec.). Anal. calcd. for
C.sub.11H.sub.15N.sub.2O.sub.4PS+0.2 HBr: C, 41.49; H, 4.81; N,
8.80. Found: C, 41.85; H, 4.12; N, 8.31.
Example 43
Preparation of
2-Amino-6-thio-7-ethyl-4-phosphonomethoxybenzothiazole
[0416] Step A. A solution of 1 mmol of
2-Amino-6-thio-7-ethyl-4-diethylphosphonomethoxybenzothiazole (for
preparation see Example 34) in 3 mL of 48% HBr in AcOH was heated
at 90.degree. C. for 16 h. Solvent was removed and the residue was
washed with water to give
2-Amino-6-thio-7-ethyl-4-phosphonomethoxybenzothiazole (43.1).
mp.>220.degree. C. (dec.). Anal. calcd. for
C.sub.10H.sub.13N.sub.2O.sub.4PS.sub.2+0.2 HBr: C, 35.69; H, 3.95;
N, 8.33. Found: C, 35.49; H, 3.74; N, 8.33.
Example 44
Preparation of
2-Amino-7-propyloxy-6-thiocyano-4-phosphonomethoxybenzothiazole
[0417] Step A. To a solution of 1 mmol of 2-chloro-5-hydroxy
nitrobenzene in 5 mL of DMF was added 1.2 mmol of NaH at 0.degree.
C. After 30 min, allyl bromide was added and the mixture was
stirred at rt for 16 h. Solvent was removed and the residue was
washed with water and extracted with EtOAc to give
2-chloro-5-propenyloxy nitrobenzene. Step B. 2-Chloro-5-propenyloxy
nitrobenzene was subjected to Step A of Example 31, Step B of
Example 32, Step A of Example 33, and Step D of Example 27 to give
2-Amino-7-propyloxy-6-thiocyano-4-phosphonomethoxy benzothiazole.
(44.1). mp.>220.degree. C. (dec.). Anal. calcd. for
C.sub.12H.sub.14N.sub.3O.sub.5PS.sub.2+0.15 HBr+0.08H.sub.2O: C,
37.06; H, 3.71; N, 10.8. Found: C, 37.46; H, 3.48; N, 10.38.
Example 45
Preparation of
2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole
[0418] Step A. 2-Hydroxy-4-methoxy nitrobenzene was subjected to
Step B of Example 32, Step B of Example 27, Step B of Example 29,
Step D of Example 27 to give
2-Amino-6-methoxy-4-phosphonomethoxybenzothiazole (45.1)
mp.>230.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.11N.sub.2O.sub.5PS+0.5H.sub.2O: C, 36.12; H, 4.04; N,
9.36. Found: C, 36.18; H, 3.81; N, 9.47.
Example 46
2-Amino-7-ethyl-6-methyl-4-phosphonomethoxybenzothiazole
[0419] Step A. 2-Fluoro-4-methyl nitrobenzene was subjected to Step
A of Example 31, Step C of Example 27, Step A of Example 34, Step B
of Example 32, Step B of Example 29, Step D of Example 27 to give
(46.1) 2-Amino-7-ethyl-6-methyl-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd, for
C.sub.11H.sub.15N.sub.2O.sub.4PS+0.1 HBr: C, 42.57; H, 4.90; N,
9.03. Found: C, 42.32; H, 4.71; N, 8.87.
Example 47
2-Amino-7-bromo-6-methyl-4-phosphonomethoxybenzothiazole
[0420] Step A. 2-Fluoro-4-methyl nitrobenzene was subjected to Step
A of Example 31, Step C of Example 27, Step B of Example 30, Step A
of Example 33, Step D of Example 27 to give
2-Amino-7-bromo-6-methyl-4-phosphonomethoxybenzothiazole. (47.1)
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.10N.sub.2O.sub.4PSBr+0.3HBr: C, 28.64; H, 2.75; N,
7.42. Found: C, 28.62; H, 2.60; N, 7.42.
Example 48
2-Amino-7-fluoro-6-methyl-4-phosphonomethoxybenzothiazole
[0421] Step A. 2-Hydroxy-4-methyl-5-fluoro nitrobenzene was
subjected to Step B of Example 27, Step B of Example 32, Step A of
Example 33, Step D of Example 27 to give (48.1)
2-Amino-7-fluoro-6-methyl-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.10N.sub.2O.sub.4PSF+0.1 HBr: C, 35.99; H, 3.39; N,
9.33. Found: C, 35.84; H, 3.32; N, 9.31. (48.2) Starting with
2-hydroxy-5-chloro-4-methyl aniline and using the same reaction
sequence as above (except the reduction of NO.sub.2 step was done
using SnCl.sub.2 method i.e. Step B of Example 30) gave
2-Amino-7-chloro-6-methyl-4-phosphonomethoxybenzothiazole. (48.2)
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.10N.sub.2O.sub.4PSCl+0.6H.sub.2O: C, 34.62; H, 3.36;
N, 8.97. Found: C, 34.48; H, 3.40; N, 8.72.
Example 49
2-Amino-6-bromo-7-methoxy-4-phosphonomethoxybenzothiazole
[0422] Step A. 2-Amino-4,7-dimethoxy benzothiazole [prepared from
1-(2,5-dimethoxyphenyl)-2-thiourea using the procedure Step A of
Example 28] was subjected to Step C to give
2-Amino-4,7-dimethoxy-6-bromo benzothiazole. Step B. To a solution
of 1 mmol of 2-Amino-4,7-dimethoxy-6-bromo benzothiazole in
CH.sub.2Cl.sub.2 was added 2.2 mmol of BBr.sub.3 in
CH.sub.2Cl.sub.2 at 0.degree. C. for 16 h. Aqueous work-up and
chromatography gave 2-amino-4-hydroxy-6-bromo-7-methoxy
benzothiazole. Step C. 2-amino-4-hydroxy-6-bromo-7-methoxy
benzothiazole was subjected to Step B of Example 27, Step D of
Example 27 to give (49.1)
2-Amino-6-bromo-7-methoxy-4-phosphonomethoxybenzothiazole.
mp.>250.degree. C. (dec.). Anal. calcd. for
C.sub.9H.sub.10N.sub.2O.sub.5PSBr: C, 29.28; H, 2.73; N, 7.59.
Found: C, 28.90; H, 3.05; N, 7.20.
Example 50
General Procedure for Bis-Phosphoroamide Prodrugs
Dichloridate Formation
[0423] To a suspension of 1 mmol of phosphonic acid in 5 mL of
dichloroethane was added 0.1 mmol of pyridine (or 0.1 mmol of DMF)
followed by 6 mmol of thionyl chloride and was heated to reflux for
2.5 h. Solvent and excess thionyl chloride were removed under
reduced pressure and dried to give the dichloridate.
Coupling Reaction:
[0424] Method A: The crude dichloridate was taken into 5 mL of dry
CH.sub.2Cl.sub.2, and was added 8 mmol of amino acid ester at
0.degree. C. The resultant mixture was allowed to come to rt where
it was stirred for 16 h. The reaction mixture was subjected to aq.
work up and chromatography.
[0425] Method B: The crude dichloridate was taken into 5 mL of dry
CH.sub.2Cl.sub.2, and was added a mixture of 4 mmol of amino acid
ester and 4 mmol of N-methylimidazole at 0: .degree. C. The
resultant mixture was allowed to come to rt where it was stirred
for 16 h. The reaction mixture was subjected to aq. work up and
chromatography.
[0426] The following compounds were prepared in this manner.
(50.1) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-glutamic acid
diethylester) phosphonoamido)furanyl]thiazole. Anal. calcd. for
C.sub.29H.sub.45N.sub.4O.sub.10PS: C, 51:78; H, 6.74; N, 8.33.
Found: C, 51.70; H, 6.64; N, 8.15. (50.2)
2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-alanine acid dibenzyl
ester)phosphonoamido)furanyl]thiazole. Anal. calcd. for
C.sub.31H.sub.37N.sub.4O.sub.6PS: C, 59.60; H, 5.97; N, 8.97.
Found: C, 59.27; H, 5.63; N, 8.74. (50.3)
2-Amino-5-isobutyl-4-{2-[5-(N,N-bis(benzyloxycarbonylmethyl)phosphonodiam-
ido]furanyl}thiazole. Anal. calcd. for
C.sub.19H.sub.25N.sub.4O.sub.6PS+0.3 CH.sub.2Cl.sub.2: C, 46.93; H,
5.22; N, 11.34. Found: C, 46.92; H, 5.00; N, 11.22. (50.4)
2-Amino-5-isobutyl-4-{2-[5-(N,N-bis(benzyloxycarbonylmethyl)phosphonodiam-
ido]furanyl}thiazole. Anal. calcd. for
C.sub.29H.sub.33N.sub.4O.sub.6PS: C, 58.38; H, 5.57; N, 9.39.
Found: C, 58.20; H, 5.26; N, 9.25. (50.5)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((R)-1-methoxycarbonyl)ethyl)phosphon-
amido]furanyl}thiazole. Anal. calcd. for
C.sub.19H.sub.29N.sub.4O.sub.6PS+0.6 CH.sub.2Cl.sub.2: C, 44.97; H,
5.82; N, 10.70. Found: C, 44.79; H, 5.46; N, 10.48. (50.6)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl)ethyl)phosphona-
mido]furanyl}thiazole. mp. 164-165.degree. C.: Anal. calcd. for
C.sub.21H.sub.33N.sub.4O.sub.6PS+0.61 CH.sub.2Cl.sub.2: C, 46.99;
H, 6.24; N, 10.14. Found: C, 47.35; H, 5.85; N, 9.85. (50.7)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((t-butoxycarbonyl)methyl)phosphonami-
do]furanyl}thiazole. Anal. calcd. for
C.sub.23H.sub.37N.sub.4O.sub.6PS+0.15 CH.sub.2Cl.sub.2: C, 51.36;
H, 6.94; N, 10.35. Found: C, 51.34; H, 6.96; N, 10.06. (50.8)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis(ethoxycarbonyl)methyl)phosphonamido)-
]furanyl}thiazole. Anal. calcd. for
C.sub.19H.sub.29N.sub.4O.sub.6PS+0.1 EtOAc+0.47 CH.sub.2Cl.sub.2:
C, 45.79; H, 5.94; N, 10.75. Found: C, 46.00; H, 5.96; N, 10.46.
(50.9)
2-Amino-5-isobutyl-4-{2-[5-(O-(2-bis(N-(1-methyl-1-ethoxycarbonyl)ethyl)p-
hosphonamido]furanyl}thiazole. mp. 142-145.degree. C.: Anal. calcd.
for C.sub.23H.sub.37N.sub.4O.sub.6PS: C, 52.26; 7.06; 10.60. Found:
C, 52.21; 6.93; 10.62. (50.10)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis(ethoxycarbonylmethyl)-N,N'-dimethylp-
hosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.21H.sub.33N.sub.4O.sub.6PS: C, 50.39; H, 6.65; N, 11.19.
Found: C, 50.57; H, 6.56; N, 11.06. (50.11)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-benzyloxycarbonyl-2-methyl)pro-
pyl)phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.35H.sub.45N.sub.4O.sub.6PS+0.5H.sub.2O: C, 60.94; H, 6.72; N,
8.12. Found: C, 61.01: H, 6.48; N, 7.82. (50.12)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-methoxycarbonyl-3-methyl)butyl-
)phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.25H.sub.41N.sub.4O.sub.6PS: C, 53.94; H, 7.42; N, 10.06.
Found: C, 54.12; H, 7.62; N, 9.82. (50.13)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((R)-1-ethoxycarbonyl-2-(S-benzyl))et-
hyl)phosphonamido]furanyl)thiazole. Anal. calcd. for
C.sub.35H.sub.45N.sub.4O.sub.6PS.sub.3+0.4 toluene: C, 58.07; H,
6.21; N, 7.17. Found: C, 57.87; H, 6.14; N, 6.81. (50.14)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-3-(S-methyl))bu-
tyl)phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.23H.sub.37N.sub.4O.sub.6PS.sub.3: C, 46.61; H, 6.92; N, 9.45.
Found: C, 46.26; H, 6.55; N, 9.06. (50.15)
2-Amino-5-propylthio-4-{2-[5-(N,N'-(1-(S)ethoxycarbonyl)ethyl)phosphonami-
do]furanyl}thiazole. Anal. calcd. for
C.sub.20H.sub.31N.sub.4O.sub.6PS.sub.2: C, 46.32; H, 6.03; N,
10.80. Found: C, 46.52; H, 6.18; H, 10.44. (50.16)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-benzyloxycarbonyl-2-methyl)iso-
butyl)phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.37H.sub.49N.sub.4O.sub.6PS: C, 62.69; H, 6.97; H, 7.90.
Found: C, 62.85; h 7.06, 7.81. (50.17)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-3-methyl)butyl)-
phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.27H.sub.45N.sub.4O.sub.6PS: C, 55.46; H, 7.76; N, 9.58.
Found: C, 55.35; H, 7.94; N, 9.41. (50.18)
2-Amino-5-isobutyl-4-{2-[5-(N
N'-bis((S)-1-ethoxycarbonyl-2-methyl)propyl)phosphonamido]furanyl}thiazol-
e. Anal. calcd. for C.sub.25H.sub.41N.sub.4O.sub.6PS: C, 53.94; H,
7.42; N, 10.06. Found: C, 54.01; H, 7.58; N, 9.94. (50.19)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-2-phenyl)ethyl)-
phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.33H.sub.41N.sub.4O.sub.6PS+0.15 CH.sub.2Cl.sub.2: C, 59.83;
H, 6.26; H, 8.42. Found: C, 59.88; H, 6.28; H, 8.32. (50.20)
2-Amino-5-propylthio-4-{2-[5-(N,N'-(1-methyl-ethoxycarbonyl)ethyl)phospho-
namido]furanyl}thiazole. mp. 110-115.degree. C.: Anal. calcd. for
C.sub.22H.sub.35N.sub.4O.sub.6PS.sub.2+0.4HCl+0.5Et.sub.2O: C,
48.18; H, 6.81; N, 9.36. Found: C, 48.38; H, 6.60; H, 8.98. (50.21)
2-Amino-5-methylthio-4-{2-[5-(N,N'-bis(1-methyl-1-ethoxycarbonyl)ethyl)ph-
osphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.20H.sub.31N.sub.4O.sub.6PS.sub.2+0.5H.sub.2O: C, 45.53; H,
6.11; N, 10.62. Found: C, 45.28; H, 5.85: N, 10.56.
Example 51
General Procedure for Mixed Bis-Phosphoroamidate Prodrugs
[0427] To a solution of crude dichloridate (1 mmol, prepared as
described in Example 50) in 5 mL of dry CH.sub.2Cl.sub.2 was added
amine (1 mmol) followed by 4-dimethylaminopyridine (3 mmol) at
0.degree. C. The resulting mixture was allowed to warm to room
temperature and stirred for 1 h. The reaction was cooled back to
0.degree. C. before adding amino acid ester (2 mmol) and left at
room temperature for 16 h. The reaction mixture was subjected to
aq. work up and the mixed bis-phosphoroamidate prodrug was purified
by column chromatography.
[0428] The following compounds were prepared in this manner.
(51.1)
2-Amino-5-isobutyl-4-{2-[5-(N-morpholino-N'-(1-methyl-1-ethoxycarb-
onyl)ethyl)phosphonamido]furanyl}thiazole. mp. 182-183.degree. C.:
Anal. calcd. for C.sub.21H.sub.33N.sub.4O.sub.5PS: C, 52.05; H,
6.86; N, 11.56. Found: C, 51.66; H, 6.68; N, 11.31. (51.2)
2-Amino-5-isobutyl-4-{2-[5-(N-pyrrolidino-N'-(1-methyl-1-ethoxycarbonyl)e-
thyl)phosphonamido]furanyl}thiazole. mp. 189-190.degree. C.: Anal.
calcd. for C.sub.21H.sub.33N.sub.4O.sub.4PS: C, 53.83; H, 7.10; N,
11.96. Found: C, 54.15; H, 7.48; N, 12.04.
Example 52
Bis-phosphoroamide Prodrug Synthesis using Mukaiyama's Method with
Some Modifications
[0429] J. Am. Chem. Soc. 1972, 94, 8528.
[0430] To a suspension of 1.0 mmol. phosphonic acid and 2.0 mmol of
amino acid ester salt (for example alanine ethyl ester HCl salt) in
9 mL of pyridine, Et.sub.3N and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidione (DMPU) (1:1:1)
was added a premixed solution of 4 mmol of aldrithiol and 4 mmol of
PPh.sub.3 in 3 mL of pyridine. After 16 h at 90.degree. C., the
solvents pyridine and Et.sub.3N were removed under reduced
pressure. The remaining solution upon dilution with hexane (100 mL)
the crude product was oiled out and was subjected to chromatography
purification.
[0431] The following compounds were prepared using this method.
(52.1)
2-Amino-4-[(N,N'-(1-(S)-ethoxycarbonyl)ethyl)phosphonodiamidometho-
xy]-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole. Mp. 153-156.degree.
C.: Anal. calcd. for C.sub.22H.sub.33N.sub.4O.sub.6PS: C, 51.55; H,
6.49; N, 10.93. Found: C, 51.39; H, 6.24; N, 10.96. (52.2)
2-Amino-5-isopropyl-4-[(N,N'-(1-(S)-ethoxycarbonyl)ethyl)phosphonodiamido-
methoxycarbonyl]-thiazole. Anal. calcd. for
C.sub.18H.sub.31N.sub.4O.sub.7PS: C, 45.18; H, 6.53; N, 11.71.
Found: C, 45.33; H, 6.56; N, 11.46. (52.3)
4-Amino-7-ethyl-5-fluoro-1-isobutyl-2-[5-({N,N'-(1-(S)
ethoxycarbonyl)ethyl}phosphonodiamido) furanyl]benzimidazole. Anal.
calcd. for C.sub.27H.sub.39N.sub.5O.sub.6 PF: C, 55.95; H, 6.78; N,
12.08. Found: C, 55.73; H, 6.65; N, 11.72. (52.4)
2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N'-(1-(S)ethoxycarbonyl)ethyl}phosph-
ono)furanyl]thiazole. Anal. calcd. for
C.sub.20H.sub.29N.sub.4O.sub.8PS+0.3 CH.sub.2Cl.sub.2: C, 44.99; H,
5.50; N, 10.34. Found: C, 44.68; H, 5.30; N, 10.37. (52.5)
2-Amino-4-[(N,N'-(1-(S)-ethoxycarbonyl)methyl)phosphonodiamidomethoxy]-5,-
6,7,8-tetrahydronaphtho[1,2-d]thiazole. Mp. 177-178.degree. C.:
Anal. calcd. for C.sub.20H.sub.29N.sub.4O.sub.6PS: C, 49.58; H,
6.03; N, 11.56. Found: C, 49.20; H, 5.95; N, 11.51. (52.6)
2-Amino-5-isopropyl-4-[(N,N'-(1-(S)-ethoxycarbonyl)methyl)phosphonodiamid-
omethoxycarbonyl]-thiazole. Mp. 122-125.degree. C.: Anal. calcd.
for C.sub.16H.sub.27N.sub.4O.sub.7PS: C, 42.66; H, 6.04; N, 12.44.
Found: C, 42.60; H, 6.08; N, 12.43. (52.7)
2-Amino-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-bromo-7-ch-
loro-benzothiazole. Mp. 210-212.degree. C.: Anal. calcd. for
C.sub.18H.sub.25N.sub.4O.sub.6PSBrCl: C, 37.81; H, 4.41; N, 9.80.
Found: C, 37.88; H, 4.35; N, 9.84. (52.8)
2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-methoxycarbonyl-2-(t-butoxy)e-
thyl)phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.26H.sub.43N.sub.4O.sub.8PS.sub.2: C, 49.20; H, 6.83; N, 8.83.
Found: C, 49.38; H, 6.68; N, 8.65. (52.9)
2-Amino-5-propylthio-4-{2-[5-(N,N'-bis(S)-1-ethoxycarbonyl-2-methylbutyl)-
phosphonamido]furanyl}thiazole. Anal. calcd. for
C.sub.26H.sub.43N.sub.4O.sub.6PS.sub.2: C, 51.81; H, 7.19; N, 9.30.
Found: C, 52.03; H, 6.78; N, 9.04. (52.10)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis(S)-1-ethoxycarbonyl-2-methylpropyl-
)phosphonamido]furanyl}thiazole. Anal. calcd for
C.sub.24H.sub.39N.sub.4O.sub.6PS.sub.2: C, 50.16; H, 6.84; N, 9.75.
Found: C, 50.01; H, 6.76; N, 9.66. (52.11)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis(S)-1-methoxycarbonyl-2-(t-butoxy)p-
ropyl)phosphonamido}furanyl]thiazole. Anal. calcd. for
C.sub.28H.sub.47N.sub.4O.sub.8PS.sub.2: C, 50.74; H, 7.15; N, 8.45.
Found: C, 51.08; H, 7.33; N, 8.25. (52.12)
2-Amino-propylthio-4-[2-{5-(N,N'-bis(1-ethoxycarbonyl)cyclopentyl)phospho-
namido}furanyl]thiazole. Anal. calcd. for
C.sub.26H.sub.39N.sub.4O.sub.6PS.sub.2: C, 52.16; H, 6.57; N, 9.36.
Found: C, 52.55; H, 6.53; N, 9.31. (52.13)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis(S)-1-ethoxycarbonyl)propylphosphon-
amido}furanyl]thiazole. Anal. calcd. for
C.sub.22H.sub.35N.sub.4O.sub.6PS.sub.2: C, 48.34; H, 6.45; N,
10.25. Found: C, 48.65; H, 6.29; N, 10.23. (52.14)
2-Amino-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-chloro-7-m-
ethyl-benzothiazole. Mp. 178-180.degree. C.: Anal. calcd. for
C.sub.19H.sub.28N.sub.4O.sub.6PSCl: C, 45.02; H, 5.57; N, 11.05.
Found: C, 45.12; H, 5.49; N, 10.92. (52.15)
2-Amino-5-methylthio-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl)ethyl)phospho-
namido]furanyl}thiazole. Mp. 94-95.degree. C.: Anal. calcd. for
C.sub.18H.sub.27N.sub.4O.sub.6PS.sub.2: C, 44.07; H, 5.55; N,
11.42. Found: C, 44.42; H, 5.44; N, 11.29. (52.16)
2-Amino-propylthio-4-[2-{5-(N,N'-bis((S)1-ethoxycarbonyl)butyl)phosphonam-
ido)}furanyl]thiazole.: Anal. calcd. for
C.sub.24H.sub.39N.sub.4O.sub.6PS.sub.2: C, 50.16; H, 6.84; N, 9.75.
Found: C, 49.96; H, 6.91; N, 9.68. (52.17)
2-Amino-propylthio-4-[2-{5-(N,N'-bis((S)
1-ethoxycarbonyl)cyclohexanylmethyl)phosphonamido)}furanyl]thiazole.
Anal. calcd. for C.sub.30H.sub.47N.sub.4O.sub.6PS.sub.2: C, 55.03;
H, 7.23; N, 8.56. Found: C, 54.89; H, 7.14; N, 8.42. (52.18)
2-Amino-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-methoxy-be-
nzothiazole. Mp. 144-146.degree. C.: Anal. calcd. for
C.sub.19H.sub.29N.sub.4O.sub.7PS: C, 46.72; H, 5.98; N, 11.47.
Found: C, 46.76; H, 5.72; N, 11.33. (52.19)
2-Amino-4-{N,N'-(ethoxycarbonyl)methyl}phosphonomethoxy-6-methoxy-benzoth-
iazole. Mp. 150-152.degree. C.: Anal. calcd. for
C.sub.17H.sub.25N.sub.4O.sub.7PS: C, 44.35; H, 5.47: N, 12.17.
Found: C, 44.74; H, 5.45; N, 11.99. (52.20)
2-Amino-7-ethyl-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-me-
thyl-benzothiazole. Anal. calcd. for
C.sub.21H.sub.33N.sub.4O.sub.6PS: C, 50.39; H, 6.65; N, 11.19.
Found: C, 50.22; H, 6.34; N, 11.30. (52.21)
2-Amino-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-methyl-ben-
zothiazole. Anal. calcd. for C.sub.19H.sub.29N.sub.4O.sub.6PS: C,
48.30; H, 6.19; N, 11.86. Found: C, 48.67; H, 5.90; N, 11.86.
(52.22)
2-Amino-4-{N,N'-(1-methyl-1-ethoxycarbonyl)ethyl}phosphonomethoxy-6-chlor-
o-7-methyl-benzothiazole. Mp. 170-172.degree. C.: Anal. calcd. for
C.sub.21H.sub.32N.sub.4O.sub.6PSCl: C, 47.15; H, 6.03; N, 10.47.
Found: C, 47.22; H, 5.87; N, 10.08. (52.23)
2-Amino-7-ethyl-4-{N,N'-bis(ethoxycarbonylmethyl)}phosphonomethoxy-6-meth-
yl-benzothiazole. Anal. calcd. for
C.sub.19H.sub.29N.sub.4O.sub.6PS: C, 48.30; H, 6.19; N, 11.86.
Found: C, 47.98; H, 6.36; N, 11.88. (52.24)
2-Amino-4-{N,N'-bis(ethoxycarbonylmethyl)}phosphonomethoxy-6-methyl-benzo-
thiazole. Anal. calcd. for
C.sub.17H.sub.25N.sub.4O.sub.6PS+0.5H.sub.2O: C, 45.03; H, 5.78; N,
12.36. Found: C, 44.80; H, 6.10; N, 12.40. (52.25)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)1-t-butoxycarbonyl)ethyl)phosph-
onamido)}furanyl]thiazole. Anal. calcd. for
C.sub.24H.sub.39N.sub.4O.sub.6PS.sub.2: C, 50.16; H, 6.84; N, 9.75.
Found: C, 50.26; H, 6.71; N, 9.51. (52.26)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)1-n-butoxycarbonyl)ethyl)phosph-
onamido)}furanyl]thiazole. Anal. calcd. for
C.sub.24H.sub.39N.sub.4O.sub.6PS.sub.2: C, 50.16; H, 6.84; N, 9.75.
Found: C, 50.38; H, 6.64; N, 9.64. (52.27)
2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N'-(1-(S)-ethoxycarbonyl)propyl}phos-
phono)furanyl]thiazole. Anal. calcd. for
C.sub.22H.sub.33N.sub.4O.sub.8PS: C, 48.52; H, 6.11; N, 10.29.
Found: C, 48.62; H, 6.02; N, 10.26. (52.28)
2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N'-(1-(S)-ethoxycarbonyl)butyl}phosp-
hono)furanyl]thiazole. Anal. calcd. for
C.sub.24H.sub.37N.sub.4O.sub.8PS: C, 50.34; H, 6.51; N, 9.78.
Found: C, 50.34; H, 6.57; N, 9.65. (52.29)
2-Amino-5-ethoxycarbonyl-4-[2-(5-({N,N'-(1-ethoxycarbonyl)cyclopentyl}pho-
sphono)furanyl]thiazole. Anal. calcd. for
C.sub.26H.sub.37N.sub.4O.sub.8PS: C, 52.34; H, 6.25; N, 9.39.
Found: C, 52.02; H, 6.20; N, 9.34. (52.30)
2-Amino-5-ethoxycarbonyl-4-[2-{5-(N,N'-bis(S)-1-ethoxycarbonyl-2-methylpr-
opyl)phosphonamido}furanyl]thiazole. Anal. calcd. for
C.sub.24H.sub.37N.sub.4O.sub.8PS: C, 50.34; H, 6.51; N, 9.78.
Found: C, 50.56; H, 6.40; N, 9.65. (52.31)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis-coumarin)phosphonamido}furanyl]thi-
azole. Anal. calcd. for C.sub.28H.sub.23N.sub.4O.sub.6PS.sub.2: C,
55.44; H, 3.82; N, 9.24. Found: C, 55.52; H, 3.66; N, 9.01. (52.32)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)1-iso-propoxycarbonyl)ethyl)pho-
sphonamido)}furanyl]thiazole. Anal. calcd. For
C.sub.22H.sub.35N.sub.4O.sub.6PS.sub.2: C, 48.34; H, 6.45; N,
10.25. Found: C, 48.03; H, 6.45; N, 10.09. (52.33)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)1-n-propoxycarbonyl)ethyl)phosp-
honamido)}furanyl]thiazole. Anal. calcd. for
C.sub.22H.sub.35N.sub.4O.sub.6PS.sub.2: C, 48.34; H, 6.45; N,
10.25. Found: C, 48.39; H, 6.27; N, 10.20. (52.34)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)1-cycloheptoxycarbonyl)ethyl)ph-
osphonamido)}furanyl]thiazole. Anal. calcd. for
C.sub.26H.sub.39N.sub.4O.sub.6PS.sub.2: C, 52.16; H, 6.57; N, 9.36.
Found: C, 52.07; H, 6.51; N, 9.10. (52.35)
2-Amino-6-ethyl-7-fluoro-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomet-
hoxy-benzothiazole. Anal. calcd. for
C.sub.20H.sub.30N.sub.4O.sub.6PSF: C, 47.61; H, 5.99; N, 11.10.
Found: C, 47.59; H, 5.79; N, 10.90. (52.36)
2-Amino-6-ethyl-7-fluoro-4-{N,N'-(1-ethoxycarbonyl)methyl}phosphonomethox-
y-benzothiazole. Anal. calcd. for
C.sub.18H.sub.26N.sub.4O.sub.6PSF: C, 45.38; H, 5.50; N, 11.76.
Found: C, 45.07; H, 5.25; N, 11.49. (52.37)
2-Amino-7-bromo-4-{N,N'-(1-(S)-ethoxycarbonyl)ethyl}phosphonomethoxy-6-me-
thylbenzothiazole. Anal. calcd. for
C.sub.19H.sub.28N.sub.4O.sub.6PSBr: C, 41.39; H, 5.12; N, 10.16.
Found: C, 41.40; H, 5.05; N, 9.94. (52.38)
2-Amino-4-{N,N'-(1-ethoxycarbonyl)methylethyl}phosphonomethoxy-6-methylbe-
nzothiazole. Anal. calcd. for
C.sub.21H.sub.33N.sub.4O.sub.6PS+0.5H.sub.2O: C, 49.50; H, 6.73; N,
11.00. Found: C, 49.18; H, 6.61; N, 11.39. (52.39)
2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-ethoxycarbonyl)propyl)phosp-
honamido)}furanyl]thiazole. Anal. calcd. for
C.sub.23H.sub.37N.sub.4O.sub.6PS: C, 52.26; H, 7.06; N, 10.60.
Found: C, 52.47; H, 7.29; N, 10.77. (52.40)
2-Amino-5-propylthio-4-[2-{5-(N,N'-bis((S)-1-cyclohexylmethoxycarbonyl)et-
hyl)phosphonamido)}furanyl]thiazole. Anal. calcd. for
C.sub.30H.sub.47N.sub.4O.sub.6PS.sub.2: C, 55.03; H, 7.23; N, 8.56.
Found: C, 55.08; H, 7.35; N, 8.39. (52.41)
2-Amino-5-isobutyl-4-[2-{5-(1-ethoxycarbonyl)cyclopentyl)phosphonamido)}f-
uranyl]thiazole. Anal. calcd. for C.sub.27H.sub.41N.sub.4O.sub.6PS:
C, 55.85; H, 7.12; N, 9.65. Found: C, 55.62; H, 6.81; N, 9.66.
(52.42)
2-Amino-4-{N,N'-(1-ethoxycarbonyl)cyclopentyl}phosphonomethoxy-7-fluoro-6-
-methyl benzothiazole. Anal. calcd. for
C.sub.26H.sub.38N.sub.4O.sub.6PSF+0.15 Et.sub.2O: C, 53.63; H,
6.68; N, 9.40. Found: C, 53.93; H, 6.39; N, 9.50. (52.43)
2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-neopentoxycarbonyl)ethyl)ph-
osphonamido)}furanyl]thiazole. Anal. calcd. for
C.sub.27H.sub.45N.sub.4O.sub.6PS+0.1H.sub.2O: C, 55.29; H, 7.77; N,
9.55. Found: C, 54.90; H, 7.68; N, 9.44. (52.44)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((R,S)-1-(1-ethoxycarbonyl)ethyl)phos-
phonamido)]furanyl}thiazole. Mp. 143-146.degree. C.: Anal. calcd.
for C.sub.21H.sub.33N.sub.4O.sub.6PS: C, 50.39; H, 6.65; N, 11.19.
Found: C, 50.33; H, 6.58; N, 11.00. (52.45)
2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-isopropoxycarbonyl)ethyl)ph-
osphonamido)}furanyl]thiazole. Anal. calcd. for
C.sub.23H.sub.37N.sub.4O.sub.6PS: C, 52.26; H, 7.06; N, 10.60.
Found: C, 52.34; H, 7.02; N, 10.50. (52.46)
2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-propoxycarbonyl)ethyl)phosp-
honamido)}furanyl]thiazole. Anal. calcd. for
C.sub.23H.sub.37N.sub.4O.sub.6PS+0.1 CH.sub.2Cl.sub.2: C, 51.66; H,
6.98; N, 10.43. Found: C, 51.50; H, 7.01; N, 10.63. (52.47)
2-Amino-5-isobutyl-4-[2-{5-(N,N'-bis((S)-1-(1-isobutoxycarbonyl)ethyl)pho-
sphonamido)}furanyl]thiazole. Anal. calcd. for
C.sub.25H.sub.41N.sub.4O.sub.6PS: C, 53.94; H, 7.42; N, 10.06.
Found: C, 53.59; H, 7.64; N, 9.98. (52.48)
2-Amino-5-propylthio-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl)ethyl)phospho-
namido]furanyl}oxazole. Anal. calcd. for
C.sub.20H.sub.31N.sub.4O.sub.7PS: C, 47.80; H, 6.22; N, 11.15.
Found: C, 47.90; H, 6.17; N, 10.92. (52.49)
2-Amino-5-propylthio-4-{2-[5-(N,N'-bis-1-ethoxycarbonyl)methyl)phosphonam-
ido]furanyl}oxazole. Anal. calcd. for
C.sub.18H.sub.27N.sub.4O.sub.7PS: C, 45.57; H, 5.74; N, 11.81.
Found: C, 45.87; H, 5.68; N, 11.68. (52.50)
2-Amino-5-(isobutyl-d.sub.9)-4-[2-{5-(N,N'-bis(S)-1-(1-ethoxycarbonyl)eth-
ylphosphonamido}furanyl]thiazole. Anal. calcd. for
C.sub.21H.sub.24D.sub.9N.sub.4O.sub.6SP: C, 49.50; H, 4.75; N,
10.99. Found: C, 49.89; H, 6.55; N, 10.97.
[0432] Examples of use of the method of the invention include the
following. It will be understood that these examples are exemplary
and that the method of the invention is not limited solely to these
examples.
[0433] For the purposes of clarity and brevity, chemical compounds
are referred to by synthetic Example number in the biological
examples below.
[0434] Compound A is
4-Amino-5-fluoro-7-ethyl-1-isobutyl-2-(2-phosphono-5-furanyl)benzimidazol-
e;
[0435] Compound B is
4-Amino-5-fluoro-1-cyclopropylmethyl-2-(2-phosphono-5-furanyl)benzimidazo-
le.
[0436] Compound C is
2-Amino-5-isobutyl-4-{2-[N-(1-methyl-1-carboxy)ethylmonophosphonamido]fur-
anyl}thiazole
[0437] Besides the following Examples, assays that may be useful
for identifying compounds which inhibit gluconeogenesis include the
following animal models of diabetes:
[0438] i. Animals with pancreatic b-cells destroyed by specific
chemical cytotoxins such as
[0439] Alloxan or Streptozotocin (e.g. the Streptozotocin-treated
mouse, rat, dog, and monkey). Kodama, H., Fujita, M., Yamaguchi,
I., Japanese Journal of Pharmacology 66, 331-336 (1994) (mouse);
Youn, J. H., Kim, J. K., Buchanan, T. A., Diabetes 43, 564-571
(1994) (rat); Le Marchand, Y., Loten, E. G., Assimacopoulos-Jannet,
F., et al., Diabetes 27, 1182-88 (1978) (dog); and Pitkin, R. M.,
Reynolds, W. A., Diabetes 19, 70-85 (1970) (monkey).
[0440] ii. Mutant mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob,
and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and
others such as Yellow Obese, T-KK, and New Zealand Obese. Coleman,
D. L., Hummel, K. P., Diabetologia 3, 238-248 (1967) (C57BL/Ks
db/db); Coleman, D. L., Diabetologia 14, 141-148 (1978) (C57BL/6J
ob/ob); Wolff, G. L., Pitot, H. C., Genetics 73, 109-123 (1973)
(Yellow Obese); Dulin, W. E., Wyse, B. M., Diabetologia 6, 317-323
(1970) (T-KK); and Bielschowsky, M., Bielschowsky, F. Proceedings
of the University of Otago Medical School 31, 29-31 (1953) (New
Zealand Obese).
[0441] iii. Mutant rats such as the Zucker fa/fa Rat rendered
diabetic with Streptozotocin or Dexamethasone, the Zucker Diabetic
Fatty Rat, and the Wistar Kyoto Fatty Rat. Stolz, K. J., Martin, R.
J. Journal of Nutrition 112, 997-1002 (1982) (Streptozotocin);
Ogawa, A., Johnson, J. H., Ohnbeda, M., McAllister, C. T., Inman,
L., Alam, T., Unger, R. H., The Journal of Clinical Investigation
90, 497-504 (1992) (Dexamethasone); Clark, J. B., Palmer, C. J.,
Shaw, W N., Proceedings of the Society for Experimental Biology and
Medicine 173, 68-75 (1983) (Zucker Diabetic Fatty Rat); and Idida,
H., Shino, A., Matsuo, T., et al., Diabetes 30, 1045-1050 (1981)
(Wistar Kyoto Fatty Rat).
[0442] iv. Animals with spontaneous diabetes such as the Chinese
Hamster, the Guinea Pig, the New Zealand White Rabbit, and
non-human primates such as the Rhesus monkey and Squirrel monkey.
Gerritsen, G. C., Connel, M. A., Blanks, M. C., Proceedings of the
Nutrition Society 40, 237 245 (1981) (Chinese Hamster); Lang, C.
M., Munger, B. L., Diabetes 25, 434-443 (1976) (Guinea Pig);
Conaway, H. H., Brown, C. J., Sanders, L. L. et al, Journal of
Heredity 71, 179-186 (1980) (New Zealand White Rabbit); Hansen, B.
C., Bodkin, M. L., Diabetologia 29, 713-719 (1986) (Rhesus monkey);
and Davidson, I. W., Lang, C. M., Blackwell, W. L., Diabetes 16,
395-401 (1967) (Squirrel monkey).
[0443] v. Animals with nutritionally induced diabetes such as the
Sand Rat, the Spiny Mouse, the Mongolian Gerbil, and the Cohen
Sucrose-Induced Diabetic Rat. Schmidt-Nielsen, K., Hainess, H. B.,
Hackel, D. B., Science 143, 689-690 (1964) (Sand Rat); Gonet, A.
E., Stauffacher, W., Pictet, R., et al., Diabetologia 1, 162-171
(1965) (Spiny Mouse); Boquist, L., Diabetologia 8, 274-282 (1972)
(Mongolian Gerbil); and Cohen, A. M., Teitebaum, A., Saliternik,
R., Metabolism 21, 235-240 (1972) (Cohen Sucrose-Induced Diabetic
Rat).
[0444] vi. Any other animal with one of the following or a
combination of the following characteristics resulting from a
genetic predisposition, genetic engineering, selective breeding, or
chemical or nutritional induction: impaired glucose tolerance,
insulin resistance, hyperglycemia, obesity, accelerated
gluconeogenesis, increased hepatic glucose output.
Example A
Inhibition of Human Liver FBPase
[0445] E. coli strain BL21 transformed with a human liver
FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at
the State University of New York at Stony Brook. The enzyme was
typically purified from 10 liters of recombinant E. coli culture as
described (M. Gidh-Jain et al., 1994, The Journal of Biological
Chemistry 269, pp 27732-27738). Enzymatic activity was measured
spectrophotometrically in reactions that coupled the formation of
product (fructose 6-phosphate) to the reduction of
dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP.sup.+ and
phenazine methosulfate (PMS), using phosphoglucose isomerase and
glucose 6-phosphate dehydrogenase as the coupling enzymes. Reaction
mixtures (200 .mu.l) were made up in 96-well microtitre plates, and
consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM
MgCl.sub.2, 0.2 mM NADP, 1 mg/ml BSA, 1 mM MTT, 0.6 mM PMS, 1
unit/ml phosphoglucose isomerase, 2 units/ml glucose 6-phosphate
dehydrogenase, and 0.150 mM substrate (fructose 1,6-bisphosphate).
Inhibitor concentrations were varied from 0.01 .mu.M to 10 .mu.M.
Reactions were started by the addition of 0.002 units of pure
hlFBPase, and were monitored for 7 minutes at 590 nm in a Molecular
Devices Plate Reader (37.degree. C.).
[0446] The table below provides the IC.sub.50 values for several
compounds prepared. The IC.sub.50 for AMP is 1 .mu.LM.
TABLE-US-00023 Compound # IC.sub.50 (hlFBPase), .mu.M 3.1 0.025 3.2
0.1 3.25 0.014 3.26 0.015 3.58* 0.018 (*non-HBr salt) 3.67 2 3.69 1
3.70 0.04 6.3 0.044 10.1 0.12 10.27 0.038 10.43 0.07 15.20 0.04
15.14 0.032 16.1 0.06 17.6 0.62 17.11 0.78 18.3 0.05 18.11 0.33
18.20 0.039 18.25 2 19.2 0.4 22.2 2.8 34.1 0.022 A 0.055 B
0.055
Inhibition of Rat Liver FBPase
[0447] E. Coli strain BL21 transformed with a rat liver
FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at
the State University of New York at Stony Brook. Recombinant FBPase
was purified as described (El-Maghrabi, M. R., and Pilkis, S. J.
(1991) BioChem. Biophys. Res. Commun. 176, 137-144) The enzyme
assay was identical to that described above for human liver
FBPase.
[0448] The table below provides the IC.sub.50 values for several
compounds prepared. The IC.sub.50 for AMP is 20 .mu.M.
TABLE-US-00024 Compound # IC.sub.50 (rlFBPase), .mu.M 3.1 0.18 3.2
2.5 3.25 0.5 3.26 0.25 3.58* 0.05 (*non-HBr salt) 3.70 0.15 6.3 0.5
10.1 2 10.2 2.5 10.27 2.9 10.43 0.8 15.2 1.3 15.4 4.1 15.6 7 15.20
0.6 15.14 0.68 16.1 1.8 18.20 0.28 18.3 0.49 34.1 0.16 A 0.55 B
2.1
Example B
AMP Site Binding
[0449] To assess whether compounds bind to the allosteric AMP
binding site of hlFBPase, the enzyme is incubated with
radio-labeled AMP in the presence of a range of test compound
concentrations. The reaction mixtures consist of 25 mM .sup.3H-AMP
(54 mCi/mmole) and 0-1000 mM test compound in 25 mM Tris-HCl, pH
7.4, 100 mM KCl and 1 mM MgCl.sub.2. 1.45 mg of homogeneous FBPase
(.+-.nmole) is added last. After a 1 minute incubation, AMP bound
to FBPase is separated from unbound AMP by means of a centrifugal
ultrafiltration unit ("Ultrafree-MC", Millipore) used according to
the instructions of the manufacturer. The radioactivity in aliquots
(100 .mu.l) of the upper compartment of the unit (the retentate,
which contains enzyme and label) and the lower compartment (the
filtrate, which contains unbound label) is quantified using a
Beckman liquid scintillation counter. The amount of AMP bound to
the enzyme is estimated by comparing the counts in the filtrate
(the unbound label) to the total counts in the retentate.
Example C
Inhibition of Gluconeogenesis in Rat Hepatocytes
[0450] Hepatocytes were prepared from overnight fasted
Sprague-Dawley rats (250-300 g) according to the procedure of Berry
and Friend (Berry, M. N., Friend, D. S., 1969, J. Cell. Biol. 43,
506-520) as modified by Groen (Groen, A. K., Sips, H. J., Vervoorn,
R. C., Tager, J. M., 1982, Eur. J. BioChem. 122, 87-93).
Hepatocytes (75 mg wet weight/ml) were incubated in 1 ml
Krebs-bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1
mg/ml BSA, and test compound concentrations from 1 to 500 .mu.M.
Incubations were carried out in a 95% oxygen, 5% carbon dioxide
atmosphere in closed, 50-ml Falcon tubes submerged in a rapidly
shaking water bath (37.degree. C.). After 1 hour, an aliquot (0.25
ml) was removed, transferred to an Eppendorf tube and centrifuged.
50 .mu.l of supernatant was then assayed for glucose content using
a Sigma Glucose Oxidase kit as per the manufacturer's
instructions.
[0451] IC.sub.50's for select compounds in this assay are shown in
the table below.
TABLE-US-00025 Compound IC.sub.50 Glucose Production, .mu.M 3.1 2.5
3.2 26 3.26 10 3.58* 2.0 (*non-HBr salt) 10.1 15 10.2 16 16.1 10
50.6 2.0 50.9 2.2 50.2 2.1
Example D
Glucose Production Inhibition and Fructose-1,6-bisphosphate
Accumulation in Rat Hepatocytes
[0452] Isolated rat hepatocytes are prepared as described in
Example C and incubated under the identical conditions described.
Reactions are terminated by removing an aliquot (250 .mu.L) of cell
suspension and spinning it through a layer of oil (0.8 ml
silicone/mineral oil, 4/1) into a 10% perchloric acid layer (100
.mu.L). After removal of the oil layer, the acidic cell extract
layer is neutralized by addition of 1/3 volume of 3 M KOH/3 M
KHCO.sub.3. After thorough mixing and centrifugation, the
supernatant is analyzed for glucose content as described in Example
C, and also for fructose-1,6-bisphosphate. Fructose
1,6-bisphosphate is assayed spectrophotometrically by coupling its
enzymatic conversion to glycerol 3-phosphate to the oxidation of
NADH, which is monitored at 340 nm. Reaction mixtures (1 mL)
consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/ml
glycerol 3-phosphate dehydrogenase, 2 units/ml triosephosphate
isomerase, and 50-100 .mu.l cell extract. After a 30 minute
preincubation at 37.degree. C., 1 unit/ml of aldolase is added and
the change in absorbance measured until a stable value is obtained.
2 moles of NADH are oxidized in this reaction per mole of
fructose-1,6-bisphosphate present in the cell extract.
[0453] A dose-dependent inhibition of glucose production
accompanied by a dose-dependent accumulation of
fructose-1,6-bisphosphate (the substrate of FBPase) is an
indication that the target enzyme in the gluconeogenic pathway,
FBPase, is inhibited.
Example E
Chemical Stability
[0454] Aim: To assess the stability of prodrugs 50.6, 50.9, 50.15,
and 50.20 in a phosphate buffered, aqueous solution at neutral
pH.
[0455] Methods: A 50 or 100 .mu.g/mL solution of prodrug in
potassium phosphate buffer at pH 7 (room temperature) was sampled
daily for up to 10 days. Samples were analyzed by reverse phase
HPLC with use of a Beckman Ultrasphere C18 column (4.6.times.250
mm). The column was equilibrated and eluted with a gradient from 50
mM sodium phosphate pH 5.5 to 70% acetonitrile at a flow rate of
1.5 mL/min. Detection was at 300 or 315 nm, column temperature at
40.degree. C. Under these conditions, the prodrugs were well
separated from parent compound standards; the retention time for
the prodrugs was between 16 and 18 minutes, whereas the parent
compounds, 3.1 and 3.58 (non-HBr salt), eluted at 9 and 10 minutes,
respectively.
[0456] Results: The prodrugs evaluated exhibited good stability at
neutral pH. Less than 10% decomposition of the prodrugs was noted
over a 4 day incubation period. The t90's for 50.6, 50.9, 50.15,
and 50.20 at pH 7 were thus >96 hours.
Example F
Estimation of Oral Bioavailability in the Rat
[0457] Aim: To estimate the oral bioavailability of prodrugs by
means of the urinary parent compound excretion method in the
rat.
[0458] Methods: Prodrugs were dissolved in 10% ethanol/90%
polyethylene glycol (mw 400) and administered by oral gavage at
doses of 10 to 40 mg/kg parent compound equivalents to 6-hour
fasted, Sprague Dawley rats (220-240 g). Parent compounds were
typically dissolved in deionized water, neutralized with sodium
hydroxide, and then administered via the tail vein at .about.10
mg/kg to rats that were briefly anesthetized with halothane. The
rats were subsequently placed in metabolic cages and urine was
collected for 24 hours. The quantity of parent compound excreted
into urine was determined by HPLC analysis. Analysis was performed
as described in Example E. The percentage oral bioavailability was
estimated by comparison of the recovery in urine of the parent
compound generated from the prodrug administered orally, to that
recovered in urine following intravenous administration of
unsubstituted parent compound.
[0459] Results: The estimated % oral bioavailability of select
prodrugs is shown below.
TABLE-US-00026 Parent Oral Prodrug compound Bioavailability, % 50.2
3.1 11 50.3 3.1 7 50.4 3.1 17 50.5 3.1 22 50.6 3.1 21.5 50.8 3.1 26
50.9 3.1 40 50.15 3.8 22 50.20 3.8 42 50.17 3.1 7 50.21 3.26 45
51.2 3.1 37 52.1 29.1 16 52.4 3.25 30 52.15 3.26 23 52.18 45.1 22
52.21 32.2 24 52.22 36.1 18 52.32 3.58 17 52.33 3.58 19 52.38 32.2
30 52.41 3.1 27 52.43 3.1 18 52.44 3.1 28 52.45 3.1 31 52.46 3.1
16
Example G
Oral Pharmacokinetics in the Rat
[0460] Aim: To determine the pharmacokinetic parameters of 50.6 and
50.9 (prodrugs of 3.1), and of 50.2 (prodrug of 3.58) following
oral administration in the rat.
[0461] Methods: Prodrugs were administered orally at 10 mg/kg to
fed rats instrumented with tail artery catheters. At appropriate
time points following drug administration, blood samples were
removed via the tail vein catheters. Plasma was prepared from the
samples by centrifugation and plasma protein subsequently
precipitated by addition of methanol to 60%. The methanolic
extracts were clarified by centrifugation and then analyzed for
prodrug and parent compound content by HPLC as described in Example
E. Pharmacokinetic parameters were calculated from the parent
compound plasma concentration-time profiles using non-compartmental
analysis (WinNonLin v. 1.1 software).
[0462] Results: Prodrugs were not detected in plasma indicating
rapid in vivo conversion to their respective parent compounds.
Pharmacokinetic parameters are summarized below.
TABLE-US-00027 Parent Compound Cmax Tmax Clearance Half-life
Compound (.mu.g/ml) (h) (L/kg/h) (h) 50.6 0.78 1.5 1.31 5.1 50.9
0.99 1.1 1.6 2.5 50.2 1 3.1 0.54 7.0
Example H
Acute Oral Efficacy in the ZDF Rat
[0463] Aim: To determine the blood glucose lowering effect of acute
50.6, 50.9 and 50.2 administration in the Zucker Diabetic Fatty
(ZDF rat).
[0464] Methods: ZDF rats were purchased from Genetics Inc
(Indianapolis, Ind.) at 8 weeks of age. Animals were maintained
under standard vivarium conditions and provided with Purina 5008
chow and water ad libitum. At 10-12 weeks of age, rats with blood
glucose levels >500 mg/dl were selected and dosed orally either
with vehicle (PEG 400), or prodrug (60 mg/kg). Blood glucose levels
were monitored at regular intervals for 6 hours following dosing.
Blood samples were taken from tail vein nicks and analyzed by means
of a HemoCue glucose analyzer (Hemocue, Mission Viejo, Calif.).
Statistical analysis was performed using the Student's t test.
Means.+-.standard error of the means are shown.
[0465] Results: The three prodrugs were orally efficacious as
indicated by the significant blood glucose lowering effects
observed (see table below).
TABLE-US-00028 Blood Glucose, mg/dl Treatment Tbaseline T6h %
Change Vehicle (n = 8) 562 .+-. 38 528 .+-. 29 -6% 50.6 (n = 8) 544
.+-. 25 406 .+-. 12* -25% 50.9 (n = 8) 602 .+-. 26 410 .+-. 18*
-32% 50.2 (n = 8) 591 .+-. 35 415 .+-. 15* -30% *P < 0.005
versus vehicle
Example I
Chronic Oral Efficacy in the ZDF Rat
[0466] Aim: To determine the glucose lowering effects of 50.6 in
the ZDF rat during 3 weeks of chronic, oral treatment.
[0467] Methods: ZDF rats (10 weeks of age) were maintained either
on powdered Purina 5008 rat chow (n=10) or the same powdered chow
supplemented with 0.4% 50.6 (n=8). Blood glucose measurements were
made as described in Example E at baseline and at weekly intervals
thereafter for a total of 3 weeks. Statistical analysis was
performed using the Student's t test. Means.+-.standard error of
the means are shown.
[0468] Results: As illustrated in the table below, efficacy was
maintained throughout the 3-week treatment period, with 45% blood
glucose lowering evident in the drug treated group (relative to
vehicle) at the end of the study.
TABLE-US-00029 Blood glucose, mg/dl, Treatment tbaseline t21 days
Vehicle 678 .+-. 19 776 .+-. 28 50.6 674 .+-. 20 436 .+-. 41* *p
< 0.0001 versus vehicle
Example J
Identification of the Intermediate Formed During Activation
50.6
[0469] The metabolism of 50.6 was evaluated in rat, monkey, and
human plasma by reverse phase HPLC with use of a Beckman
Ultrasphere ODS column (4.6.times.150 mm) equipped with an Alltech
All-Guard column. The column was equilibrated with 20 mM potassium
phosphate, pH 6.2 and eluted with a linear gradient of 0-60%
acetonitrile over 20 minutes at a flow rate of 1.5 mL/min and at a
temperature of 40.degree. C. UV absorbance was monitored at 300 nM.
Exposure of 50.6 (100 .mu.M) to the plasma samples resulted in the
formation of a single metabolite. This metabolite had the same
retention time and UV spectrum as a product formed following
incubation of the prodrug with pig liver esterase (Sigma Chemical
Co, MO), suggesting that it was a product of an esterase-catalyzed
reaction. The metabolite formed in rat plasma was collected and
subjected to mass spectrum analysis at Mass Consortium Corporation
(San Diego, Calif.). The sample yielded a negative ion peak at 372,
indicating that the metabolite formed had a molecular weight of
373. This molecular weight is consistent with that of a
monophosphoramidate intermediate. This intermediate is likely
formed via a reaction mechanism in which the prodrug first
undergoes full de-esterification followed by intramolecular,
hydrolytic cleavage of one of the amino acyl substituents.
Formation of the postulated monophosphoramidate intermediate was
confirmed following the synthesis of a synthetic standard, Compound
C. The standard had the identical HPLC and UV profile as the
metabolite formed in plasma samples.
Example K
Metabolism of 50.6 in Human Hepatocytes
[0470] Cryopreserved human hepatocytes were obtained from In Vitro
Technologies and thawed according to the vendor's recommendations.
Cells were incubated at 37.degree. C. in a Krebs-bicarbonate based
buffer containing 50.6 at 10 .mu.M. At various time points over the
course of 4 hours, aliquots of cells were removed and extracted by
addition of methanol to 60%. Cell extracts were clarified by
centrifugation and analyzed by reverse phase HPLC with use of a
Beckman Ultrasphere ODS column (4.6.times.150 mm) equipped with an
Alltech All-Guard column. The column was equilibrated with 20 mM
potassium phosphate, pH 6.2 and eluted with a linear gradient of
0-60% acetonitrile over 20 minutes at a flow rate of 1.5 mL/min and
at a temperature of 40.degree. C. UV absorbance was monitored at
300 nM. 50.6, Compound C, and 3.1 were quantified by comparison to
authentic standards. Disappearance of 50.6 was rapid and
essentially complete within 60 minutes of incubation. Two
metabolites of 50.6 were detected: Compound C and 3.1. The initial
rate of 3.1 formation was 24 pmol/million cells/minute. This study
indicates that 50.6 is converted to the active FBPase inhibitor,
3.1, in intact human hepatocytes.
Example L
Structure Activity Relationship of Human Liver Phosphoramidase
[0471] Human liver, purchased from the Anatomic Gift Foundation
(Laurel, Md.), was homogenized in Krebs-bicarbonate buffer and
clarified by a slow-speed centrifugation. Prodrug metabolism was
evaluated in reaction mixtures containing human liver homogenate (4
mgs protein), 50 mM Tris-HCl, pH 7.4, 10 mM MgCl.sub.2, and 10 mM
dithiothreitol. At various time intervals over the course of 2
hours, aliquots were removed from the reaction mixtures and
deproteinated by addition of methanol to 60%. Following
clarification by centrifugation, metabolites were analyzed by
reverse phase HPLC with use of a Beckman Ultrasphere ODS column
(4.6.times.150 mm) equipped with an Alltech All-Guard column. The
column was equilibrated with 20 mM potassium phosphate, pH 6.2 and
eluted with a linear gradient of 0-60% acetonitrile over 20 minutes
at a flow rate of 1.5 mL/min and at a temperature of 40.degree. C.
UV absorbance was monitored at 300 nM. Most of the prodrugs
evaluated were metabolized via a non-rate limiting,
esterase-catalyzed step to their monophosphoramidate form within 5
minutes of incubation. The rate of phosphonic acid appearance was
therefore essentially a reflection of the rate of the final
phosphoramidate-catalyzed cleavage step. Results for representative
prodrugs for which the esterase-catalyzed step was non-rate
limiting are shown below:
TABLE-US-00030 Phosphoramidase Activity (Rate of 3.1 or 3.58
production, Prodrug nmoles/mn/mg liver protein) 50.6 0.022 50.8
0.019 50.10 0.005 50.12 0.022 50.20 0.085 50.19 0.029 52.8 0.025
52.12 0.032 52.16 0.033
[0472] The results indicate that human liver phosphoramidase
readily cleaves the phosphorus-nitrogen bond of a variety of
phosphonic acid-monoamidate substrates, thereby liberating the free
phosphonic acid FBPase inhibitor. The lowest P--N cleavage rate was
observed with a secondary amine substrate, the monophosphoramidate
of 50.10. The first step in prodrug activation, esterase-catalyzed
de-esterification, was not rate-limiting for the majority of
substrates evaluated.
[0473] While in accordance with the patent statures, description of
the various embodiments and processing conditions have been
provided, the scope of the invention is not to be limited thereto
or thereby. Modifications and alterations of the present invention
will be apparent to those skilled in the art without departing from
the scope and spirit of the present invention. Therefore, it will
be appreciated that the scope of this invention is to be defined by
the appended claims, rather than by the specific examples which
have been presented by way of example.
* * * * *