U.S. patent application number 11/841886 was filed with the patent office on 2008-01-03 for combination of fbpase inhibitors and insulin sensitizers for the treatment of diabetes.
This patent application is currently assigned to Metabasis Therapeutics, Inc.. Invention is credited to Mark D. Erion, Paul D. van Poelje.
Application Number | 20080004226 11/841886 |
Document ID | / |
Family ID | 32658744 |
Filed Date | 2008-01-03 |
United States Patent
Application |
20080004226 |
Kind Code |
A1 |
Erion; Mark D. ; et
al. |
January 3, 2008 |
Combination of FBPase Inhibitors and Insulin Sensitizers for the
Treatment of Diabetes
Abstract
Pharmaceutical compositions containing an FBPase inhibitor and
an insulin sensitizer are provided as well as methods for treating
diabetes and diseases responding to increased glycemic control, an
improvement in insulin sensitivity, a reduction in insulin levels,
or an enhancement of insulin secretion.
Inventors: |
Erion; Mark D.; (Del Mar,
CA) ; van Poelje; Paul D.; (La Jolla, CA) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK;A PROFESSIONAL ASSOCIATION
PO BOX 142950
GAINESVILLE
FL
32614-2950
US
|
Assignee: |
Metabasis Therapeutics,
Inc.
La Jolla
CA
|
Family ID: |
32658744 |
Appl. No.: |
11/841886 |
Filed: |
August 20, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10780948 |
Feb 17, 2004 |
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11841886 |
Aug 20, 2007 |
|
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09470649 |
Dec 22, 1999 |
6756360 |
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10780948 |
Feb 17, 2004 |
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60114718 |
Dec 24, 1998 |
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Current U.S.
Class: |
514/43 ; 514/114;
514/263.32; 514/342; 514/369; 514/423; 514/47; 514/92 |
Current CPC
Class: |
A61K 31/675 20130101;
A61K 45/06 20130101; A61K 31/7056 20130101; A61K 31/4439 20130101;
A61K 31/7076 20130101; A61K 31/426 20130101; A61K 31/522 20130101;
A61K 31/7076 20130101; A61K 31/426 20130101; A61K 31/522 20130101;
A61K 31/675 20130101; A61K 31/4439 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/7056 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/043 ;
514/342; 514/369; 514/423; 514/114; 514/047; 514/263.32;
514/092 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; A61K 31/7056 20060101 A61K031/7056; A61K 31/522
20060101 A61K031/522; A61K 31/675 20060101 A61K031/675; A61K 31/426
20060101 A61K031/426; A61K 31/4439 20060101 A61K031/4439 |
Claims
1. A method of treating a mammal having diabetes comprising the
administration to said mammal a pharmaceutically effective amount
of an insulin sensitizer agent and a pharmaceutically effective
amount of an FBPase inhibitor or prodrug or salt thereof.
2. The method of claim 1 wherein said insulin sensitizer is a
thiazolidinedione.
3. The method of claim 2 wherein said thiazolidinedione is selected
from the group consisting of BRL 49653, troglitazone, pioglitazone,
ciglitazone, WAY-120,744, englitazone, AD 5075, GI-262570,
SB219994, SB219993, and darglitazone.
4. The method of claim 1 wherein said insulin sensitizer is a PPAR
.gamma. agonist.
5. The method of claim 4 wherein said PPAR .gamma. agonist is
selected from the group consisting of BRL 49653, troglitazone,
pioglitazone, ciglitazone, WAY-120,744, englitazone, AD 5075,
darglitazone, GI-262570, SB217092, SB 236636, SB 217092, SB 219994,
and SB 219993.
6. The method of claim 95 wherein said insulin sensitizer is a RXR
ligand.
7. The method of claim 6 wherein said RXR ligand is selected from
the group consisting of 9-cis-retinoic acid, LG 100268 and LG
1069.
8. The method of claim 1 wherein said insulin sensitizer is
selected from the group consisting of an angiotensin converting
enzyme inhibitor, a renin inhibitor, and an angiotensin
antagonist.
9. The method of claim 1 wherein said FBPase inhibitor is a
compound selected from the group consisting of formulae I and IA:
##STR126## wherein in vivo or in vitro compounds of formulae I and
IA are converted to M-PO.sub.3.sup.2- which inhibits FBPase and
wherein Y is independently selected from the group consisting of
--O--, and --NR.sup.6--; when Y is --O--, then R.sup.1 attached to
--O-- is independently selected from the group consisting of --H,
alkyl, optionally substituted aryl, optionally substituted
alicyclic where the cyclic moiety contains a carbonate or
thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2, --NR.sup.2--C(O)--R.sup.3,
--C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy, when Y
is --NR.sup.6, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3; or when either Y is independently
selected from --O-- and --NR.sup.6--, then together R.sup.1 and
R.sup.1 are -alkyl-S--S-alkyl- to form a cyclic group, or together
R.sup.1 and R.sup.1 are ##STR127## wherein: V, W, and W' are
independently selected from the group consisting of --H, alkyl,
aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and Z are
connected via an additional 3-5 atoms to form a cyclic group
containing 5-7 atoms, optionally 1 heteroatom, substituted with
hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached
to a carbon atom that is three atoms from both Y groups attached to
the phosphorus; or together V and Z are connected via an additional
3-5 atoms to form a cyclic group, optionally containing 1
heteroatom, that is fused to an aryl group at the beta and gamma
position to the Y attached to the phosphorus; together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and substituted
with one substituent selected from the group consisting of hydroxy,
acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and
aryloxycarbonyloxy, attached to one of said carbon atoms that is
three atoms from a Y attached to the phosphorus; together Z and W
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; together W
and W' are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR)OH, --R.sup.2,
--NR.sup.12, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2; p is an integer 2 or 3; q is an
integer 1 or 2; with the provisos that: a) V, Z, W, W' are not all
--H; and b) when Z is --R.sup.2, then at least one of V, W, and W'
is not --H, alkyl, aralkyl, or alicyclic; 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.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; n is
an integer from 1 to 3; 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.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 carbon atoms 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, and --SR.sup.17;
R.sup.15 is selected from the group consisting of --H, lower alkyl,
lower aryl, lower arakyl, 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), --C(O)--R.sup.14, 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, 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; with the proviso
that when only one Y is --O--, and it is not part of a cyclic group
containing the other Y, then the other Y must be
--N(R.sup.18)--(CR.sup.2R.sup.3)--C(O)--R.sup.14.
10. The method of claim 9 wherein said M is: ##STR128## wherein Z'
is selected from the group consisting of alkyl or halogen, U and V'
are independently selected from the group consisting of hydrogen,
hydroxy, acyloxy or when taken together form a lower cyclic ring
containing at least one oxygen; W' is selected from the group
consisting of amino and lower alkyl amino; and pharmaceutically
acceptable salts thereof.
11. The method of claim 10 wherein said insulin sensitizer is a
thiazolidinedione.
12. The method of claim 10 wherein said insulin sensitizer is a
PPAR .gamma. agonist.
13. The method of claim 10 wherein said insulin sensitizer is a RXR
ligand.
14. The method of claim 9 wherein M is: ##STR129## wherein A.sup.2
is selected from the group consisting of --NR.sup.8.sub.2,
NHSO.sub.2R.sup.3, --OR.sup.5, --SR.sup.5, halogen, lower alkyl,
--CON(R.sup.4).sub.2, guanidine, amidine, --H, and perhaloalkyl;
E.sup.2 is selected from the group consisting of --H, halogen,
lower alkylthio, lower perhaloalkyl, lower alkyl, lower alkenyl,
lower alkynyl, lower alkoxy, --CN, and --NR.sup.7.sub.2; 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; 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.5 is selected from the group consisting
of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
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 bidendate alkyl;
R.sup.10 is selected from the group consisting of --H, lower alkyl,
--NH.sub.2, lower aryl, and lower perhaloalkyl; and R.sup.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.2, and pharmaceutically acceptable
prodrugs and salts thereof.
15. The method of claim 14 wherein said insulin sensitizer is a
thiazolidinedione.
16. The method of claim 14 wherein said insulin sensitizer is a
PPAR .delta. agonist.
17. The method of claim 14 wherein said insulin sensitizer is a RXR
ligand.
18. The method of claim 9 wherein M is: ##STR130## wherein: A, E,
and L are selected from the group 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.5, --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 and L
form a cyclic group, or together L and E form a cyclic group, or
together E and J form a cyclic group including aryl, cyclic alkyl,
and heterocyclic; J 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 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; 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.5 is selected from the group consisting
of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
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 bidendate alkyl;
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
prodrugs and salts thereof.
19. The method of claim 18 wherein said insulin sensitizer is a
thiazolidinedione.
20. The method of claim 18 wherein said insulin sensitizer is a
PPAR .delta. agonist.
21. The method of claim 18 wherein said insulin sensitizer is a RXR
ligand.
22. The method of claim 103 wherein M is: ##STR131## wherein B is
selected from the group consisting of --NH--, --N.dbd. and
--CH.dbd.; is selected from the group consisting of ##STR132## Q is
selected from the group consisting of --C.dbd. and --N-- with the
proviso that when B is --NH-- then Q is --C.dbd. and D is
##STR133## when B is --CH.dbd. then Q is --N-- and D is ##STR134##
when B is --N.dbd., then D is ##STR135## and Q is --C.dbd.; A, E,
and L are selected from the group 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.5, --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 and L
form a cyclic group, or together L and E form a cyclic group, or
together E and J form a cyclic group including aryl, cyclic alkyl,
and heterocyclic; J 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 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; 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.5 is selected from the group consisting
of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic;
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 bidendate alkyl;
R.sup.10 is selected from the group consisting of --H, lower alkyl,
--NH.sub.2, lower aryl, and lower perhaloalkyl; and R.sup.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.3, and pharmaceutically acceptable
prodrugs and salts thereof.
23. The method of claim 22 wherein said insulin sensitizer is a
thiazolidinedione.
24. The method of claim 22 wherein said insulin sensitizer is a
PPAR .gamma. agonist.
25. The method of claim 22 wherein said insulin sensitizer is a RXR
ligand.
26. The method of claim 9 wherein M is R.sup.5--X-- wherein R.sup.5
is selected from the group consisting of: ##STR136## wherein: 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; each G' is independently selected from the group
consisting of C and N and wherein no more than two G' groups are N;
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.3, --SR.sup.3,
--N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc, and null; 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; 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; J is selected from the group consisting of
--H and null; X is 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 are 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; 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; 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.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.2; and with the proviso that: 1)
when G' is N, then the respective A, B, D, or E is null; 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; 3) when R.sup.5 is a six-membered
ring, then X is not any 2 atom linker, an optionally substituted
-alkyloxy-, or an optionally substituted -alkylthio-; 4) when G is
N, then the respective A or B is not halogen or a group directly
bonded to G via a heteroatom; 5) when X is not a -heteroaryl-
group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
27. The method of claim 26 wherein said insulin sensitizer is a
thiazolidinedione.
28. The method of claim 26 wherein said insulin sensitizer is a
PPAR .delta. agonist.
29. The method of claim 26 wherein said insulin sensitizer is a RXR
ligand.
30. The method of claim 1 wherein said combination is administered
orally.
31. The method of claim 4 wherein said combination is administered
separately during the day.
32. The method of claim 4 wherein said combination is administered
simultaneously during the day.
33. A method of treating a mammal having a disease characterized by
insulin resistance and/or hyperglycemia comprising the
administration to said mammal an effective amount of an insulin
sensitizer agent and an FBPase inhibiting amount of an FBPase
inhibitor.
34. The method of claim 33 wherein said disease is characterized by
insulin resistance.
35. The method of claim 33 wherein said disease is characterized by
hyperglycemia.
36. The method of claim 33 wherein said disease is obesity.
37. The method of claim 33 wherein said disease is
hypertension.
38. The method of claim 33 wherein said disease is polycystic
ovarian syndrome.
39. The method of claim 9 wherein M is: ##STR137## wherein: G'' is
selected from the group consisting of --O-- and --S--; A.sup.2,
L.sup.2, E.sup.2 and J.sup.2 are selected from the group consisting
of --NR.sup.4.sub.2, --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.9, --SO.sub.2NR.sup.4.sub.2, --CN, --S(O)R.sup.3,
perhaloacyl, perhaloalkyl, perhaloalkoxy, C.sub.1-C.sub.5 alkyl,
C2-C5 alkenyl, C2-C5 alkynyl, 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; X.sup.2 is selected from the group consisting of
--CR.sup.2.sub.2--, --CF.sub.2--, --OCR.sup.2.sub.2--,
--SCR.sup.2.sub.2--, --O--C(O)--, --S--C(O)--, --O--C(S)--, and
--NR.sup.19CR.sup.2.sub.2--, 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; 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; 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.11 is selected from the group
consisting of alkyl, aryl, --NR.sup.2.sub.2, and --OR.sup.2;
R.sup.19 is selected from the group consisting of lower alkyl, --H,
and --COR.sup.2; and pharmaceutically acceptable prodrugs and salts
thereof.
40. The method of claim 39 wherein said insulin sensitizer is a
thiazolidinedione.
41. The method of claim 39 wherein said insulin sensitizer is a
PPAR .gamma. agonist.
42. The method of claim 39 wherein said insulin sensitizer is a RXR
ligand.
43. A method of preventing diabetes in animals comprising
administering to animals at risk of developing diabetes a
pharmaceutically effective amount of an insulin sensitizer agent
and a pharmaceutically effective amount of an FBPase inhibitor or
prodrugs or salts thereof.
44. A method of treating impaired glucose tolerance comprising
administering to patients in need thereof a pharmaceutically
effective amount of an insulin sensitizer agent and a
pharmaceutically effective amount of an FBPase inhibitor or
prodrugs or salts thereof.
45. A method of treating insulin resistance comprising
administering to patients in need thereof a pharmaceutically
effective amount of an insulin sensitizer agent and a
pharmaceutically effective amount of an FBPase inhibitor or
prodrugs or salts thereof.
46. The method of claim 43 wherein said animals at risk of
developing diabetes have a disease or condition selected from the
group consisting of impaired glucose tolerance, insulin resistance,
hyperglycemia, obesity, accelerated gluconeogenesis, and increased
hepatic glucose output.
47. A method of treating or preventing a disease or condition
selected from the group consisting of hyperlipidemia,
atherosclerosis, ischemic injury, hypertension, and
hypercholesterolemia which comprises administering to an animal in
need thereof a pharmaceutically effective amount of an insulin
sensitizer agent and a pharmaceutically effective amount of an
FBPase inhibitor or prodrugs or salts thereof.
48. The method of claim 1 wherein said FBPase inhibitor is
##STR138## and said insulin sensitizer is troglitazone.
49. The method of claim 33 wherein said FBPase inhibitor is a
compound selected from the group consisting of formulae I and IA:
##STR139## wherein in vivo or in vitro compounds of formulae I and
IA are converted to M-PO.sub.3.sup.2- which inhibits FBPase and
wherein Y is independently selected from the group consisting of
--O--, and --NR.sup.6--; when Y is --O--, then R.sup.1 attached to
--O-- is independently selected from the group consisting of --H,
alkyl, optionally substituted aryl, optionally substituted
alicyclic where the cyclic moiety contains a carbonate or
thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2, --NR.sup.2--C(O)--R.sup.3,
--C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy, when Y
is --NR.sup.6--, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, [C(R.sup.2).sub.2].sub.q--C(O)SR, and
-cycloalkylene-COOR.sup.3; or when either Y is independently
selected from --O-- and --NR.sup.6--, then together R.sup.1 and
R.sup.1 are -alkyl-S--S-alkyl- to form a cyclic group, or together
R.sup.1 and R.sup.1 are ##STR140## wherein: V, W, and W' are
independently selected from the group consisting of --H, alkyl,
aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and Z are
connected via an additional 3-5 atoms to form a cyclic group
containing 5-7 atoms, optionally 1 heteroatom, substituted with
hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached
to a carbon atom that is three atoms from both Y groups attached to
the phosphorus; or together V and Z are connected via an additional
3-5 atoms to form a cyclic group, optionally containing 1
heteroatom, that is fused to an aryl group at the beta and gamma
position to the Y attached to the phosphorus; together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and substituted
with one substituent selected from the group consisting of hydroxy,
acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and
aryloxycarbonyloxy, attached to one of said carbon atoms that is
three atoms from a Y attached to the phosphorus; together Z and W
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; together W
and W' are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2; p is an integer 2 or 3; q is an
integer 1 or 2; with the provisos that: a) V, Z, W, W' are not all
--H; and b) when Z is --R.sup.2, then at least one of V, W, and W'
is not --H, alkyl aralkyl, or alicyclic; 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.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; n is
an integer from 1 to 3; 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.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 carbon atoms 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, and --SR.sup.17;
R.sup.15 is selected from the group consisting of --H, lower alkyl,
lower aryl, lower arakyl, 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,
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, 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; with the proviso
that when only one Y is --O--, and it is not part of a cyclic group
containing the other Y, then the other Y must be
--N(R.sup.18)--(CR.sup.12R.sup.13)--C(O)--R.sup.14.
50. The method of claim 49 wherein M is R.sup.5--X-- wherein
R.sup.5 is selected from the group consisting of: ##STR141##
wherein: 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; each G' is independently selected from the
group consisting of C and N and wherein no more than two G' groups
are N; 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null; 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; 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; J is selected from the group consisting of --H and
null; X is 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 are 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; 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; 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.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.2; and with the proviso that: 1)
when G' is N, then the respective A, B, D, or E is null; 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; 3) when R.sup.5 is a six-membered
ring, then X is not any 2 atom linker, an optionally substituted
-alkyloxy-, or an optionally substituted -alkylthio-; 4) when G is
N, then the respective A or B is not halogen or a group directly
bonded to G via a heteroatom; 5) when X is not a -heteroaryl-
group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
51. The method of claim 48 wherein said insulin sensitizer is a
thiazolidinedione.
52. The method of claim 33 wherein said FBPase inhibitor is
##STR142## and said insulin sensitizer is troglitazone.
53. The method of claim 43 wherein said FBPase inhibitor is
##STR143## and said insulin sensitizer is troglitazone.
54. The method of claim 43 wherein said FBPase inhibitor is a
compound selected from the group consisting of formulae I and IA:
##STR144## wherein in vivo or in vitro compounds of formulae I and
IA are converted to M-PO.sub.3.sup.2- which inhibits FBPase and
wherein Y is independently selected from the group consisting of
--O--, and --NR.sup.6--; when Y is --O--, then R.sup.1 attached to
--O-- is independently selected from the group consisting of --H,
alkyl, optionally substituted aryl, optionally substituted
alicyclic where the cyclic moiety contains a carbonate or
thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2, --NR.sup.2--C(O)--R.sup.3,
--C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy, when Y
is --NR.sup.6--, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3; or when either Y is independently
selected from --O-- and --NR.sup.6--, then together R.sup.1 and
R.sup.1 are -alkyl-S--S-alkyl- to form a cyclic group, or together
R.sup.1 and R.sup.1 are ##STR145## wherein: V, W, and W' are
independently selected from the group consisting of --H, alkyl,
aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and Z are
connected via an additional 3-5 atoms to form a cyclic group
containing 5-7 atoms, optionally 1 heteroatom, substituted with
hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached
to a carbon atom that is three atoms from both Y groups attached to
the phosphorus; or together V and Z are connected via an additional
3-5 atoms to form a cyclic group, optionally containing 1
heteroatom, that is fused to an aryl group at the beta and gamma
position to the Y attached to the phosphorus; together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and substituted
with one substituent selected from the group consisting of hydroxy,
acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and
aryloxycarbonyloxy, attached to one of said carbon atoms that is
three atoms from a Y attached to the phosphorus; together Z and W
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; together W
and W' are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2; p is an integer 2 or 3; q is an
integer 1 or 2; with the provisos that: a) V, Z, W, W' are not all
--H; and b) when Z is --R.sup.2, then at least one of V, W, and W'
is not --H, alkyl, aralkyl, or alicyclic; 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.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; n is
an integer from 1 to 3; 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.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 carbon atoms to form a cyclic group; each
R.sup.14 is independently selected from the group consisting of
--OR.sup.7, --N(R.sup.17).sub.2, --NHR.sup.17, and --SR.sup.17;
R.sup.15 is selected from the group consisting of --H, lower alkyl,
lower aryl, lower arakyl, 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,
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, 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; with the proviso
that when only one Y is --O--, and it is not part of a cyclic group
containing the other Y, then the other Y must be
--N(R.sup.18)--(CR.sup.12R.sup.13)--C(O)--R.sup.14.
55. The method of claim 54 wherein M is R.sup.5--X-- wherein
R.sup.5 is selected from the group consisting of: ##STR146##
wherein: 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; each G' is independently selected from the
group consisting of C and N and wherein no more than two G' groups
are N; 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null; 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; 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; J is selected from the group consisting of --H and
null; X is 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 are 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; 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; 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.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.2; and with the proviso that: 1)
when G' is N, then the respective A, B, D, or E is null; 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; 3) when R.sup.5 is a six-membered
ring, then X is not any 2 atom linker, an optionally substituted
-alkyloxy-, or an optionally substituted -alkylthio-; 4) when G is
N, then the respective A or B is not halogen or a group directly
bonded to G via a heteroatom; 5) when X is not a -heteroaryl-
group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
56. The method of claim 43 wherein said insulin sensitizer is a
thiazolidinedione.
57. The method of claim 43 wherein said FBPase inhibitor is
##STR147## and said insulin sensitizer is troglitazone.
58. The method of claim 44 wherein said FBPase inhibitor is
##STR148## and said insulin sensitizer is troglitazone.
59. The method of claim 44 wherein said FBPase inhibitor is a
compound selected from the group consisting of formulae I and IA:
##STR149## wherein in vivo or in vitro compounds of formulae I and
IA are converted to M-PO.sub.3.sup.2- which inhibits FBPase and
wherein Y is independently selected from the group consisting of
--O--, and --NR.sup.6--; when Y is --O--, then R.sup.1 attached to
--O-- is independently selected from the group consisting of --H,
alkyl, optionally substituted aryl, optionally substituted
alicyclic where the cyclic moiety contains a carbonate or
thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2, --NR.sup.2--C(O)--R.sup.3,
--C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy, when Y
is --NR.sup.6--, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, [C(R.sup.2).sub.2].sub.q--C(O)SR, and
-cycloalkylene-COOR.sup.3; or when either Y is independently
selected from --O-- and --NR.sup.6--, then together R.sup.1 and
R.sup.1 are -alkyl-S--S-alkyl- to form a cyclic group, or together
R.sup.1 and R.sup.1 are ##STR150## wherein: V, W, and W' are
independently selected from the group consisting of --H, alkyl,
aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and Z are
connected via an additional 3-5 atoms to form a cyclic group
containing 5-7 atoms, optionally 1 heteroatom, substituted with
hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached
to a carbon atom that is three atoms from both Y groups attached to
the phosphorus; or together V and Z are connected via an additional
3-5 atoms to form a cyclic group, optionally containing 1
heteroatom, that is fused to an aryl group at the beta and gamma
position to the Y attached to the phosphorus; together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and substituted
with one substituent selected from the group consisting of hydroxy,
acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and
aryloxycarbonyloxy, attached to one of said carbon atoms that is
three atoms from a Y attached to the phosphorus; together Z and W
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; together W
and W' are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.2, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2CO.sub.2R.sub.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2; p is an integer 2 or 3; q is an
integer 1 or 2; with the provisos that: a) V, Z, W, W' are not all
--H; and b) when Z is --R.sup.2, then at least one of V, W, and W'
is not --H, alkyl, aralkyl, or alicyclic; 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.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; n is
an integer from 1 to 3; 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.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 carbon atoms 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, and --SR.sup.17;
R.sup.15 is selected from the group consisting of --H, lower alkyl,
lower aryl, lower arakyl, 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), --C(O)--R.sup.14, 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, 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; with the proviso
that when only one Y is --O--, and it is not part of a cyclic group
containing the other Y, then the other Y must be
--N(R.sup.18)--(CR.sup.12R.sup.13)--C(O)--R.sup.14.
60. The method of claim 59 wherein M is R.sup.5--X-- wherein
R.sup.5 is selected from the group consisting of: ##STR151##
wherein: 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; each G' is independently selected from the
group consisting of C and N and wherein no more than two G' groups
are N; 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null; 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; 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; J is selected from the group consisting of --H and
null; X is 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 are 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; 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; 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.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.2; and with the proviso that: 1)
when G' is N, then the respective A, B, D, or E is null; 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; 3) when R.sup.5 is a six-membered
ring, then X is not any 2 atom linker, an optionally substituted
-alkyloxy-, or an optionally substituted -alkylthio-; 4) when G is
N, then the respective A or B is not halogen or a group directly
bonded to G via a heteroatom; 5) when X is not a -heteroaryl-
group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
61. The method of claim 44 wherein said insulin sensitizer is a
thiazolidinedione.
62. The method of claim 44 wherein said FBPase inhibitor is
##STR152## and said insulin sensitizer is troglitazone.
63. The method of claim 45 wherein said FBPase inhibitor is
##STR153## and said insulin sensitizer is troglitazone.
64. The method of claim 45 wherein said FBPase inhibitor is a
compound selected from the group consisting of formulae I and IA:
##STR154## wherein in vivo or in vitro compounds of formulae I and
IA are converted to M-PO.sub.3.sup.2- which inhibits FBPase and
wherein Y is independently selected from the group consisting of
--O--, and --NR.sup.6--; when Y is --O--, then R.sup.1 attached to
--O-- is independently selected from the group consisting of --H,
alkyl, optionally substituted aryl, optionally substituted
alicyclic where the cyclic moiety contains a carbonate or
thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2, --NR.sup.2--C(O)--R.sup.3,
--C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy, when Y
is --NR.sup.6--, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3; or when either Y is independently
selected from --O-- and --NR.sup.6--, then together R.sup.1 and
R.sup.1 are -alkyl-S--S-alkyl- to form a cyclic group, or together
R.sup.1 and R.sup.1 are ##STR155## wherein: V, W, and W' are
independently selected from the group consisting of --H, alkyl,
aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and 7 are
connected via an additional 3-5 atoms to form a cyclic group
containing 5-7 atoms, optionally 1 heteroatom, substituted with
hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached
to a carbon atom that is three atoms from both Y groups attached to
the phosphorus; or together V and 7 are connected via an additional
3-5 atoms to form a cyclic group, optionally containing 1
heteroatom, that is fused to an aryl group at the beta and gamma
position to the Y attached to the phosphorus; together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and substituted
with one substituent selected from the group consisting of hydroxy,
acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and
aryloxycarbonyloxy, attached to one of said carbon atoms that is
three atoms from a Y attached to the phosphorus; together Z and W
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; together W
and W' are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2; p is an integer 2 or 3; q is an
integer 1 or 2; with the provisos that: a) V, Z, W, W' are not all
--H; and b) when Z is --R.sup.2, then at least one of V, W, and W'
is not --H, alkyl, aralkyl, or alicyclic; 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.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; n is
an integer from 1 to 3; 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.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 carbon atoms 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, and --SR.sup.17;
R.sup.15 is selected from the group consisting of --H, lower alkyl,
lower aryl, lower arakyl, 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,
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, 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; with the proviso
that when only one Y is --O--, and it is not part of a cyclic group
containing the other Y, then the other Y must be
--N(R.sup.18)--(CR.sup.12R.sup.13)--C(O)--R.sup.14.
65. The method of claim 64 wherein M is R.sup.5--X-- wherein
R.sup.5 is selected from the group consisting of: ##STR156##
wherein: 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; each G' is independently selected from the
group consisting of C and N and wherein no more than two G' groups
are N; 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null; 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; 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; J is selected from the group consisting of --H and
null; X is 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 are 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; 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; 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.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR; and with the proviso that: 1) when G'
is N, then the respective A, B, D, or E is null; 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; 3) when R.sup.5 is a six-membered ring,
then X is not any 2 atom linker, an optionally substituted
-alkyloxy-, or an optionally substituted -alkylthio-; 4) when G is
N, then the respective A or B is not halogen or a group directly
bonded to G via a heteroatom; 5) when X is not a -heteroaryl-
group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
66. The method of claim 45 wherein said insulin sensitizer is a
thiazolidinedione.
67. The method of claim 45 wherein said FBPase inhibitor is
##STR157## and said insulin sensitizer is troglitazone.
68. The method of claim 47 wherein said FBPase inhibitor is
##STR158## and said insulin sensitizer is troglitazone.
69. The method of claim 47 wherein said FBPase inhibitor is a
compound selected from the group consisting of formulae I and IA:
##STR159## wherein in vivo or in vitro compounds of formulae I and
IA are converted to M-PO.sub.3.sup.2- which inhibits FBPase and
wherein Y is independently selected from the group consisting of
--O--, and --NR.sup.6--; when Y is --O--, then R.sup.1 attached to
--O-- is independently selected from the group consisting of --H,
alkyl, optionally substituted aryl, optionally substituted
alicyclic where the cyclic moiety contains a carbonate or
thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2, --NR.sup.2--C(O)--R.sup.3,
--C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy, when Y
is --NR.sup.6--, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3; or when either Y is independently
selected from --O-- and --NR.sup.6--, then together R.sup.1 and
R.sup.1 are -alkyl-S--S-alkyl- to form a cyclic group, or together
R.sup.1 and R.sup.1 are ##STR160## wherein: V, W, and W' are
independently selected from the group consisting of --H, alkyl,
aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, 1-alkenyl, and 1-alkynyl; or together V and Z are
connected via an additional 3-5 atoms to form a cyclic group
containing 5-7 atoms, optionally 1 heteroatom, substituted with
hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached
to a carbon atom that is three atoms from both Y groups attached to
the phosphorus; or together V and Z are connected via an additional
3-5 atoms to form a cyclic group, optionally containing 1
heteroatom, that is fused to an aryl group at the beta and gamma
position to the Y attached to the phosphorus; together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and substituted
with one substituent selected from the group consisting of hydroxy,
acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and
aryloxycarbonyloxy, attached to one of said carbon atoms that is
three atoms from a Y attached to the phosphorus; together Z and W
are connected via an additional 3-5 atoms to form a cyclic group,
optionally containing one heteroatom, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; together W
and W' are connected via an additional 2-5 atoms to form a cyclic
group, optionally containing 0-2 heteroatoms, and V must be aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2C(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.dbd.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2; p is an integer 2 or 3; q is an
integer 1 or 2; with the provisos that: a) V, Z, W, W' are not all
--H; and b) when Z is --R.sup.2, then at least one of V, W, and W'
is not --H, alkyl, aralkyl, or alicyclic; 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.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; n is
an integer from 1 to 3; 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.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 carbon atoms 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, and --SR.sup.17;
R.sup.15 is selected from the group consisting of --H, lower alkyl,
lower aryl, lower arakyl, 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,
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, 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; with the proviso
that when only one Y is --O--, and it is not part of a cyclic group
containing the other Y, then the other Y must be
--N(R.sup.18)--(CR.sup.12R.sup.13)--C(O)--R.sup.14.
70. The method of claim 69 wherein M is R.sup.5--X-- wherein
R.sup.5 is selected from the group consisting of: ##STR161##
wherein: 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; each G' is independently selected from the
group consisting of C and N and wherein no more than two G' groups
are N; 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null; 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; 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; J is selected from the group consisting of --H and
null; X is 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 are 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; 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; 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.11 is
selected from the group consisting of alkyl, aryl,
--NR.sup.2.sub.2, and --OR.sup.2; and with the proviso that: 1)
when G' is N, then the respective A, B, D, or E is null; 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; 3) when R.sup.5 is a six-membered
ring, then X is not any 2 atom linker, an optionally substituted
-alkyloxy-, or an optionally substituted -alkylthio-; 4) when G is
N, then the respective A or B is not halogen or a group directly
bonded to G via a heteroatom; 5) when X is not a -heteroaryl-
group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
71. The method of claim 47 wherein said insulin sensitizer is a
thiazolidinedione.
72. The method of claim 47 wherein said FBPase inhibitor is
##STR162## and said insulin sensitizer is troglitazone.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/780,948, filed Feb. 17, 2004, which is a divisional of U.S.
application Ser. No. 09/470,649, filed Dec. 22, 1999, now U.S. Pat.
No. 6,756,360, which claims benefit of U.S. Provisional Application
No. 60/114,718, filed Dec. 24, 1998 and which are incorporated by
reference herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] A combination therapy of an insulin sensitizer and an FBPase
inhibitor is disclosed for the treatment of diabetes, and other
diseases where the control of blood glucose levels or an
improvement in insulin sensitivity, reduction in insulin levels or
an enhancement of insulin secretion is beneficial. Compositions
used in the therapy are also disclosed.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus (or diabetes) is one of the most prevalent
diseases in the world today. Diabetes patients have been divided
into two classes, namely type I or insulin-dependent diabetes
mellitus and type II or non-insulin dependent diabetes mellitus
(NIDDM). NIDDM accounts for approximately 90% of all diabetics and
is estimated to affect 12-14 million adults in the U.S. alone (6.6%
of the population). NIDDM is characterized by both fasting
hyperglycemia and exaggerated postprandial increases in plasma
glucose levels. NIDDM is associated with a variety of long-term
complications, including microvascular diseases such as
retinopathy, nephropathy and neuropathy, and macrovascular diseases
such as coronary heart disease. Numerous studies in animal models
demonstrate a causal relationship between long term hyperglycemia
and complications. Results from the Diabetes Control and
Complications Trial (DCCT) and the Stockholm Prospective Study
demonstrate this relationship for the first time in man by showing
that insulin-dependent diabetics with tighter glycemic control are
at substantially lower risk for the development and progression of
these complications. Tighter control is also expected to benefit
NIDDM patients.
[0004] Current therapies used to treat NIDDM patients entail both
controlling lifestyle risk factors and pharmaceutical intervention.
First-line therapy for NIDDM is typically a tightly-controlled
regimen of diet and exercise since an overwhelming number of NIDDM
patients are overweight or obese (67%) and since weight loss can
improve insulin secretion, insulin sensitivity and lead to
normoglycemia. Normalization of blood glucose occurs in less than
30% of these patients due to poor compliance and poor response.
Patients with hyperglycemia not controlled by diet alone are
subsequently treated with oral hypoglycemics or insulin. Until
recently, the sulfonylureas were the only class of oral
hypoglycemic agents available for NIDDM. Treatment with
sulfonylureas leads to effective blood glucose lowering in only 70%
of patients and only 40% after 10 years of therapy. Patients that
fail to respond to diet and sulfonylureas are subsequently treated
with daily insulin injections to gain adequate glycemic
control.
[0005] Although the sulfonylureas represent a major therapy for
NIDDM patients, four factors limit their overall success. First, as
mentioned above, a large segment of the NIDDM population do not
respond adequately to sulfonylurea therapy (i.e. primary failures)
or become resistant (i.e. secondary failures). This is particularly
true in NIDDM patients with advanced NIDDM since these patients
have severely impaired insulin secretion. Second, sulfonylurea
therapy is associated with an increased risk of severe hypoglycemic
episodes. Third, chronic hyperinsulinemia has been associated with
increased cardiovascular disease although this relationship is
considered controversial and unproven. Last, sulfonylureas are
associated with weight gain, which leads to worsening of peripheral
insulin sensitivity and thereby can accelerate the progression of
the disease.
[0006] Results from the U.K. Diabetes Prospective Study also showed
that patients undergoing maximal therapy of a sulfonylurea,
metformin, or a combination of the two, were unable to maintain
normal fasting glycemia over the six year period of the study. U.K.
Prospective Diabetes Study 16. Diabetes, 44:1249-158 (1995). These
results further illustrate the great need for alternative
therapies.
[0007] Another drug therapy recently developed for NIDDM patients
acts on the underlying mechanisms of insulin resistance and thereby
lower glucose by enhancing insulin action at both peripheral and
hepatic sites. Saltiel & Olefsky Diabetes 45: 1661-1669 (1996).
Accordingly, these agents are reported to increase
insulin-dependent glucose disposal and to inhibit HGO. These agents
are commonly referred to as "insulin sensitizers".
[0008] One class of insulin sensitizers are compounds containing a
thiazolidinedione. These compounds are reported to enhance insulin
action without directly stimulating insulin secretion.
Thiazolidinediones markedly decrease glucose levels in a variety of
obese, insulin-resistant diabetic animal models including the
KK-mouse, ob/ob mouse, Zucker Diabetic Fatty rat and db/db mouse.
Similar effects are found in non-genetic diabetic animal models,
including the fructose fed rat and high fat fed rat. Animal models
characterized by severe hypoinsulinemia, e.g. the STZ rat, fail to
respond to these agents unless treated with insulin.
Thiazolidinediones are also reported to restore the ability of
insulin to suppress HGO.
[0009] Although the molecular target of insulin sensitizers and
more specifically thiazolidinedione analogs is unknown, several
studies suggest that peroxisome proliferator-activated receptors
(PPAR .gamma.s) may be the target and therefore that ligands to
these receptors will be useful antihyperglycemic agents. Lehmann et
al. J. Biol. Chem. 270: 12953-12956 (1995). PPAR .gamma.s are
members of the steroid/thyroid hormone receptor superfamily of
transcription factors. At least three PPAR .gamma.s exist, namely
the .alpha., .beta. and .gamma. receptors and thiazolidinediones
have been identified as ligands that activate the .beta. and
.gamma. receptors. Binding occurs at a concentration achieved in
vivo and some data suggests that there is a correlation between
PPAR .gamma. binding affinity and in vivo activity. Wilson et al.
J. Med. Chem. 39: 665-668 (1996).
[0010] PPAR .gamma.s exist as a heterodimer with the retinoic acid
X receptor (RXR). A co-repressor protein has been postulated to
maintain the receptor in an inactive state similar to other nuclear
receptors. Binding of molecules to the complex, i.e. PPAR .gamma.
ligands and/or RXR ligands may lead to dissociation of the
co-repressor protein and activation of the receptor, which in turn
is postulated to interact with specific DNA sequences, PPRE's, and
to activate or repress gene transcription. Accordingly, RXR ligands
are thought to enhance insulin sensitivity and therefore be useful
as antidiabetics either alone or in combination with PPAR .gamma.
agonists such as a thiazolidinedione. Heyman et al., WO 97/10819.
In db/db mice, the combination of an RXR ligand and a PPAR .gamma.
agonist reduces glucose levels more than either component
alone.
[0011] Other classes of insulin sensitizers (i.e.
non-thiazolidinediones) have been identified. For example, the
insulin sensitizers SB 236636 and SB 219994 are 3-aryl-2-alkoxy
propanoic acids. These compounds are reported to bind to human PPAR
.gamma. with high affinity. SB 236636 is equipotent with
thiazolidinedione BRL 49653 in stimulation of glucose transport in
differentiated 3T3-L1 adipocytes and in glucose lowering activity
in ob/ob mice. Young et al. Diabetes (1997). Relative to other
thiazolidinediones, SB 236636 was shown to bind with higher
affinity to crude extracts of Sf9 cells transfected with full
length hPPAR .gamma. and rat adipocytes. This higher binding
affinity correlated well with in vivo potency.
[0012] Some data suggests that chronic activation of PKC isoenzymes
is involved in the generation of muscle insulin resistance and that
insulin sensitizers may decrease the translocation of PKC
isoenzymes from the cytosolic to particulate fractions in red
skeletal muscle and therefore PKC activation. Schmitz-Peiffer et
al. Am. J. Physiol. 273: E915-E921 (1997)
[0013] Angiotensin II antagonists and angiotensin converting enzyme
inhibitors may be useful in enhancing insulin sensitivity based on
potential interactions between angiotensin II and insulin signaling
systems. Torlone et al. Diabetes Care 16: 1347-1355 (1993); Howard
G. et al., Circulation 93: 1809-1817 (1996); Folli et al. J. Clin.
Invest. 100: 2158-2169 (1997); Tamura et al., WO9737688 A2.
[0014] Thus, there are several mechanisms by which agents may act
as insulin sensitizers.
[0015] Gluconeogenesis from pyruvate is a highly regulated
biosynthetic pathway requiring eleven enzymes. Seven enzymes
catalyze reversible reactions and are common to both
gluconeogenesis and glycolysis. Four enzymes catalyze reactions
unique to gluconeogenesis, namely pyruvate carboxylase,
phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and
glucose-6-phosphatase. Overall flux through the pathway is
controlled by the specific activities of these enzymes, the enzymes
that catalyzed the corresponding steps in the glycolytic direction,
and by substrate availability. Dietary factors (glucose, fat) and
hormones (insulin, glucagon, glucocorticoids, epinephrine)
coordinatively regulate enzyme activities in the gluconeogenesis
and glycolysis pathways through gene expression and
post-translational mechanisms.
[0016] Synthetic inhibitors of fructose-1,6-bisphosphatase
(hereinafter "FBPase") have been reported. McNiel reported that
fructose-2,6-bisphosphate analogs inhibit FBPase by binding to the
substrate site. J. Am. Chem. Soc., 106:7851-7853 (1984); U.S. Pat.
No. 4,968,790 (1984). These compounds, however, were relatively
weak and did not inhibit glucose production in hepatocytes
presumably due to poor cell penetration.
[0017] Gruber reported that some nucleosides can lower blood
glucose in the whole animal through inhibition of FBPase. These
compounds exert their activity by first undergoing phosphorylation
to the corresponding monophosphate. EP 0 427 799 B1.
[0018] Gruber et al. U.S. Pat. No. 5,658,889 described the use of
inhibitors of the AMP site of FBPase to treat diabetes. WO
98/39344, WO 98/39343, and WO 98/39342 describe the use of FBPase
inhibitors to treat diabetes.
SUMMARY OF THE INVENTION
[0019] The instant invention is a combination therapy and a
composition for the treatment for diabetes and diseases responding
to improved glycemic control or to improve peripheral insulin
sensitivity. The therapy requires administration of a insulin
sensitizer agent, e.g. PPAR .gamma. agonist, RXR ligand, or another
agent known to enhance insulin action and an FBPase inhibitor
either together or at a different time such that improved glycemic
control is achieved. In another aspect of the invention, the
combined therapy results in decreases in hepatic glucose output
beyond that observed for glucose lowering doses of the insulin
sensitizer agent. Furthermore, the combined therapy can result in
improvements in insulin resistance and/or insulin secretion beyond
that observed for either agent alone. Yet another aspect of the
invention is that a combination therapy achieves similar benefits
as observed with one or the other therapies alone but at
significantly lower doses.
[0020] The present invention relates to methods and compositions
for treating an animal having NIDDM or a condition associated with
insulin resistance by administering to the animal a composition
containing a pharmaceutically effective amount of an agent that
enhances insulin sensitivity and a pharmaceutically effective
amount of an FBPase inhibitor. The compositions of this invention
are adapted to cure, improve or prevent one or more symptoms of
NIDDM. A preferred drug combination will have high potency and low
toxicity.
[0021] Another object of the invention relates to methods and
compositions for treating insulin-requiring NIDDM patients. The
combination therapy decreases the insulin requirement and
associated safety risks.
[0022] Another object of the invention relates to methods and
compositions for treating diseases or conditions characterized by
insulin resistance, including obesity, hypertension, impaired
glucose tolerance, and polycystic ovarian syndrome. Individuals
with syndrome X, renal disease, or pancreatitis are also
effectively treated with the combination therapy.
[0023] Another object of the invention is the use of insulin
sensitizer to attenuate certain potentially adverse effects that
could be associated with FBPase inhibitor therapy such as lactate
and triglyceride elevation.
[0024] Another object of the invention is the use of FBPase
inhibitors to attenuate certain potentially adverse effects that
could be associated with insulin sensitizers such as weight
gain.
[0025] Another aspect of the invention is to use FBPase inhibitors
in combination with insulin sensitizer therapies that include
administration of agents that enhance endogenous or exogenous
insulin levels, such as sulfonylureas, insulin, or insulin
mimetics.
Definitions
[0026] In accordance with the present invention and as used herein,
the following terms are defined with the following meanings, unless
explicitly stated otherwise.
[0027] X and X.sup.3 group nomenclature as used herein in formulae
I and X 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:
(heteroaromatic ring)-NR-alk-P(O)(OR.sup.1).sub.2
[0028] Likewise, A, B, C, D, E, A'', B'', C'', D'', E'', A.sup.2,
L.sup.2, E.sup.2 and J.sup.2 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.
[0029] 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.
[0030] 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.
[0031] 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 selendum.
Suitable heteroaryl groups include furanyl, thienyl, pyridyl,
pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl,
pyrazinyl, imidazolyl, and the like, all optionally
substituted.
[0032] The term "annulation" or "annulated" refers to the formation
of an additional cyclic moiety onto an existing 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 ##STR1##
[0033] 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.
[0034] 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.
[0035] 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, 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" preferably refers
to aryl and heteroaryl groups substituted with 1-3 substituents.
Preferably these substituents are selected from the group
consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo,
hydroxy, and amino. "Substituted" when describing an R.sup.5 group
does not include annulation.
[0036] 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.
[0037] 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.
[0038] The term "lower" referred to herein in connection with
organic radicals or compounds respectively defines such as with up
to and including 10, preferably up to and including 6, and
advantageously one to four carbon atoms. Such groups may be
straight chain, branched, or cyclic.
[0039] 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.
[0040] The term "acyl" refers to --C(O)R where R is alkyl and
aryl.
[0041] The term "carboxy esters" refers to --C(O)OR where R is
alkyl, aryl, aralkyl, and alicyclic, all optionally
substituted.
[0042] The term "carboxyl" refers to --C(O)OH.
[0043] The term "oxo" refers to .dbd.O in an alkyl group.
[0044] The term "amino" refers to --NRR' where R and R' 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.
[0045] The term "carbonylamino" and "-carbonylamino-" refers to
RCONR-- and --CONR--, respectively, where each R is independently
hydrogen or alkyl.
[0046] The term "halogen" or "halo" refers to --F, --Cl, --Br and
--I.
[0047] The term "-oxyalkylamino-" refers to --O-alk-NR--, where
"alk" is an alkylene group and R is H or alkyl.
[0048] 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.
[0049] 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.
[0050] The term "-oxyalkyl-" refers to the group --O-alk- where
"alk" is an alkylene group.
[0051] The term "-alkylcarboxyalkyl-" refers to the group
-alk-C(O)--O-alk- where each alk is independently an alkylene
group.
[0052] 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.
[0053] The term "cyclic alkyl" or "cycloalkyl" refers to alkyl
groups that are cyclic. Suitable cyclic groups include norbornyl
and cyclopropyl. Such groups may be substituted.
[0054] The term "heterocyclic" and "heterocyclic alkyl" refer to
cyclic groups of 3 to 10 atoms, more preferably 3 to 6 atoms,
containing at least one heteroatom, preferably 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.
[0055] 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.
[0056] The term "sulphonyl" or "sulfonyl" refers to --SO.sub.3R,
where R is H, alkyl, aryl, aralkyl, and alicyclic.
[0057] 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.
[0058] 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, e.g. it is a W substituent attached
to the cyclic phosph(oramid)ate, it is attached at the first
carbon.
[0059] The term "alkylene" refers to a divalent straight chain,
branched chain or cyclic saturated aliphatic group.
[0060] 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.
[0061] The term "acyloxy" refers to the ester group --O--C(O)R,
where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or
alicyclic.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] The term "alkyloxyaryl-" refers to an aryl group substituted
with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group
is lower alkyl.
[0068] The term "aryloxyalkyl-" refers to an alkyl group
substituted with an aryloxy group.
[0069] 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.
[0070] 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--.
[0071] 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.
[0072] The terms "alkylthio-" and "-alkylthio-" refer to the groups
alkyl-S--, and -alk-S--, respectively, wherein "alk" is alkylene
group.
[0073] 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.
[0074] The term "alkoxycarbonyloxy-" refers to
alkyl-O--C(O)--O--.
[0075] The term "aryloxycarbonyloxy-" refers to
aryl-O--C(O)--O--.
[0076] The term "alkylthiocarbonyloxy-" refers to
alkyl-S--C(O)--O--.
[0077] 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.
[0078] 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.
[0079] 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--.
[0080] The terms "carboxamidoalkylaryl" and "carboxamidoaryl"
refers to an aryl-alk-NR.sup.1--C(O)--, and an
--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
aliyclic.
[0081] 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.
[0082] The term "-alkylaminocarbonyl-" refers to the group
-alk-NR--C(O)-- wherein "alk" is an alkylene group and R is H or
lower alkyl.
[0083] 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.
[0084] The term "thiocarbonate" refers to --O--C(S)--O-- either in
a chain or in a cyclic group.
[0085] The term "hydroxyalkyl" refers to an alkyl group substituted
with one --OH.
[0086] The term "haloalkyl" refers to an alkyl group substituted
with one halo, selected from the group I, Cl, Br, F.
[0087] The term "cyano" refers to --C.ident.N.
[0088] The term "nitro" refers to --NO.sub.2.
[0089] The term "acylalkyl" refers to an alkyl-C(O)-alk-, where
"alk" is alkylene.
[0090] The term "heteroarylalkyl" refers to an alkyl group
substituted with a heteroaryl group.
[0091] The term "-1,1-dihaloalkyl-" refers to an X group where the
1 position and therefore halogens are a to the phosphorus atom.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] The term "2-thiazolyl-" or "2-oxazolyl-" or "2-selenozoly"
refers to the corresponding base and its attachment of the X group
at the 2-position of the heterocycle.
[0096] The term "pharmaceutically acceptable salt" includes salts
of compounds of formula I and its prodrugs derived from the
combination of a compound of this invention and an organic or
inorganic acid or base. Suitable acids include HCl.
[0097] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the
"drug".sup.1 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 and X, 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.
[0098] The term "prodrug ester" as employed herein includes, but is
not limited to, the following groups and combinations of these
groups:
[0099] [1] Acyloxyalkyl esters which are well described in the
literature (Farquhar et al., J. Pharm. Sci. 72, 324-325 (1983)) and
are represented by formula A ##STR2## [0100] wherein R, R', and R''
are independently H, alkyl, aryl, alkylaryl, and [0101] alicyclic;
(see WO 90/08155; WO 90/10636).
[0102] [2] Other acyloxyalkyl esters are possible in which an
alicyclic ring is formed such as shown in formula B. These esters
have been shown to generate phosphorus-containing nucleotides
inside cells through a postulated sequence of reactions beginning
with deesterification and followed by a series of elimination
reactions (e.g. Freed et al., Biochem. Pharm. 38: 3193-3198
(1989)). ##STR3##
[0103] wherein R is --H, alkyl, aryl, alkylaryl, alkoxy, aryloxy;
alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or
alicyclic.
[0104] [3] Another class of these double esters known as
alkyloxycarbonyloxymethyl esters, as shown in formula A, where R is
alkoxy, aryloxy, alkylthio, arylthio, alkylamino, and arylamino;
R', and R'' are independently H, alkyl, aryl, alkylaryl, and
alicyclic, have been studied in the area of .beta.-lactam
antibiotics (Tatsuo Nishimura et al. J. Antibiotics, 1987, 40(1),
81-90; for a review see Ferres, H., Drugs of Today, 1983, 19,
499.). More recently Cathy, M. S., et al. (Abstract from AAPS
Western Regional Meeting, April, 1997) showed that these
alkyloxycarbonyloxymethyl ester prodrugs on
(9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable
up to 30% in dogs.
[0105] [4] Aryl esters have also been used as phosphonate prodrugs
(e.g Erion, DeLambert et al., J. Med. Chem. 37: 498, 1994;
Serafinowska et al., J. Med. Chem. 38: 1372, 1995). Phenyl as well
as mono and poly-substituted phenyl proesters have generated the
parent phosphonic acid in studies conducted in animals and in man
(Formula C). Another approach has been described where Y is a
carboxylic ester ortho to the phosphate. Khamnei and Torrence, J.
Med. Chem.; 39:4109-4115 (1996). ##STR4## [0106] wherein Y is H,
alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino,
alkoxycarbonyl, hydroxy, cyano, and alicyclic.
[0107] [5] Benzyl esters have also been reported to generate the
parent phosphonic acid. In some cases, using substituents at the
para-position can accelerate the hydrolysis. Benzyl analogs with
4-acyloxy or 4-alkyloxy group [Formula D, X=H, OR or O(CO)R or
O(CO)OR] can generate the 4-hydroxy compound more readily through
the action of enzymes, e.g. oxidases, esterases, etc. Examples of
this class of prodrugs are described in Mitchell et al., J. Chem.
Soc. Perkin Trans. 12345 (1992); Brook, et al. WO 91/19721.
##STR5## [0108] wherein X and Y are independently H, alkyl, aryl,
alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl,
halo, or alkyloxycarbonyl; and [0109] R' and R'' are independently
H, alkyl, aryl, alkylaryl, halogen, and alicyclic.
[0110] [6] Thio-containing phosphonate proesters have been
described that are useful in the delivery of FBPase inhibitors to
hepatocytes. These proesters contain a protected thioethyl moiety
as shown in formula E. One or more of the oxygens of the
phosphonate can be esterified. Since the mechanism that results in
de-esterification requires the generation of a free thiolate, a
variety of thiol protecting groups are possible. For example, the
disulfide is reduced by a reductase-mediated process (Puech et al.,
Antiviral Res., 22: 155-174 (1993)). Thioesters will also generate
free thiolates after esterase-mediated hydrolysis. Benzaria, et
al., J. Med. Chem., 39:4958 (1996). Cyclic analogs are also
possible and were shown to liberate phosphonate in isolated rat
hepatocytes. The cyclic disulfide shown below has not been
previously described and is novel. ##STR6##
[0111] wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,
aryloxycarbonyl, or alkylthio.
[0112] Other examples of suitable prodrugs include proester classes
exemplified by Biller and Magnin (U.S. Pat. No. 5,157,027);
Serafinowska et al. (J. Med. Chem. 38, 1372 (1995)); Starrett et
al. (J. Med. Chem. 37, 1857 (1994)); Martin et al. J. Pharm. Sci.
76, 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59,
1853 (1994)); and EPO patent application 0 632 048 A1. Some of the
structural classes described are optionally substituted, including
fused lactones attached at the omega position (formulae E-1 and
E-2) and optionally substituted 2-oxo-1,3-dioxolenes attached
through a methylene to the phosphorus oxygen (formula E-3) such as:
##STR7##
[0113] wherein R is --H, alkyl, cycloalkyl, or alicyclic; and
[0114] wherein Y is --H, alkyl, aryl, alkylaryl, cyano, alkoxy,
acyloxy, halogen, amino, alicyclic, and alkoxycarbonyl.
[0115] The prodrugs of Formula E-3 are an example of "optionally
substituted alicyclic where the cyclic moiety contains a carbonate
or thiocarbonate."
[0116] [7] Propyl phosphonate proesters can also be used to deliver
FBPase inhibitors into hepatocytes. These proesters may contain a
hydroxyl and hydroxyl group derivatives at the 3-position of the
propyl group as shown in formula F. The R and X groups can form a
cyclic ring system as shown in formula F. One or more of the
oxygens of the phosphonate can be esterified. ##STR8## wherein R is
alkyl, aryl, heteroaryl; [0117] X is hydrogen, alkylcarbonyloxy,
alkyloxycarbonyloxy; and [0118] Y is alkyl, aryl, heteroaryl,
alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy,
amino.
[0119] [8] 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. ##STR9##
[0120] 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).
[0121] 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. ##STR10##
[0122] Other prodrugs are possible based on literature reports such
as substituted ethyls for example, bis(trichloroethyl)esters as
disclosed by McGuigan, et al. Bioorg Med. Chem. Lett., 3:1207-1210
(1993), and the phenyl and benzyl combined nucleotide esters
reported by Meier, C. et al. Bioorg. Med. Chem. Lett., 7:99-104
(1997).
[0123] The structure ##STR11## has a plane of symmetry running
through the phosphorus-oxygen double bond when R.sup.6=R.sup.6, V=W
W'=H, and V and W are either both pointing up or both pointing
down. The same is true of structures where each --NR.sup.6 is
replaced with --O--.
[0124] The term "cyclic 1',3'-propane ester", "cyclic 1,3-propane
ester", "cyclic 1',3'-propanyl ester", and "cyclic 1,3-propanyl
ester" refers to the following: ##STR12##
[0125] The phrase "together V and Z are connected via an additional
3-5 atoms to form a cyclic group containing 5-7 atoms, optionally
containing 1 heteroatom, substituted with hydroxy, acyloxy,
alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom
that is three atoms from both Y groups attached to the phosphorus"
includes the following: ##STR13##
[0126] The structure shown above (left) has an additional 3 carbon
atoms that forms a five member cyclic group. Such cyclic groups
must possess the listed substitution to be oxidized.
[0127] The phrase "together V and Z are connected via an additional
3-5 atoms to form a cyclic group, optionally containing one
heteroatom, that is fused to an aryl group attached at the beta and
gamma position to the Y attached to the phosphorus" includes the
following: ##STR14##
[0128] The phrase "together V and W are connected via an additional
3 carbon atoms to form an optionally substituted cyclic group
containing 6 carbon atoms and substituted with one substituent
selected from the group consisting of hydroxy, acyloxy,
alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy,
attached to one of said additional carbon atoms that is three atoms
from a Y attached to the phosphorus" includes the following:
##STR15##
[0129] The structure above has an acyloxy substituent that is three
carbon atoms from a Y, and an optional substituent, --CH.sub.3, on
the new 6-membered ring. There has to be at least one hydrogen at
each of the following positions: the carbon attached to Z; both
carbons alpha to the carbon labelled "3"; and the carbon attached
to "OC(O)CH.sub.3" above.
[0130] The phrase "together W and W' are connected via an
additional 2-5 atoms to form a cyclic group, optionally containing
0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl,
or substituted heteroaryl" includes the following: ##STR16##
[0131] The structure above has V=aryl, and a spiro-fused
cyclopropyl group for W and W'.
[0132] The term "cyclic phosph(oramid)ate" refers to ##STR17##
where Y is independently --O-- or --NR.sup.6--. The carbon attached
to V must have a C--H bond. The carbon attached to Z must also have
a C--H bond.
[0133] The term "enhancing" refers to increasing or improving a
specific property.
[0134] 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. More preferably it 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.
[0135] The term "parent drug" refers to any compound which delivers
the same biologically active compound. The parent drug form is
M-X--P(O)(OH).sub.2 and standard prodrugs, such as esters.
[0136] 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.
[0137] 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.
Pharmacodynamic half-life is enhanced when the half-life is
increased by preferably at least 50%.
[0138] The term "pharmacokinetic half-life" refers to the time
after administration of the drug or prodrug to observe a dimunition
of one half of the drug concentration in plasma or tissues.
[0139] The term "therapeutic index" refers to the ratio of the dose
of a drug or prodrug that produces a therapeutically beneficial
response relative to the dose that produces an undesired response
such as death, an elevation of markers that are indicative of
toxicity, and/or pharmacological side effects.
[0140] 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-X--P(O)(OH).sub.2 are
biologically active.
[0141] The term "therapeutically effective amount" refers to an
amount that has any beneficial effect in treating a disease or
condition.
[0142] FBPase inhibitors used in the invention are compounds that
inhibit human FBPase activity (Example A), inhibit glucose
production from hepatocytes (Examples C and D), lower glucose
levels in fasted animals (Examples E-F), and decrease blood glucose
levels in diabetic animal models (Examples N-T).
[0143] Insulin sensitizers used in this invention are compounds
that alter the body's response to endogenous or exogeneous insulin
or insulin-like molecules. This response can include an improvement
in whole-body glucose disposal, a reduction in hepatic glucose
output, an increase in insulin-mediated glycogenesis, and other
manifestations of improved peripheral insulin resistance. In some
instances, the insulin sensitizers used in this invention may also
lower circulating triglycerides and/or free fatty acids, may
increase HDL cholesterol levels, may reduce hyperinsulinemia, or
may improve the pancreatic insulin secretory response. Examples of
insulin sensitizers include compounds that activate or are agonists
of the PPAR.gamma. receptor, are ligands of RXR that activate
transcriptional activity of the RXR:PPAR .gamma. heterodimer, or
are compounds that achieve enhanced insulin sensitivity through
modulation of enzyme activities in cell signalling pathways
associated with insulin receptor activation. Enzymes in the latter
pathways include protein kinase C, tyrosine phosphatase,
PI-3-kinase, MAP kinase, and others. The insulin sensitizers used
in this invention have affinity for PPAR.gamma.1, PPAR.gamma.2,
and/or other isoforms of the PPAR.gamma. family, and contain either
a thiazolidinedione ring structures a modified thiazolidinedione
ring structure, or have a structure that is unrelated to the
thiazolidinediones (eg. the 3-aryl-2-alkoxy propanoic acids). The
insulin sensitizers also include compounds with affinity for
RXR.alpha., RXR.beta., RXR.gamma. and/or other RXR receptor
isoforms, and are either retinoids such as 9-cis-retinoic acid and
its analogs, rexinoids such as
(tetramethyltetrahydronaphthyl)carbonylbenzoic acid analogs, or are
of other structural classes. Insulin sensitizers used in this
invention typically exhibit activity in assays known to be useful
for characterizing compounds that act as insulin sensitizers. The
assays include but are not limited to: (a) PPAR.gamma. binding
assays; (b) RXR or RXR-PPAR.gamma. activation assays (eg.
co-transfection or cis-trans assays); (c) insulin signaling assays
such as those measuring receptor or signaling protein
phosphorylation/expression (d) adipocyte binding assays; (e)
glucose uptake assays in adipocytes or L6 myocytes; (f) adipocyte
differentiation assays using triglyceride accumulation, glucose
oxidation, or fat/carbohydrate metabolism gene expression as
indeces; (g) insulin secretion assays in beta cell islets or the
perfused pancreas; (h) pancreatic islet histology assays; (i) in
vivo glucose disposal assays; (j) whole body insulin sensitivity
assays using the in vivo hyperinsulinemic-glucose clamp technique;
(k) hepatic glucose output assays utilizing labeling or NMR
techniques; and (l) antihyperglycemic and/or triglyceride/free
fatty acid lowering activity in animal models of diabetes such as
the KK, ob/ob, or db/db mouse or the ZDF rat.
DETAILED DESCRIPTION OF THE INVENTION
[0144] The instant invention is a combination therapy and a
composition for the treatment for diabetes and diseases responding
to increased glycemic control or to decreased insulin levels. The
combination therapy consists of administering one or more FBPase
inhibitors and one or more agents known to enhance insulin action,
i.e. an insulin sensitizer agent. Known insulin sensitizers include
thiazolidinediones, PPAR .gamma. agonists, RXR ligands and
inhibitors of the RAX system or angiotensin II action. The therapy
is useful for treating diseases characterized by hyperglycemia,
impaired glucose tolerance or insulin resistance. Such diseases
include diabetes, obesity, hypertension, impaired glucose tolerance
and polycystic ovarian syndrome, pancreatitis and renal
disease.
[0145] In some cases, the combined therapy provides a method for
improved glycemic control. The combined therapy will provide
improved therapy for one or more of these conditions relative to
either agent alone. The combined therapy provides a method for
improved glycemic control in NIDDM subjects beyond that achievable
by either agent alone. The combined therapy can result in decreases
in hepatic glucose output beyond that observed for glucose-lowering
doses of the insulin sensitizer agent. Furthermore, the combined
therapy can result in improvements in insulin resistance and/or
insulin secretion beyond that observed for FBPase inhibitors. In
other cases, combining an insulin sensitizer with an FBPase
inhibitor or visa versa has an insignificant effect on glycemia but
instead results in an improved therapy by minimizing potential
adverse pharmacologies sometimes associated with FBPase and insulin
sensitizer therapies. For example, FBPase therapy may be associated
with elevations of lactate, tryglicerides, free fatty acids or
potential side-effects resulting from the renal clearance of the
inhibitor. Insulin sensitizer therapy is known to be associated
with weight gain, elevation of liver enzymes, and reductions in
heamatocrit. In still another aspect of the invention is that the
combination therapy achieves similar benefits as observed with one
or the other therapies alone but at significantly lower doses. The
lower doses improve or eliminate side effects and/or toxicologies
associated with the individual drug treatment. The combined therapy
entails administration to the host the agents either separately or
simultaneously.
[0146] Most preferred would be the administration of both agents
simultaneously in either the same capsule or as separate pills.
Another preferred embodiment is the administration of both agents
during meal time (just prior to feeding or just after feeding).
Another preferred embodiment is the administration of the insulin
sensitizer during meal time and the FBPase inhibitor during times
of fasting such as at bed time.
[0147] The compounds of the invention may be administered for
therapy by any suitable route including, oral, rectal, nasal,
topical, vaginal, parenteral (including subcutaneous,
intramuscular, intravenous and intradermal) and transdermal. The
preferred route is oral.
[0148] The present invention relates to methods and compositions
for treating a host having NIDDM or a condition associated with
insulin resistance by administering to the host a composition
containing a pharmaceutically effective amount of an agent that
enhances insulin sensitivity and a pharmaceutically effective
amount of an FBPase inhibitor. The compositions of this invention
are adapted to cure, improve or prevent one or more symptoms of
NIDDM. A preferred drug combination will have high potency and low
toxicity as can be determined by standard pharmaceutical procedures
in cell cultures or experimental animal models, e.g. by determining
the LD50 and the ED50.
[0149] Preferred FBPase inhibitors encompassed by the instant
invention are compounds that inhibit enzyme activity as determined
by conducting in vitro inhibition studies (Examples A-D). In some
cases, in vivo metabolic activation of a compound may be required
to generate the FBPase inhibitor. This class of compounds may be
inactive in the enzyme inhibition screen (Example A), may or may
not be active in hepatocytes (Examples C and D), but is active in
vivo as evidenced by glucose lowering in the normal, fasted rat
(Examples E and F) and/or in animal models of diabetes (Examples
N-T).
[0150] Although the present invention is not limited to the
following structures, the FBPase inhibitors generally are of the
following formulae: ##STR18## ##STR19## ##STR20##
Preferred Compounds
[0151] 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,
preferably 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, preferably independently selected from nitrogen,
oxygen, phosphorous, and sulfur.
[0152] Preferred are the following compounds of formula IA
##STR21## wherein in vivo or in vitro compounds of formula IA are
converted to M-PO.sub.3.sup.2- which is an inhibitor of
fructose-1,6-bisphosphatase and
[0153] n is an integer from 1 to 3;
[0154] 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;
[0155] 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 carbon atoms to form a cyclic group;
[0156] each R.sup.14 is independently selected from the group
consisting of --OR.sup.17, --N(R.sup.17).sub.2, --NHR.sup.17, and
--SR.sup.17;
[0157] 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;
[0158] R.sup.16 is selected from the group consisting of
--(CR.sup.12R.sup.13), --C(O)--R.sup.14, 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;
[0159] each R.sup.17 is independently selected from the group
consisting of lower alkyl, lower aryl, and lower aralkyl, 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;
[0160] and pharmaceutically acceptable salts thereof.
[0161] More preferred are FBPase inhibitors where M-PO.sub.3.sup.2-
has an IC.sub.50 on isolated human FBPase enzyme of less than or
equal to 5 .mu.M. Especially preferred are such compounds that bind
to the AMP site of FBPase.
[0162] In one aspect, preferred are compounds of formula IA or
formula I wherein M is R.sup.5--X--
wherein
[0163] R.sup.5 is selected from the group consisting of: ##STR22##
wherein:
[0164] 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;
[0165] each G' is independently selected from the group consisting
of C and N and wherein no more than two G' groups are N;
[0166] 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null;
[0167] 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;
[0168] 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;
[0169] is selected from the group consisting of --H and null;
[0170] 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;
[0171] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0172] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0173] 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;
[0174] 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;
[0175] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2,
[0176] and with the proviso that: [0177] 1) when G' is N, then the
respective A, B, D, or E is null; [0178] 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; [0179] 3) when R.sup.5 is a six-membered ring, then X
is not any 2 atom linker, an optionally substituted -alkyloxy-, or
an optionally substituted -alkylthio-; [0180] 4) when G is N, then
the respective A or B is not halogen or a group directly bonded to
G via a heteroatom; [0181] 5) when X is not a -heteroaryl- group,
then R.sup.5 is not substituted with two or more aryl groups;
[0182] and pharmaceutically acceptable prodrugs and salts
thereof.
[0183] More preferred are such compounds wherein when R.sup.5 is
2-thiazolyl, 2-oxazolyl, or 2-selenazolyl, and X is -alkoxyalkyl-,
-alkylthioalkyl-, -alkyloxy-, or -alkylthio-, then A is not
--CONH.sub.2 and B is not --H. Also more preferred are such
compounds wherein when R.sup.5 is 2-thiazolyl, 2-oxazolyl, or
2-selenazolyl, then X is not -alkyloxyalkyl-, -alkylthioalkyl-,
-alkyloxy-, or -alkylthio-.
[0184] Preferably, compounds of formula IA have an IC.sub.50 of
.ltoreq.50 .mu.M on glucose production in isolated rat
hepatocytes.
[0185] More preferred R.sup.5 groups include 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. Preferably, R.sup.5 is not
2-thiazolyl, or 2-oxazolyl.
[0186] In one aspect, preferred R.sup.5 groups are substituted with
the following groups:
[0187] 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,
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.4, --SR.sup.4,
--N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc, and null;
[0188] 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.2.sub.2,
--OR.sup.3, --SR.sup.3, perhaloalkyl, halo, and null, all except
--H, --CN, perhaloalkyl, and halo are optionally substituted;
[0189] E is selected from the group consisting of --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.12, --OR.sup.3,
--SR.sup.3, C1-C6 perhaloalkyl, halo, and null, all except --H,
--CN, perhaloalkyl, and halo are optionally substituted; and
[0190] each R.sup.4 is independently selected from the group
consisting of --H, and C1-C2 alkyl.
[0191] In another aspect, preferred are compounds wherein R.sup.5
is: ##STR23##
[0192] In another aspect, preferred are compounds wherein R.sup.5
is: ##STR24##
[0193] More preferred are compounds wherein R.sup.5 is selected
from the group consisting of: ##STR25## wherein
[0194] 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,
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.3, --SR.sup.3,
--N.sub.3, --NHC(S)NR.sup.4.sub.2, and --NHAc;
[0195] 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, and halo, all except --H,
--CN, perhaloalkyl, and halo are optionally substituted;
[0196] E'' is selected from the group consisting of --H, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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, and halo, all except H,
--CN, perhaloalkyl, and halo are optionally substituted; and
[0197] each R.sup.4 is independently selected from the group
consisting of --H and C1-C2 alkyl.
[0198] Especially preferred are those compounds of formula V-1A and
formula V-2A wherein
[0199] A'' is selected from the group consisting of --NH.sub.2,
--CONH.sub.2, halo, --CH.sub.3, --CF.sub.3, --CH.sub.2-halo, --CN,
--OCH.sub.3, --SCH.sub.3, and --H;
[0200] B'' is selected from the group consisting of --H,
--C(O)R.sup.11, --C(O)SR.sup.3, alkyl, aryl, alicyclic, halo, --CN,
--SR.sup.3, OR.sup.3 and --NR.sup.9.sub.2;
[0201] D'' is selected from the group consisting of --H,
--C(O)R.sup.11, --C(O)SR.sup.3, --NR.sup.9.sub.2, alkyl, aryl,
alicyclic, halo, and --SR.sup.3;
[0202] E'' is selected from the group consisting of --H,
C.sub.1-C.sub.6 alkyl, lower alicyclic, halo, --CN, --C(O)OR.sup.3,
and --SR.sup.3.
[0203] X is selected from the group consisting of -heteroaryl-,
-alkoxycarbonyl-, and -alkylaminocarbonyl-, all optionally
substituted;
[0204] R.sup.18 and R.sup.15 are selected from the group consisting
of H, and methyl;
[0205] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0206] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0207] each R.sup.12 and R.sup.13 is independently selected from
the group consisting of --H, methyl, i-propyl, i-butyl, and benzyl,
or together R.sup.12 and R.sup.13 are connected via 2-5 carbon
atoms to form a cycloalkyl group;
[0208] n is 1;
[0209] R.sup.14 is --OR.sup.17;
[0210] R.sup.16 is --(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14;
and
[0211] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, phenyl, and benzyl. Most preferred are such
compounds with ##STR26##
[0212] wherein C* has S stereochemistry.
[0213] Also particularly preferred are such compounds wherein
R.sup.5 is selected from the group consisting of: ##STR27##
[0214] Also particularly preferred are such compounds wherein
R.sup.5 is selected from the group consisting of: ##STR28##
[0215] Also particularly preferred are such compounds wherein
R.sup.5 is selected from the group consisting of: ##STR29##
[0216] In one especially preferred aspect, R.sup.5 is ##STR30## X
is selected from the group consisting of methylenoxycarbonyl, and
furan-2,5-diyl, and pharmaceutically acceptable salts and prodrugs
thereof. More preferred are such compounds wherein A'' is
--NH.sub.2, X is furan-2,5-diyl, and B'' is
--S(CH.sub.2).sub.2CH.sub.3; wherein A'' is --NH.sub.2, X is
furan-2,5-diyl, and B'' is --CH.sub.2--CH(CH.sub.3).sub.2; wherein
A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is --COOEt; wherein
A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is --SMe; or
wherein A'' is --NH.sub.2, X is methyleneoxycarbonyl, and B'' is
--CH(CH.sub.3).sub.2.
[0217] Most preferred are such thiazoles where A'' is --NH.sub.2, X
is furan-2,5-diyl, B'' is --S(CH.sub.2).sub.2CH.sub.3 and wherein
##STR31##
[0218] is ##STR32##
[0219] wherein ##STR33##
[0220] is ##STR34##
[0221] wherein C* has S stereochemistry. Also most preferred are
such thiazoles where A'' is --NH.sub.2, X is furan-2,5-diyl, B'' is
--CH.sub.2--CH(CH.sub.3).sub.2, and wherein ##STR35##
[0222] is ##STR36##
[0223] is ##STR37##
[0224] wherein C* has S stereochemistry.
[0225] In another preferred aspect, R.sup.5 is ##STR38##
[0226] X is selected from the group consisting of furan-2,5-diyl,
and methyleneoxycarbonyl, A'' is --NH.sub.2, and pharmaceutically
acceptable salts and prodrugs thereof. More preferred are such
compounds wherein X is furan-2,5-diyl, and B'' is
--SCH.sub.2CH.sub.2CH.sub.3.
[0227] In another preferred aspect, R.sup.5 is ##STR39##
[0228] A'' is --NH.sub.2, E'' and D'' are --H, B'' is selected from
the group consisting of cyclopropyl, and n-propyl, --X is selected
from the group consisting of methyleneoxycarbonyl, and
furan-2,5-diyl, and pharmaceutically acceptable salts and prodrugs
thereof.
[0229] In another preferred aspect, R.sup.5 is ##STR40##
[0230] A'' is --NH.sub.2, D'' is --H, B'' is selected from the
group consisting of n-propyl, and cyclopropyl, X is selected from
the group consisting of furan-2,5-diyl, and methyleneoxycarbonyl,
and pharmaceutically acceptable salts and prodrugs thereof.
[0231] Preferred groups include -heteroaryl-, -alkylcarbonylamino-,
-alkylaminocarbonyl-, and -alkoxycarbonyl-. More preferred is
-heteroaryl-, and -alkoxycarbonyl-.
[0232] The compounds of formula 1A are preferred. ##STR41##
##STR42##
[0233] More preferred are compounds of formulae VII or IX:
##STR43##
[0234] Preferred A'' groups include --NH.sub.2, --CONH.sub.2, halo,
--CH.sub.3, --CF.sub.3, --CH.sub.2-halo, --CN, --OCH.sub.3,
--SCH.sub.3, and --H.
[0235] More preferred A'' groups include --NH.sub.2, --Cl, --Br,
and --CH.sub.3.
[0236] Preferred B'' groups include --H, --C(O)R.sup.11,
--C(O)SR.sup.3, alkyl, aryl, alicyclic, halo, --CN, --SR.sup.3,
--NR.sup.12, and --OR.sup.3. More preferred is --H, --C(O)OR.sup.3,
--C(O)SR.sup.3, C1-C6 alkyl, alicyclic, halo, heteroaryl, and
--SR.sup.3.
[0237] Preferred D'' groups include --H, --C(O)R.sup.11,
--C(O)SR.sup.3, alkyl, aryl, alicyclic, halo, --NR.sup.9.sub.2, and
--SR.sup.3. More preferred is --H, --C(O)OR.sup.3, lower alkyl,
alicyclic, and halo.
[0238] Preferred E'' groups include --H, C1-C6 alkyl, lower
alicyclic, halogen, --CN, --C(O)OR.sup.3, --SR.sup.3, and
--CONR.sup.4.sub.2. More preferred is --H, --Br, and --Cl.
[0239] Preferred R.sup.18 groups include --H, methyl, and ethyl.
More preferred is --H and methyl. Especially preferred is --H.
[0240] Preferred compounds include those wherein each R.sup.12 and
R.sup.13 is independently selected from the group consisting of
--H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--CH.sub.2CH.sub.7--SCH.sub.3, phenyl, and benzyl, or together
R.sup.12 and R.sup.13 are connected via 2-5 carbon atoms to form a
cycloalkyl group. More preferred is each R.sup.12 and R.sup.13 is
independently selected from the group consisting of --H, methyl,
i-propyl, i-butyl, and benzyl, or together R.sup.12 and R.sup.13
are connected via 2-5 carbon atoms to form a cycloalkyl group. Also
more preferred are such compounds wherein each R.sup.12 and
R.sup.13 is independently selected from the group consisting of
--H, methyl, i-propyl, and benzyl, or together R.sup.12 and
R.sup.13 are connected via 4 carbon atoms to form a cyclopentyl
group. Especially preferred are those compounds wherein R.sup.12
and R.sup.13 are both --H, both methyl, or R.sup.12 is H and
R.sup.13 is selected from the group consisting of methyl, i-propyl,
and benzyl. Most preferred are such compounds wherein n is 1, and
R.sup.12 is --H, then the carbon attached to R.sup.12 and R.sup.13
has S stereochemistry.
[0241] Preferably, n is an integer of from 1-2. More preferred is
when n is 1.
[0242] Preferred compounds include those wherein each R.sup.14 is
independently selected from the group consisting of --OR.sup.17,
and --SR.sup.17; and R.sup.17 is selected from the group consisting
of optionally substituted methyl, ethyl, propyl, t-butyl, and
benzyl. More preferred are such compounds wherein each R.sup.14 is
independently selected from the group consisting of --OR.sup.17;
and R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, and benzyl. Most preferred are such compounds
wherein R.sup.17 is selected from the group consisting of ethyl,
and benzyl.
[0243] Preferred are compounds wherein R.sup.15 is not H. More
preferred are compounds wherein R.sup.15 and R.sup.16 are
independently selected from the group consisting of lower alkyl,
and lower aralkyl, 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 O, N, and S. Also more preferred are compounds
wherein R.sup.15 and R.sup.16 are independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 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 O, N, and S. In
one aspect, particularly preferred are compounds wherein
--NR.sup.15R.sup.16 is a cyclic amine. Especially preferred are
such compounds wherein --NR.sup.15R.sup.16 is selected from the
group consisting of morpholinyl and pyrrolidinyl.
[0244] Preferred are compounds where R.sup.16 is
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14. Particularly preferred
are such compounds that are of the formula: ##STR44##
[0245] More preferred are such compounds wherein n is 1. Especially
preferred are such compounds wherein when R.sup.12 and R.sup.13 are
not the same, then H.sub.2N--CR.sup.12R.sup.13--C(O)--R.sup.14 is
an ester, or thioester of a naturally occurring amino acid; and
R.sup.14 is selected from the group consisting of --OR.sup.17 and
--SR.sup.17.
[0246] More preferred are compounds where n is 1 and wherein
[0247] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0248] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0249] R.sup.14 is OR.sup.17;
[0250] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0251] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and lower aralkyl, 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 O, and
N.
[0252] In one aspect, preferred are compounds of Formula IA wherein
M is ##STR45## wherein:
[0253] G'' is selected from the group consisting of --O-- and
--S--;
[0254] A.sup.2, L.sup.2, E.sup.2, and J.sup.2 are selected from the
group consisting of --NR.sup.4.sub.2, --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,
alkyoxyalkyl, --SCN, --NHSO.sub.2R.sup.9, --SO.sub.2NR.sup.4.sub.2,
--CN, --S(O)R.sup.3, perhaloacyl, perhaloalkyl, perhaloalkoxy,
C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, 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;
[0255] X.sup.2 is selected from the group consisting of
--CR.sup.2.sub.2--, --CF.sub.2--, --OCR.sup.2.sub.2--,
--SCR.sup.2.sub.2--, --O--C(O)--, --S--C(O)--, --O--C(S)--; and
--NR.sup.19CR.sup.2.sub.2--, 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;
[0256] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0257] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0258] 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;
[0259] 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;
[0260] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2;
[0261] R.sup.19 is selected from the group consisting of lower
alkyl, --H, and --COR.sup.2; and
[0262] pharmaceutically acceptable prodrugs and salts thereof. More
preferred are compounds wherein G'' is --S--. Most preferred are
compounds wherein A.sup.2, L.sup.2, E.sup.2, and J.sup.2 are
independently selected from the group consisting of --H,
--NR.sup.4.sub.2, --S--C.ident.N, halogen, --OR.sup.3, hydroxy,
-alkyl(OH), aryl, alkyloxycarbonyl, --SR.sup.3, lower perhaloalkyl,
and C1-C5 alkyl, or together L.sup.2 and E.sup.2 form an annulated
cyclic group. More preferably A.sup.2, L.sup.2, E.sup.2 and J.sup.2
are independently selected from the group consisting of --H,
--NR.sup.4.sub.2, --S--C.ident.N, halogen lower alkoxy, hydroxy,
lower alkyl(hydroxy), lower aryl, and C1-C5 alkyl, or together
L.sup.2 and E.sup.2 form an annulated cyclic group.
[0263] Most preferred A.sup.2 groups include --NH.sub.2, --H, halo,
and C1-C5 alkyl.
[0264] Most preferred L.sup.2 and E.sup.2 groups are those
independently selected from the group consisting of --H,
--S--C.ident.N, lower alkoxy, C1-C5 alkyl, lower alkyl(hydroxy),
lower aryl, and halogen or together L.sup.2 and E.sup.2 form an
annulated cyclic group containing an additional 4 carbon atoms.
[0265] Most preferred J.sup.2 groups include --H, and C1-C5
alkyl.
[0266] Preferred X.sup.2 groups include --CF.sub.2--, --CH.sub.2--,
--OC(O)-- --OCH.sub.2--, --SCH.sub.2--, --NHCH.sub.2--, and
--N(C(O)CH.sub.3)--CH.sub.2--. More preferred are --OCH.sub.2--,
--SCH.sub.2--, and --N(C(O)CH.sub.3)--CH.sub.2--. Most preferred is
--OCH.sub.2--.
[0267] One preferred aspect include compound wherein A.sup.2 is
selected from the group consisting of --H, --NH.sub.2, --CH.sub.3,
--Cl, and --Br;
[0268] L.sup.2 is --H, lower alkyl, halogen, lower alkyloxy,
hydroxy, -alkenylene-OH, or together with E.sup.2 forms a cyclic
group including aryl, cyclic alkyl, heteroaryls, heterocyclic
alkyl;
[0269] E.sup.2 is selected from the groups consisting of H, lower
alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or
together with L.sup.2 forms a cyclic group including aryl, cyclic
alkyl, heteroaryl, or heterocyclic alkyl;
[0270] J.sup.2 is selected from the groups consisting of H,
halogen, and lower alkyl;
[0271] G'' is --S--;
[0272] X.sup.2 is --OCH.sub.2--;
[0273] and pharmaceutically acceptable salts and prodrugs thereof.
More preferred are such compounds wherein
[0274] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0275] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0276] R.sup.14 is --OR.sup.17;
[0277] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0278] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and lower aralkyl, 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 O, and
N.
[0279] Also more preferred are such compounds where A.sup.2 is
NH.sub.2, L.sup.2 is selected from the group consisting of -Et and
--Cl, E.sup.2 is selected from the group consisting of --SCN, -Et,
and --Br, and J.sup.2 is --H. Particularly preferred are such
compounds wherein ##STR46## is selected from the group consisting
of ##STR47##
[0280] wherein C* has S stereochemistry.
[0281] Preferred R.sup.18 groups include --H, methyl, and ethyl.
More preferred is --H and methyl. Especially preferred is --H.
[0282] Preferred compounds include those wherein each R.sup.12 and
R.sup.13 is independently selected from the group consisting of
--H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--CH.sub.2CH.sub.2--SCH.sub.3, phenyl, and benzyl, or together
R.sup.12 and R.sup.13 are connected via 2-5 carbon atoms to form a
cycloalkyl group. More preferred is each R.sup.12 and R.sup.13 is
independently selected from the group consisting of --H, methyl,
i-propyl, i-butyl, and benzyl, or together R.sup.12 and R.sup.13
are connected via 2-5 carbon atoms to form a cycloalkyl group. Also
more preferred are such compounds wherein each R.sup.12 and
R.sup.13 is independently selected from the group consisting of
--H, methyl, i-propyl, and benzyl, or together R.sup.12 and
R.sup.13 are connected via 4 carbon atoms to form a cyclopentyl
group. Especially preferred are those compounds wherein R.sup.12
and R.sup.13 are both --H, both methyl, or R.sup.12 is H and
R.sup.13 is selected from the group consisting of methyl, i-propyl,
and benzyl. Most preferred are such compounds wherein n is 1, and
R.sup.12 is --H, then the carbon attached to R.sup.12 and R.sup.13
has S stereochemistry.
[0283] Preferably, n is an integer of from 1-2. More preferred is
when n is 1.
[0284] Preferred compounds include those wherein each R.sup.14 is
independently selected from the group consisting of --OR.sup.17,
and --SR.sup.17, and R.sup.17 is selected from the group consisting
of optionally substituted methyl, ethyl, propyl, t-butyl, and
benzyl. More preferred are such compounds wherein each R.sup.14 is
independently selected from the group consisting of --OR.sup.17;
and R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, and benzyl. Most preferred are such compounds
wherein R.sup.17 is selected from the group consisting of ethyl,
and benzyl.
[0285] Preferred are compounds wherein R.sup.15 is not H. More
preferred are compounds wherein R.sup.15 and R.sup.16 are
independently selected from the group consisting of lower alkyl,
and lower aralkyl, 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 O, N, and S. Also more preferred are compounds
wherein R.sup.15 and R.sup.16 are independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 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 O, N, and S. In
one aspect, particularly preferred are compounds wherein
--NR.sup.15R.sup.16 is a cyclic amine. Especially preferred are
such compounds wherein --NR.sup.15R.sup.16 is selected from the
group consisting of morpholinyl and pyrrolidinyl.
[0286] Preferred are compounds R.sup.16 is
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14.
[0287] More preferred are compounds where n is 1, and wherein
[0288] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0289] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0290] R.sup.14 is --OR.sup.17;
[0291] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0292] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and lower aralkyl, 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 O, and
N. Particularly preferred are such compounds that are of the
formula: ##STR48##
[0293] More preferred are such compounds wherein n is 1. Especially
preferred are such compounds wherein when R.sup.12 and R.sup.13 are
not the same, then H.sub.2N--CR.sup.12R.sup.13--C(O)--R.sup.14 is
an ester, or thioester of a naturally occurring amino acid; and
R.sup.14 is selected from the group consisting of --OR.sup.17 and
--SR.sup.17.
[0294] In one aspect, preferred are compounds of formula IA or
formula I wherein M is ##STR49## wherein:
[0295] A, E, and L 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.5, --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 and L form a cyclic group, or together L and E form a
cyclic group, or together E and J form a cyclic group including
aryl, cyclic alkyl, and heterocyclic;
[0296] J 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 forms a
cyclic group including aryl, cyclic alkyl and heterocyclic
alkyl;
[0297] 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;
[0298] 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;
[0299] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0300] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0301] 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;
[0302] R.sup.5 is selected from the group consisting of lower
alkyl, lower aryl, lower aralkyl, and lower alicyclic;
[0303] 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;
[0304] 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 bidendate alkyl;
[0305] 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;
[0306] R.sup.10 is selected from the group consisting of --H, lower
alkyl, --NH.sub.2, lower aryl, and lower perhaloalkyl;
[0307] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and pharmaceutically
acceptable prodrugs and salts thereof; with the provisos that:
[0308] a) when X.sup.3 is alkyl or alkene, then A is
--N(R.sup.8.sub.2);
[0309] b) X.sup.3 is not alkylamine and alkylaminoalkyl substituted
with phosphonic esters and acids; and
[0310] c) A, L, E, J, and Y.sup.3 together may only form 0-2 cyclic
groups.
[0311] More preferred are such compounds wherein X.sup.3 is not
-alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, and -alkylthio-.
Particularly preferred are such compounds with the additional
proviso that when X.sup.3 is aryl or alkylaryl, said aryl or
alkylaryl group is not linked 1,4 through a six-membered aromatic
ring.
[0312] Especially preferred benzimidazole compounds include those
wherein A, L, and E 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 and J together form a cyclic group; and
wherein J 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 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-. More preferred are such
compounds wherein
[0313] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0314] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0315] R.sup.14 is --OR.sup.17;
[0316] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0317] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and lower aralkyl, 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 O, and
N. Most preferred are such compounds wherein A is selected from the
group consisting of --H, --NH.sub.2, --F, and --CH.sub.3;
[0318] L is selected from the group consisting of --H, --F,
--OCH.sub.3, Cl and --CH.sub.3;
[0319] E is selected from the group consisting of --H, and
--Cl;
[0320] J is selected from the group consisting of --H, halo, C1-C5
hydroxyalkyl, C1-C5 haloalkyl, C1-C5 R.sup.8.sub.2 N-alkyl, C1-C5
alicyclic, and C1-C5 alkyl;
[0321] X.sup.3 is selected from the group consisting of
--CH.sub.2OCH.sub.2--, -methyleneoxycarbonyl-, and
-furan-2,5-diyl-; and
[0322] Y is lower alkyl.
[0323] Also more preferred are such benzimidazoles where A is
--NH.sub.2, L is --F, E is --H, J is ethyl, Y is isobutyl, and
X.sup.3 is -furan-2,5-diyl-; or
[0324] where A is --NH.sub.2, L is --F, E is --H, J is
N,N-dimethylaminopropyl, Y is isobutyl, and X.sup.3 is
-furan-2,5-diyl-.
[0325] Particularly preferred are those compounds wherein ##STR50##
is selected from the group consisting of ##STR51##
[0326] wherein C* has S stereochemistry.
Preferably, oral bioavailability is at least 5%. More preferably,
oral bioavailability is at least 10%.
[0327] The prodrugs of formula IA may have two isomeric forms
around the phosphorus. Preferred is when the phosphorus is not
chiral. Also preferred is when there is no chiral center in the
amino groups attached to the phosphorus. Also preferred is when n
is 1 and R.sup.12 is --H, then the carbon attached to R.sup.12 and
R.sup.13 has S stereochemistry.
[0328] In another aspect preferred are compounds of formula I or
I-A where M is ##STR52## wherein
[0329] Z' is selected from the group consisting of alkyl or
halogen,
[0330] U and V' are independently selected from the group
consisting of hydrogen, hydroxy, acyloxy or when taken together
form a lower cyclic ring containing at least one oxygen;
[0331] W' is selected from the group consisting of amino and lower
alkyl amino;
[0332] and pharmaceutically acceptable salts thereof.
[0333] In another aspect, preferred are compounds of formula II
##STR53## wherein
[0334] A.sup.2 is selected from the group consisting of
--NR.sup.8.sub.2, NHSO.sub.2R.sup.3, --OR.sup.5, --SR.sup.5,
halogen, lower alkyl, --CON(R.sup.4).sub.2, guanidine, amidine,
--H, and perhaloalkyl;
[0335] E.sup.2 is selected from the group consisting of --H,
halogen, lower alkylthio, lower perhaloalkyl, lower alkyl, lower
alkenyl, lower alkynyl, lower alkoxy, --CN, and
--NR.sup.7.sub.2;
[0336] 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;
[0337] 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;
[0338] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0339] when Y is --O--, then R.sup.1 attached to --O-- is
independently selected from the group consisting of --H, alkyl,
optionally substituted aryl, optionally substituted alicyclic where
the cyclic moiety contains a carbonate or thiocarbonate, optionally
substituted -alkylaryl, --C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2,
--NR.sup.2--C(O)--R.sup.3, --C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy,
[0340] when Y is --NR--, then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3;
[0341] or when either Y is independently selected from --O-- and
NR.sup.6--, then together R.sup.1 and R.sup.1 are
-alkyl-S--S-alkyl- to form a cyclic group, or together R.sup.1 and
R.sup.1 are ##STR54## wherein
[0342] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
or
[0343] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group containing 5-7 atoms, optionally 1
heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy,
or aryloxycarbonyloxy attached to a carbon atom that is three atoms
from both Y groups attached to the phosphorus; or
[0344] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing 1 heteroatom, that is
fused to an aryl group at the beta and gamma position to the Y
attached to the phosphorus;
[0345] together V and W are connected via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0346] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0347] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0348] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.dbd.CR.sup.2)OH, --R.sup.2,
NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2;
[0349] p is an integer 2 or 3;
[0350] q is an integer 1 or 2;
[0351] with the provisos that:
[0352] a) V, Z, W, W' are not all --H; and
[0353] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0354] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0355] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0356] 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;
[0357] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0358] R.sup.5 is selected from the group consisting of lower
alkyl, lower aryl, lower aralkyl, and lower alicyclic;
[0359] R.sup.9 is independently selected from the group consisting
of --H, loweralkyl, lower alicyclic, lower aralkyl, lower aryl, and
--(CO)R.sup.10;
[0360] 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 bidendate alkyl;
[0361] R.sup.9 is selected from the group consisting of alkyl,
aralkyl, and alicyclic;
[0362] R.sup.10 is selected from the group consisting of --H, lower
alkyl, --NH.sub.2, lower aryl, and lower perhaloalkyl; and
[0363] R.sup.1 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and
[0364] pharmaceutically acceptable prodrugs and salts thereof.
[0365] Preferred A.sup.2 groups for formula II include
--NR.sup.8.sub.2, lower alkyl, lower perhaloalkyl, lower alkoxy,
and halogen. Particularly preferred are --NR.sup.8.sub.2, and
halogen. Especially preferred is --NR.sup.8.sub.2. Most preferred
is --NH.sub.2.
[0366] Preferred E.sup.2 groups for formula II include --H,
halogen, lower perhaloalkyl, --CN, lower alkyl, lower alkoxy, and
lower alkylthio. Particularly preferred E.sup.2 groups include --H,
--SMe, -Et, and --Cl. Especially preferred is --H and
--SCH.sub.3.
[0367] Preferred X.sup.3 groups for formula II include -alkyl-,
-alkynyl-, -alkoxyalkyl-, -alkylthio-, -aryl-, -1,1-dihaloalkyl-,
-carbonylalkyl-, -heteroaryl-, -alkylcarbonylamino-, and
-alkylaminocarbonyl. Particularly preferred is -alkyl- substituted
with 1 to 3 substituents selected from halogen, and --OH.
Particularly preferred are -alkylaminocarbonyl-, -alkoxyalkyl-, and
-heteroaryl-. Preferred -alkoxyalkyl- groups include
-methoxymethyl-. Preferred -heteroaryl- groups include
-furan-2,5-diyl-, optionally substituted.
[0368] Preferred Y.sup.3 groups for formula II include aralkyl,
alicyclic, alkyl, and aryl, all optionally substituted.
Particularly preferred is lower alkyl. Particularly preferred
Y.sup.3 groups include (2-naphthyl)methyl, cyclohexylethyl,
phenylethyl, nonyl, cyclohexylpropyl, ethyl, cyclopropylmethyl,
cyclobutylmethylphenyl, (2-methyl)propyl, neopentyl, cyclopropyl,
cyclopentyl, (1-imidozolyl)propyl, 2-ethoxybenzyl,
1-hydroxy-2,2-dimethylpropyl, 1-chloro-2,2-dimethylpropyl,
2,2-dimethylbutyl, 2-(spiro-3,3-dimethylcyclohex-4-enyl)propyl, and
1-methylneopentyl. Especially preferred is neopentyl and
isobutyl.
[0369] Preferred R.sup.4 and R.sup.7 groups are --H, and lower
alkyl. Particularly preferred are --H, and methyl.
[0370] In another preferred aspect, A2 is --NR.sup.8.sub.2 or
halogen, E.sup.2 is --H, halogen, --CN, lower alkyl, lower
perhaloalkyl, lower alkoxy, or lower alkylthio, X.sup.3 is -alkyl-,
-alkoxyalkyl-, -alkynyl-, -1,1-dihaloalkyl-, -carbonylalkyl-,
-alkyl(OH)--, -alkylcarbonylamino-, -alkylaminocarbonyl-,
-alkylthio-, -aryl-, or -heteroaryl-, and R.sup.4 and R.sup.7 is
--H or lower alkyl. Particularly preferred are such compounds where
Y.sup.3 is aralkyl, aryl, alicyclic, or alkyl.
[0371] In another preferred aspect, A is --NR.sup.8.sub.2, E.sup.2
is --H, Cl--, or methylthio, and X is optionally substituted
-furan-2,5-diyl-, or -alkoxyalkyl-. Particularly preferred are such
compounds where A.sup.2 is --NH.sub.2, X.sup.3 is -furan-2,5-diyl-,
or -methoxymethyl-, and Y.sup.3 is lower alkyl. Most preferred are
such compounds where E.sup.2 is H, X.sup.3 is -furan-2,5-diyl-, and
Y.sup.3 is neopentyl; those where E.sup.2 is --SCH.sub.3, X.sup.3
is -furan-2,5-diyl-, and Y.sup.3 is isobutyl; and those where
E.sup.2 is --H, X.sup.3 is -furan-2,5-diyl-, and Y.sup.3 is
1-(3-chloro-2,2-dimethyl)-propyl. Especially preferred are such
compounds where R.sup.1 is
--CH.sub.2O--C(O)--C(CH.sub.3).sub.3.
[0372] In another aspect, preferred are compounds of formula III
##STR55## wherein:
[0373] A, E, and L 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.5, --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 and L form a cyclic group, or together L and E form a
cyclic group, or together E and J form a cyclic group including
aryl, cyclic alkyl, and heterocyclic;
[0374] J 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 forms a
cyclic group including aryl, cyclic alkyl and heterocyclic
alkyl;
[0375] 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;
[0376] 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;
[0377] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0378] when Y is --O--, then R.sup.1 attached to --O-- is
independently selected from the group consisting of --H, alkyl,
optionally substituted aryl, optionally substituted alicyclic where
the cyclic moiety contains a carbonate or thiocarbonate, optionally
substituted -alkylaryl, --C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2,
--NR.sup.2--C(O)--R.sup.3, --C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy,
[0379] when Y is --NR.sup.6--, then R.sup.1 attached to
--NR.sup.6-- is independently selected from the group consisting of
--H, --[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3;
[0380] or when either Y is independently selected from --O-- and
--NR.sup.6--, then together R.sup.1 and R.sup.1 are
-alkyl-S--S-alkyl- to form a cyclic group, or together R.sup.1 and
R.sup.1 are ##STR56## wherein
[0381] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
or
[0382] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group containing 5-7 atoms, optionally 1
heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy,
or aryloxycarbonyloxy attached to a carbon atom that is three atoms
from both Y groups attached to the phosphorus; or
[0383] together V and Z are connected via an additional 3-5 atoms
to form-a cyclic group, optionally containing 1 heteroatom, that is
fused to an aryl group at the beta and gamma position to the Y
attached to the phosphorus;
[0384] together V and W are connected via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0385] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0386] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2-heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0387] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2;
[0388] p is an integer 2 or 3;
[0389] q is an integer 1 or 2;
[0390] with the provisos that:
[0391] a) V, Z, W, W' are not all --H; and
[0392] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0393] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0394] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0395] 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;
[0396] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0397] R.sup.5 is selected from the group consisting of lower
alkyl, lower aryl, lower aralkyl, and lower alicyclic;
[0398] 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;
[0399] 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 bidendate alkyl;
[0400] R.sup.9 is selected from the group consisting of alkyl,
aralkyl, and alicyclic;
[0401] R.sup.10 is selected from the group consisting of --H, lower
alkyl, --NH.sub.2, lower aryl, and lower perhaloalkyl;
[0402] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2, and
[0403] pharmaceutically acceptable prodrugs and salts thereof.
[0404] Preferred A, L, and E groups for formula III include --H,
--NR.sup.8.sub.2, --NO.sub.2, hydroxy, alkylaminocarbonyl, halogen,
--OR.sup.7, --SR.sup.7, lower perhaloalkyl, and C1-C8 alkyl or
together E and J form a cyclic group. Such a cyclic group may be
aromatic, cyclic alkyl, or heterocyclic alkyl, and may be
optionally substituted. Suitable aromatic groups include thiazole.
Particularly preferred A, L and E groups are --NR.sup.8.sub.2, --H,
hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower
alkyl.
[0405] Preferred A groups for formula III include,
--NR.sup.8.sub.2, --H, halogen, lower perhaloalkyl, and lower
alkyl.
[0406] Preferred L and E groups for formula III include --H, lower
alkoxy, lower alkyl, and halogen.
[0407] Preferred J groups for formula III include --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, or
together with Y forms a cyclic group. Such a cyclic group may be
aromatic, cyclic alkyl, or heterocyclic, and may be optionally
substituted. Particularly preferred J groups include --H, halogen,
and lower alkyl, lower hydroxyalkyl, --NR.sup.8.sub.2, lower
R.sup.8.sub.2N-alkyl, lower haloalkyl, lower alkenyl, alicyclic,
and aryl. Especially preferred are alicyclic and lower alkyl.
[0408] Preferred X.sup.3 groups for formula III include -alkyl-,
-alkynyl-, -aryl-, -alkoxyalkyl-, -alkylthio-,
-alkylaminocarbonyl-, -alkylcarbonylamino-, -1,1-dihaloalkyl-,
-carbonylalkyl-, and -alkyl(OH)--. Particularly preferred is
-heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl-, and
-alkoxyalkyl-. Also particularly preferred are -heteroaryl-,
-alkylaminocarbonyl-, and -alkoxyalkyl-. Especially preferred are
-methylaminocarbonyl-, -methoxymethyl-, and -furan-2,5-diyl-.
[0409] In another preferred aspect, when X.sup.3 is aryl or
alkylaryl, these groups are not linked 1,4 through a 6-membered
aromatic ring.
[0410] Preferred Y.sup.3 groups for formula III include --H, alkyl,
aralkyl, aryl, and alicyclic, all except --H may be optionally
substituted. Particularly preferred are lower alkyl, and
alicyclic.
[0411] Preferred R.sup.4 and R.sup.7 groups include --H, and lower
alkyl.
[0412] In one preferred aspect of compounds of formula III, A, L,
and E are independently --H, lower alkyl, hydroxy, halogen, lower
alkoxy, lower perhaloalkyl, and --NR.sup.8.sub.2; X.sup.3 is
-aryl-, -alkoxyalkyl-, -alkyl-, -alkylthio-, -1,1-dihaloalkyl-,
-carbonylalkyl-, -alkyl(hydroxy)-, -alkylaminocarbonyl-, and
-alkylcarbonylamino-; and each R.sup.4 and R.sup.7 is independently
--H, and lower alkyl. Particularly preferred are such compounds
where A, L, and E are independently --H, lower alkyl, halogen, and
--NR.sup.8.sub.2; J is --H, halogen, haloalkyl, hydroxyalkyl,
R.sup.8.sub.2N-alkyl, lower alkyl, lower aryl, heterocyclic, and
alicyclic, or together with Y.sup.3 forms a cyclic group; and
X.sup.3 is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl-,
and -alkoxyalkyl-. Especially preferred are such compounds where A
is --H, --NH.sub.2, --F, and --CH.sub.3, L is --H, --F,
--OCH.sub.3, --Cl, and --CH.sub.3, E is --H and --Cl, J is --H,
halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, C1-C5
R.sup.8.sub.2N-alkyl, C1-C5 alicyclic, and C1-C5 alkyl, X.sup.3 is
--CH.sub.2OCH.sub.2--, and -furan-2,5-diyl-, and Y.sup.3 is lower
alkyl. Most preferred are the following such compounds and their
salts, and prodrug and their salts:
[0413] 1) A is --NH.sub.2, L is --F, E is --H, J is --H, Y.sup.3 is
isobutyl, and X.sup.3 is -furan-2,5-diyl-;
[0414] 2) A, L, and J are --H, E is --Cl, Y.sup.3 is isobutyl, and
X.sup.3 is -furan-2,5-diyl-;
[0415] 3) A is --NH.sub.2, L is --F, E and J are --H, Y.sup.3 is
cyclopropylmethyl, and X.sup.3 is -furan-2,5-diyl-;
[0416] 4) A is --NH.sub.2, L is --F, E is --H, J is ethyl, Y.sup.3
is isobutyl, and X.sup.3 is -furan-2,5-diyl-;
[0417] 5) A is --CH.sub.3, L is --Cl, E and J are --H, Y.sup.3 is
isobutyl, and X.sup.3 is -furan-2,5-diyl-;
[0418] 6) A is --NH.sub.2, L is --F, E is --H, J is --Cl, Y.sup.3
is isobutyl, and X.sup.3 is -furan-2,5-diyl-;
[0419] 7) A is --NH.sub.2, L is --F, E is --H, J is --Br, Y.sup.3
is isobutyl, and X.sup.3 is --CH.sub.2OCH.sub.2--; and
[0420] 8) A, L, E, and J are --CH.sub.3, Y.sup.3 is
cyclopropylmethyl, and X.sup.3 is -furan-2,5-diyl-.
[0421] Also especially preferred are compounds where A is
--NH.sub.2, L is --F, E is --H, J is bromopropyl, bromobutyl,
chlorobutyl, cyclopropyl, hydroxypropyl, or
N,N-dimethylaminopropyl, and X.sup.3 is -furan-2,5-diyl-. The
preferred prodrug is where R.sup.1 is pivaloyloxymethyl or its HCl
salt.
[0422] In another aspect, preferred are compounds of formula IV
##STR57## wherein:
[0423] B is selected from the group consisting of --NH--, --N.dbd.
and --CH.dbd.;
[0424] D is selected from the group consisting of ##STR58##
[0425] Q is selected from the group consisting of --C.dbd. and
--N-- with the proviso that when B is --NH-- then Q is ##STR59##
and D is ##STR60## when B is --CH.dbd. then Q is --N-- and D is
##STR61## when B is --N.dbd., then D is --N-- and Q is
--C.dbd.;
[0426] A, E, and L 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,
guanidino, amidino, --NHSO.sub.2R.sup.5, --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 and L form a cyclic group, or together L and E form a
cyclic group, or together E and J form a cyclic group including
aryl, cyclic alkyl, and heterocyclic;
[0427] J 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 forms a
cyclic group including aryl, cyclic alkyl and heterocyclic
alkyl;
[0428] 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;
[0429] 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;
[0430] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0431] when Y is --O--, then R.sup.1 attached to --O-- is
independently selected from the group consisting of --H, alkyl,
optionally substituted aryl, optionally substituted alicyclic where
the cyclic moiety contains a carbonate or thiocarbonate, optionally
substituted -alkylaryl, --C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2,
--NR.sup.2--C(O)--R.sup.3, --C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy,
[0432] when Y is --NR.sup.6--, then R.sup.1 attached to
--NR.sup.6-- is independently selected from the group consisting of
--H, --[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, [C(R.sup.2).sub.2].sub.q--C(O)SR, and
-cycloalkylene-COOR.sup.3;
[0433] or when either Y is independently selected from --O-- and
--NR.sup.6--, then together R.sup.1 and R.sup.1 are
-alkyl-S--S-alkyl- to form a cyclic group, or together R.sup.1 and
R.sup.1 are ##STR62## wherein
[0434] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
or
[0435] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group containing 5-7 atoms, optionally 1
heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy,
or aryloxycarbonyloxy attached to a carbon atom that is three atoms
from both Y groups attached to the phosphorus; or
[0436] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing 1 heteroatom, that is
fused to an aryl group at the beta and gamma position to the Y
attached to the phosphorus;
[0437] together V and W are connected via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0438] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0439] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0440] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3--NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2;
[0441] p is an integer 2 or 3;
[0442] q is an integer 1 or 2;
[0443] with the provisos that:
[0444] a) V, Z, W, W' are not all --H; and
[0445] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0446] R.sup.2 is selected from the group consisting of R.sup.3,
and --H;
[0447] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0448] 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;
[0449] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0450] R.sup.5 is selected from the group consisting of lower
alkyl, lower aryl, lower aralkyl, and lower alicyclic;
[0451] 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;
[0452] 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;
[0453] R.sup.9 is selected from the group consisting of alkyl,
aralkyl, and alicyclic;
[0454] R.sup.10 is selected from the group consisting of --H, lower
alkyl, --NH.sub.2, lower aryl, and lower perhaloalkyl;
[0455] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2 and --OR.sup.2; and
[0456] pharmaceutically acceptable prodrugs and salts thereof.
[0457] Preferred A, L, and E groups in formula IV include --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 and J form a cyclic group. Such a cyclic group
may be aromatic or cyclic alkyl, and may be optionally substituted.
Suitable aromatic groups include thiazole. Particularly preferred
A, L and E groups are --NR.sup.8.sub.2, --H, hydroxy, halogen,
lower alkoxy, lower perhaloalkyl, and lower alkyl.
[0458] Preferred A groups in formula IV include --NR.sup.8.sub.2,
lower alkyl, --H, halogen, and lower perhaloalkyl.
[0459] Preferred L and E groups in formula IV include --H, lower
alkoxy, lower alkyl, and halogen.
[0460] Preferred J groups in formula IV include --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 or
together with Y.sup.3 forms a cyclic group. Such a cyclic group may
be aromatic or cyclic alkyl, and may be optionally substituted.
Particularly preferred J groups --H, halogen, lower alkyl, lower
hydroxyalkyl, --NR.sup.8.sub.2, lower R.sup.8.sub.2N-alkyl, lower
haloalkyl, lower alkenyl, alicyclic, and aryl.
[0461] Preferred X.sup.3 groups in formula IV include -alkyl
-alkynyl-, -alkoxyalkyl-, -alkylthio-, -aryl-,
-alkylaminocarbonyl-, -alkylcarbonylamino-, -1,1-dihaloalkyl-,
-carbonylalkyl-, and -alkyl(OH)--. Particularly preferred is
-1,1-dihaloalkyl-, -alkylaminocarbonyl-, -alkoxyalkyl-, and
-heteroaryl-. Such compounds that are especially preferred are
-heteroaryl-, -alkylaminocarbonyl-, and -alkoxyalkyl-. Most
preferred is -methylaminocarbonyl-, -methoxymethyl-, and
-furan-2,5-diyl.
[0462] In one preferred aspect, X.sup.3 is not --(C2-C3
alkyl)aminocarbonyl-.
[0463] Preferred Y.sup.3 groups for formula IV include --H, alkyl,
aryl, aralkyl, and alicyclic, all except --H may be optionally
substituted. Particularly preferred Y.sup.3 groups include lower
alkyl, and alicyclic.
[0464] Preferred R.sup.4 and R.sup.7 groups include --H, and lower
alkyl.
[0465] In one preferred aspect of formula IV, B is NH, D is
##STR63## and Q is --C.dbd.. In another preferred aspect, B is
--N.dbd., D is ##STR64## and Q is --C.dbd..
[0466] In another preferred aspect of formula IV, A, L, and E are
independently --NR.sup.8.sub.2, lower alkyl, lower perhaloalkyl,
lower alkoxy, halogen, --OH, or --H, X.sup.3 is -aryl-,
-alkoxyalkyl-, -alkyl-, -alkylthio-, -1,1-dihaloalkyl-,
-carbonylalkyl-, -alkyl(hydroxy)-, -alkylaminocarbonyl-, and
-alkylcarbonylamino-, and each R.sup.4 and R.sup.7 is independently
--H, or lower alkyl. Particularly preferred are such compounds
where A, L, and E are independently --H, lower alkyl, halogen, and
--NR.sup.8.sub.2; J is --H, halogen, haloalkyl, hydroxyalkyl,
--R.sup.8.sub.2N-alkyl, lower alkyl, lower aryl, heterocyclic, and
alicyclic, or together with Y.sup.3 forms a cyclic group; and
X.sup.3 is -heteroaryl-, -alkylaminocarbonyl-, -1,1-dihaloalkyl-,
and -alkoxyalkyl-. Especially preferred are such compounds where A
is --H, --NH.sub.2, --F, or --CH.sub.3, L is --H, --F, --OCH.sub.3,
or --CH.sub.3, E is --H, or --Cl, J is --H, halo, C1-C8
hydroxyalkyl, C1-C8 haloalkyl, C1-C8 R.sup.8.sub.2N-alkyl, C1-C5
alicyclic or C1-C5 alkyl, X.sup.3 is --CH.sub.2OCH.sub.2--, or
-furan-2,5-diyl-; and Y.sup.3 is lower alkyl. Preferred are such
compounds where B is NH, D is ##STR65## and Q is --C.dbd. or where
B is --N.dbd., D is ##STR66## and Q is --C.dbd..
[0467] Most preferred are compounds where:
[0468] 1) A is --NH.sub.2, L is --F, E is --H, J is --H, Y.sup.3 is
isobutyl, and X.sup.3 is -furan-2,5-diyl-;
[0469] 2) A is --NH.sub.2, L is --F, E is --H, Y.sup.3 is --Cl,
Y.sup.3 is isobutyl, and X.sup.3 is -furan-2,5-diyl-.
[0470] 3) A is --H, L is --H, E is --Cl, J is --H, B is --NH, D is
##STR67## Q is --C.dbd., and Y.sup.3 is isobutyl; and
[0471] 4) A is --CH.sub.3, L is --H, E is --H, J is --H, B is
--N.dbd., D is ##STR68## Q is --C.dbd., and Y.sup.3 is
isobutyl.
[0472] Particularly preferred are such compounds where R.sup.1 is
--CH.sub.2OC(O)--C(CH.sub.3).sub.3.
[0473] Another especially preferred aspect are such compounds where
A, L, and E are --H, lower alkyl, halogen, or --NR.sup.8.sub.2, J
is --H, halogen, lower alkyl, lower aryl, heterocyclic, or
alicyclic, or together with Y.sup.3 forms a cyclic group, and
X.sup.3 is -heteroaryl-, -alkylaminocarbonyl-, or
-alkoxyalkyl-.
[0474] In another aspect, preferred are compounds of formula V
wherein M is R.sup.5--X-- wherein
[0475] R.sup.5 is selected from the group consisting of: ##STR69##
wherein:
[0476] 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;
[0477] each G' is independently selected from the group consisting
of C and N and wherein no more than two G' groups are N;
[0478] 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.3, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null;
[0479] 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;
[0480] 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;
[0481] J is selected from the group consisting of --H and null;
[0482] 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;
[0483] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0484] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0485] 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;
[0486] 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;
[0487] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2;
[0488] and with the proviso that: [0489] 1) when G' is N, then the
respective A, B, D, or E is null; [0490] 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; [0491] 3) when R.sup.5 is a six-membered ring, then X
is not any 2 atom linker, an optionally substituted -alkyloxy-, or
an optionally substituted -alkylthio-; [0492] 4) when G is N, then
the respective A or B is not halogen or a group directly bonded to
G via a heteroatom; [0493] 5) when X is not a -heteroaryl- group,
then R.sup.5 is not substituted with two or more aryl groups;
[0494] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0495] when Y is --O--, then R.sup.1 attached to --O-- is
independently selected from the group consisting of --H, alkyl,
optionally substituted aryl, optionally substituted alicyclic where
the cyclic moiety contains a carbonate or thiocarbonate, optionally
substituted -alkylaryl, --C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2,
--NR.sup.2--C(O)--R.sup.3, --C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy,
[0496] when Y is NR.sup.6--, then R.sup.1 attached to NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3;
[0497] or when either Y is independently selected from --O-- and
NR.sup.6--, then together R.sup.1 and R.sup.1 are
-alkyl-S--S-alkyl- to form a cyclic group, or together R.sup.1 and
R.sup.1 are ##STR70## wherein
[0498] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
or
[0499] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group containing 5-7 atoms, optionally 1
heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy,
or aryloxycarbonyloxy attached to a carbon atom that is three atoms
from both Y groups attached to the phosphorus; or
[0500] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing 1 heteroatom, that is
fused to an aryl group at the beta and gamma position to the Y
attached to the phosphorus;
[0501] together V and W are connected via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0502] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0503] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0504] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, CR.sup.2, --NR.sup.2.sub.2,
--OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3, --SCO.sub.2R.sup.3,
--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --CH.sub.2NHaryl,
--(CH.sub.2).sub.p--OR.sup.2, and --(CH.sub.2).sub.p--SR.sup.2;
[0505] p is an integer 2 or 3;
[0506] q is an integer 1 or 2;
[0507] with the provisos that:
[0508] a) V, Z, W, W' are not all --H; and
[0509] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0510] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0511] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0512] 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;
[0513] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0514] In one preferred aspect of formula V-1 and formula V-2
compounds,
[0515] A'' is selected from the group consisting of --NH.sub.2,
--CONH.sub.2, halo, --CH.sub.3, --CF.sub.3, --CH.sub.2-halo, --CN,
--OCH.sub.3, --SCH.sub.3, and --H;
[0516] B'' is selected from the group consisting of --H,
--C(O)R.sup.11, --C(O)SR.sup.3, alkyl, aryl, alicyclic, halo, --CN,
--SR.sup.3, OR.sup.3 and --NR.sup.9.sub.2;
[0517] D'' is selected from the group consisting of --H,
--C(O)R.sup.11, --C(O)SR.sup.3, --NR.sup.9.sub.2, alkyl, aryl,
alicyclic, halo, and --SR.sup.3;
[0518] E'' is selected from the group consisting, of --H, C1-C6
alkyl, lower alicyclic, halo, --CN, --C(O)OR.sup.3, and --SR.
[0519] X 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;
[0520] when both Y groups are --O--, then R.sup.1 is independently
selected from the group consisting of optionally substituted aryl,
optionally substituted benzyl, --C(R.sup.2).sub.2OC(O)R.sup.3,
--C(R.sup.2).sub.2OC(O)OR.sup.3, and --H; or
[0521] when one Y is --O--, then R.sup.1 attached to --O-- is
optionally substituted aryl; and the other Y is --NR.sup.6--, then
R.sup.1 attached to --NR.sup.6-- is selected from the group
consisting of --C(R.sup.4).sub.2COOR.sup.3, and
--C(R.sup.2).sub.2COOR.sup.3; or
[0522] when Y is --O-- or --NR.sup.6--, then together R.sup.1 and
R.sup.1 are ##STR71## wherein
[0523] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl,
or
[0524] together V and W are connected via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0525] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0526] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0527] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2C(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2, --R.sup.2,
--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.2,
and --(CH.sub.2).sub.p--SR.sup.2;
[0528] p is an integer 2 or 3;
[0529] with the provisos that:
[0530] a) V, Z, W, W' are not all --H;
[0531] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic; and
[0532] c) both Y groups are not --NR.sup.6--;
[0533] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0534] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0535] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0536] In one particularly preferred aspect of formula I where M is
R.sup.5--X-- and R.sup.5 is ##STR72##
[0537] X is selected from the group consisting of
methylenoxycarbonyl, and furan-2,5-diyl; at least one Y group is
--O--; and pharmaceutically acceptable salts and prodrugs thereof.
More preferred are such compounds wherein when Y is --O--, then
R.sup.1 attached to --O-- is independently selected from the group
consisting of --H, optionally substituted phenyl,
--CH.sub.2OC(O)-tBu, --CH.sub.2OC(O)Et and --CH.sub.2OC(O)-iPr;
[0538] when Y is --NR.sup.6--, then R.sup.1 is attached to
--NR.sup.6-- independently selected from the group consisting of
--C(R.sup.2).sub.2COOR.sup.3, --C(R.sup.4).sub.2COOR.sup.3, or
[0539] when Y is --O-- or --NR.sup.6--, and at least one Y is
--O--, then together R.sup.1 and R.sup.1 are ##STR73##
[0540] wherein
[0541] V is selected from the group consisting of optionally
substituted aryl, and optionally substituted heteroaryl; and Z, W',
and W are H; and
[0542] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0543] The following such compounds and their salts are most
preferred: [0544] 1) A'' is --NH.sub.2, X is furan-2,5-diyl, and
B'' is --CH.sub.2--CH(CH.sub.3).sub.2; [0545] 2) A'' is --NH.sub.2,
X is furan-2,5-diyl, and B'' is --COOEt; [0546] 3) A'' is
--NH.sub.2, X is furan-2,5-diyl, and B'' is --SCH.sub.3; [0547] 4)
A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is
--SCH.sub.2CH.sub.2SCH.sub.3; [0548] 5) A'' is --NH.sub.2, X is
methyleneoxycarbonyl, and B'' is --CH(CH.sub.3).sub.2.
[0549] In another particularly preferred aspect of formula I where
M is R.sup.5--X--, R.sup.5 is ##STR74##
[0550] X is furan-2,5-diyl, and methyleneoxycarbonyl, and A'' is
--NH.sub.2; at least one Y group is --O--; and pharmaceutically
acceptable salts and prodrugs thereof. Especially preferred are
such compounds wherein
[0551] when Y is --O--, then each R.sup.1 is independently selected
from the group consisting of --H, optionally substituted phenyl,
--CH.sub.2OC(O)-tBu, --CH.sub.2OC(O)Et, and
--CH.sub.2OC(O)-iPr;
[0552] or when Y is --NR.sup.6, then each R.sup.1 is independently
selected from the group consisting of
--C(R.sup.2).sub.2C(O)OR.sup.3, and
--C(R.sup.4).sub.2COOR.sup.3;
[0553] or when Y is independently selected from --O-- and
NR.sup.6--, then together R.sup.1 and R.sup.1 are ##STR75##
wherein
[0554] V selected from the group consisting of optionally
substituted aryl and optionally substituted heteroaryl; and Z, W',
and W are H. Also especially preferred are such compounds wherein
B'' is --SCH.sub.2CH.sub.2CH.sub.3.
[0555] In another particularly preferred aspect of formula I where
M is R.sup.5--X-- and R.sup.5 is ##STR76##
[0556] A'' is --NH.sub.2, E'' and D'' are --H, B'' is n-propyl and
cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl; at least
one Y group is --O--; and pharmaceutically acceptable salts and
prodrugs thereof. Especially preferred are such compounds wherein
R.sup.1 is selected from the group consisting of --H, optionally
substituted phenyl --CH.sub.2OC(O)-tBu, --CH.sub.2OC(O)Et, and
--CH.sub.2OC(O)-iPr,
[0557] or when Y is --NR.sup.6--, then each R.sup.1 is
independently selected from the group consisting of
--C(R.sup.2).sub.2C(O)OR.sup.3, and
--C(R.sup.4).sub.2COOR.sup.3;
[0558] or when either Y is independently selected from --O-- and
--NR.sup.6--, and at least one Y is --O--, then together R.sup.1
and R.sup.1 are ##STR77## wherein
[0559] V is selected from the group consisting of optionally
substituted aryl and optionally substituted heteroaryl; and Z, W',
and W are H.
[0560] In another particularly preferred aspect of formula I where
M is R.sup.5--X-- and R.sup.5 is ##STR78##
[0561] A'' is --NH.sub.2, D'' is --H, B'' is n-propyl and
cyclopropyl, X is furan-2,5-diyl and methyleneoxycarbonyl; at least
one Y group is --O--; and pharmaceutically acceptable salts and
prodrugs thereof. Especially preferred are such compounds wherein
when Y is --O-- then R.sup.1 is selected from the group consisting
of --H, optionally substituted phenyl, --CH.sub.2OC(O)-tBu,
--CH.sub.2OC(O)Et, and --CH.sub.2OC(O)-iPr;
[0562] or when one Y is --O-- and its corresponding R.sup.1 is
-phenyl while the other Y is --NH-- and its corresponding R.sup.1
is --CH(Me)C(O)OEt, or
[0563] when at least one Y group is --O--, then together R.sup.1
and R.sup.1 are ##STR79## wherein
[0564] V is selected from the group consisting of optionally
substituted aryl and optionally substituted heteroaryl; and Z, W',
and W are H.
[0565] Preferred are compounds of formula (X): ##STR80##
wherein:
[0566] G'' is selected from the group consisting of --O-- and
--S--;
[0567] A.sup.22, L.sup.2, E.sup.2, and J.sup.2 are selected from
the group consisting of
[0568] --NR.sup.4.sub.2, --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, alkyoxyalkyl, --SCN,
--NHSO.sub.2R.sup.9, --SO.sub.2NR.sup.4.sub.2, --CN, --S(O)R.sup.3,
perhaloacyl, perhaloalkyl, perhaloalkoxy, C1-C5 alkyl, C2-C5
alkenyl, C2-C5 alkynyl, and lower alicyclic, or together L and E or
E.sup.2 and J.sup.2 form an annulated cyclic group;
[0569] X.sup.2 is selected from the group consisting of
--CR.sup.2.sub.2--, --CF.sub.2--, --OCR.sup.2.sub.2--,
--SCR.sup.2.sub.2--, --O--C(O)--, --S--C(O)--, --O--C(S)--, and
--NR.sup.19CR.sup.2.sub.2--, 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;
[0570] R.sup.19 is selected from the group consisting of lower
alkyl, --H, and --COR.sup.2; and
[0571] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0572] when Y is --O--, then R.sup.1 attached to --O-- is
independently selected from the group consisting of --H, alkyl,
optionally substituted aryl, optionally substituted alicyclic where
the cyclic moiety contains a carbonate or thiocarbonate, optionally
substituted -alkylaryl, --C(R.sup.2).sub.2OC(O)NR.sup.2.sub.2,
--NR.sup.2--C(O)--R.sup.3, --C(R.sup.2).sub.2--OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3,
-alkyl-S--S-alkylhydroxy, and -alkyl-S--S--S-alkylhydroxy,
[0573] when Y is NR.sup.6 then R.sup.1 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, --[C(R.sup.2).sub.2].sub.q--C(O)SR,
and -cycloalkylene-COOR.sup.3;
[0574] or when either Y is independently selected from --O-- and
--NR.sup.6, then together R.sup.1 and R.sup.1 are
-alkyl-S--S-alkyl- to form a cyclic group, or together R.sup.1 and
R.sup.1 are ##STR81## wherein
[0575] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl;
or
[0576] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group containing 5-7 atoms, optionally 1
heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy,
or aryloxycarbonyloxy attached to a carbon atom that is three atoms
from both Y groups attached to the phosphorus; or
[0577] together V and Z are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing 1 heteroatom, that is
fused to an aryl group at the beta and gamma position to the Y
attached to the phosphorus;
[0578] together V and W are connected-via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0579] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0580] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0581] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2,
--CHR.sup.2N.sub.3, --CH.sub.2aryl, --CH(aryl)OH,
--CH(CH.dbd.CR.sup.2.sub.2)OH, --CH(C.ident.CR.sup.2)OH, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.3, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2;
[0582] p is an integer 2 or 3;
[0583] q is an integer 1 or 2;
[0584] with the provisos that:
[0585] a) V, Z, W, W' are not all --H; and
[0586] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0587] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0588] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0589] each R.sup.4 is independently selected from the group
consisting of --H, alkyl, or together R.sup.4 and R.sup.4 form a
cyclic alkyl;
[0590] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0591] 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;
[0592] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2, and --OR.sup.2; and
[0593] pharmaceutically acceptable prodrugs and salts thereof.
[0594] More preferred are compounds wherein G'' is --S--. Most
preferred are compounds wherein A.sup.2, L.sup.2, E.sup.2, and
J.sup.2 are independently selected from the group consisting of
--H, --NR.sup.4.sub.2, --S--C.ident.N, halogen, --OR.sup.3,
hydroxy, -alkyl(OH), aryl, alkyloxycarbonyl, --SR.sup.3, lower
perhaloalkyl, and C1-C5 alkyl, or together L.sup.2 and E.sup.2 form
an annulated cyclic group. More preferably A.sup.2, L.sup.2,
E.sup.2 and J.sup.2 are independently selected from the group
consisting of --H, --NR.sup.4.sub.2, --S--C--N, halogen, lower
alkoxy, hydroxy, lower alkyl(hydroxy), lower aryl, and
C.sub.1-C.sub.5 alkyl, or together L.sup.2 and E.sup.2 form an
annulated cyclic group.
[0595] Most preferred A.sup.2 groups include --NH.sub.2, --H, halo,
and C1-C5 alkyl.
[0596] Most preferred L.sup.2 and E.sup.2 groups are those
independently selected from the group consisting of --H,
--S--C.ident.N, lower alkoxy, C1-C5 alkyl, lower alkyl(hydroxy),
lower aryl, and halogen or together L.sup.2 and E.sup.2 form an
annulated cyclic group containing an additional 4 carbon atoms.
[0597] Most preferred J.sup.2 groups include --H, and C1-C5
alkyl.
[0598] Preferred X.sup.2 groups include --CF.sub.2--, --CH.sub.2--,
--OC(O)-- --OCH.sub.2--, --SCH.sub.2--, --NHCH.sub.2--, and
--N(C(O)CH.sub.3)--CH.sub.2--. More preferred are --OCH.sub.2--,
--SCH.sub.2--, and --N(C(O)CH.sub.3)--CH.sub.2--. Most preferred is
--OCH.sub.2--.
[0599] One preferred aspect include compound wherein A.sup.2 is
selected from the group consisting of --H, --NH.sub.2, --CH.sub.3,
--Cl, and --Br;
[0600] L.sup.2 is --H, lower alkyl, halogen, lower alkyloxy,
hydroxy, -alkenylene-OH, or together with E.sup.2 forms a cyclic
group including aryl, cyclic alkyl, heteroaryls, heterocyclic
alkyl;
[0601] E.sup.2 is selected from the groups consisting of H, lower
alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or
together with L.sup.2 forms a cyclic group including aryl, cyclic
alkyl, heteroaryl, or heterocyclic alkyl;
[0602] J.sup.2 is selected from the groups consisting of H,
halogen, and lower alkyl;
[0603] G'' is --S--;
[0604] X.sup.2 is --OCH.sub.2--;
[0605] and pharmaceutically acceptable salts and prodrugs thereof.
More preferred are such compounds wherein
[0606] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0607] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0608] R.sup.14 is --OR.sup.17;
[0609] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0610] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and lower aralkyl, 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 O, and
N.
[0611] Also more preferred are such compounds where A.sup.2 is
NH.sub.2, L is selected from the group consisting of -Et and --Cl,
E.sup.2 is selected from the group consisting of --SCN, -Et, and
--Br, and J.sup.2 is --H. Particularly preferred are such compounds
wherein ##STR82## is selected from the group consisting of
##STR83##
[0612] wherein C* has S stereochemistry.
[0613] Preferred R.sup.18 groups include --H, methyl, and ethyl.
More preferred is --H and methyl. Especially preferred is --H.
[0614] Preferred compounds include those wherein each R.sup.12 and
R.sup.13 is independently selected from the group consisting of
--H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
--CH.sub.2CH.sub.2--SCH.sub.3, phenyl, and benzyl, or together
R.sup.12 and R.sup.13 are connected via 2-5 carbon atoms to form a
cycloalkyl group. More preferred is each R.sup.12 and R.sup.13 is
independently selected from the group consisting of --H, methyl,
i-propyl, i-butyl, and benzyl, or together R.sup.12 and R.sup.13
are connected via 2-5 carbon atoms to form a cycloalkyl group. Also
more preferred are such compounds wherein each R.sup.12 and
R.sup.13 is independently selected from the group consisting of
--H, methyl, i-propyl, and benzyl, or together R.sup.12 and
R.sup.13 are connected via 4 carbon atoms to form a cyclopentyl
group. Especially preferred are those compounds wherein R.sup.12
and R.sup.13 are both --H, both methyl, or R.sup.12 is H and
R.sup.13 is selected from the group consisting of methyl, i-propyl,
and benzyl. Most preferred are such compounds wherein n is 1, and
R.sup.12 is --H, then the carbon attached to R.sup.12 and R.sup.13
has S stereochemistry.
[0615] Preferably, n is an integer of from 1-2. More preferred is
when n is 1.
[0616] Preferred compounds include those wherein each R.sup.14 is
independently selected from the group consisting of --OR.sup.17,
and --SR.sup.17; and R.sup.17 is selected from the group consisting
of optionally substituted methyl, ethyl, propyl, t-butyl, and
benzyl. More preferred are such compounds wherein each R.sup.14 is
independently selected from the group consisting of --OR.sup.17;
and R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, and benzyl. Most preferred are such compounds
wherein R.sup.17 is selected from the group consisting of ethyl,
and benzyl.
[0617] Preferred are compounds wherein R.sup.15 is not H. More
preferred are compounds wherein R.sup.15 and R.sup.16 are
independently selected from the group consisting of lower alkyl,
and lower aralkyl, 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 O, N, and S. Also more preferred are compounds
wherein R.sup.15 and R.sup.16 are independently selected from the
group consisting of C1-C6 alkyl, 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 O, N, and S. In one aspect,
particularly preferred are compounds wherein --NR.sup.15R.sup.16 is
a cyclic amine. Especially preferred are such compounds wherein
--NR.sup.15R.sup.16 is selected from the group consisting of
morpholinyl and pyrrolidinyl.
[0618] Preferred are compounds R.sup.16 is
--(CR.sup.12R.sup.13).sub.n--C(O)--R.sup.14.
[0619] More preferred are compounds where n is 1, and wherein
[0620] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0621] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0622] R.sup.14 is --OR.sup.17;
[0623] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0624] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and lower aralkyl, 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 O, and
N. Particularly preferred are such compounds that are of the
formula: ##STR84##
[0625] More preferred are such compounds wherein n is 1. Especially
preferred are such compounds wherein when R.sup.12 and R.sup.13 are
not the same, then H.sub.2N--CR.sup.12R.sup.13--C(O)--R.sup.14 is
an ester, or thioester of a naturally occurring amino acid; and
R.sup.14 is selected from the group consisting of --OR.sup.17 and
--SR.sup.17.
[0626] In one aspect, preferred are compounds of formula IA or
formula I wherein M is ##STR85## wherein:
[0627] A, E, and L 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.5, --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 and L form a cyclic group, or together L and E form a
cyclic group, or together E and J form a cyclic group including
aryl, cyclic alkyl, and heterocyclic;
[0628] J 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 forms a
cyclic group including aryl, cyclic alkyl and heterocyclic
alkyl;
[0629] 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;
[0630] 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;
[0631] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0632] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0633] 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;
[0634] R.sup.5 is selected from the group consisting of lower
alkyl, lower aryl, lower aralkyl, and lower alicyclic;
[0635] 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;
[0636] 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 bidendate alkyl;
[0637] 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;
[0638] R.sup.10 is selected from the group consisting of --H, lower
alkyl, --NH.sub.2, lower aryl, and lower perhaloalkyl;
[0639] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and pharmaceutically
acceptable prodrugs and salts thereof; with the provisos that:
[0640] a) when X.sup.3 is alkyl or alkene, then A is
--N(R.sup.8.sub.2);
[0641] b) X.sup.3 is not alkylamine and alkylaminoalkyl substituted
with phosphonic esters and acids; and
[0642] c) A, L, E, J, and Y.sup.3 together may only form 0-2 cyclic
groups.
[0643] More preferred are such compounds wherein X.sup.3 is not
-alkoxyalkyl-, -alkyloxy-, -alkythioalkyl-, and -alkylthio-.
Particularly preferred are such compounds with the additional
proviso that when X.sup.3 is aryl or alkylaryl, said aryl or
alkylaryl group is not linked 1,4 through a six-membered aromatic
ring.
[0644] Especially preferred benzimidazole compounds include those
wherein A, L, and E 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-C8 alkyl, or together E and J together form a cyclic group; and
wherein J 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 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-. More preferred are such
compounds wherein
[0645] R.sup.18 is selected from the group consisting of --H,
methyl, and ethyl;
[0646] R.sup.12 and R.sup.13 are independently selected from the
group consisting of --H, methyl, i-propyl, i-butyl, and benzyl, or
together are connected via 2-5 carbon atoms to form a cycloalkyl
group;
[0647] R.sup.14 is --OR.sup.17;
[0648] R.sup.17 is selected from the group consisting of methyl,
ethyl, propyl, t-butyl, and benzyl; and
[0649] R.sup.15 and R.sup.16 are independently selected from the
group consisting of lower alkyl, and tower aralkyl, 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 O, and
N. Most preferred are such compounds wherein A is selected from the
group consisting of --H, --NH.sub.2, --F, and --CH.sub.3;
[0650] L is selected from the group consisting of --H, --F,
--OCH.sub.3, Cl and --CH.sub.3;
[0651] E is selected from the group consisting of --H, and
--Cl;
[0652] J is selected from the group consisting of --H, halo,
C.sub.1-C.sub.5 hydroxyalkyl, C.sub.1-C.sub.5 haloalkyl, C1-C5
R.sup.8.sub.2N-alkyl, C.sub.1-C.sub.5 alicyclic, and
C.sub.1-C.sub.5 alkyl;
[0653] X.sup.3 is selected from the group consisting of
--CH.sub.2OCH.sub.2--, -methyleneoxycarbonyl-, and
-furan-2,5-diyl-; and
[0654] Y is lower alkyl.
[0655] Also more preferred are such benzimidazoles where A is
--NH.sub.2, L is --F, E is --H, 3 is ethyl, Y is isobutyl, and
X.sup.3 is -furan-2,5-diyl-; or
[0656] where A is --NH.sub.2, L is --F, E is --H, J is
N,N-dimethylaminopropyl, Y is isobutyl, and X.sup.3 is
-furan-2,5-diyl-.
[0657] Particularly preferred are those compounds wherein ##STR86##
is selected from the group consisting of ##STR87##
[0658] wherein C* has S stereochemistry.
Preferably, oral bioavailability is at least 5%. More preferably,
oral bioavailability is at least 10%.
[0659] The prodrugs of formula IA may have two isomeric forms
around the phosphorus. Preferred is when the phosphorus is not
chiral. Also preferred is when there is no chiral center in the
amino groups attached to the phosphorus. Also preferred is when n
is 1 and R.sup.12 is --H, then the carbon attached to R.sup.12 and
R.sup.13 has S stereochemistry.
[0660] In one aspect, preferred are compounds of formula X wherein
A.sup.2 is selected from the group consisting of --H, --NH.sub.2,
--CH.sub.3, --Cl, and --Br;
[0661] L.sup.2 is --H, lower alkyl, halogen, lower alkyloxy,
hydroxy, -alkenylene-OH, or together with E.sup.2 forms a cyclic
group including aryl, cyclic alkyl, heteroaryls, heterocyclic
alkyl;
[0662] E.sup.2 is selected from the groups consisting of H, lower
alkyl, halogen, SCN, lower alkyloxycarbonyl, lower alkyloxy, or
together with L.sup.2 forms a cyclic group including aryl, cyclic
alkyl, heteroaryl, or heterocyclic alkyl;
[0663] J.sup.2 is selected from the groups consisting of H,
halogen, and lower alkyl;
[0664] G'' is --S--;
[0665] X.sup.2 is --OCH.sub.2--; and
[0666] at least one Y group is --O--; and pharmaceutically
acceptable salts and prodrugs thereof. Also particularly preferred
are such compounds where A is NH.sub.2, G'' is --S--, L.sup.2 is
Et, E.sup.2 is SCN, and J.sup.2 is H. More preferred are such
compounds wherein one Y is --O-- and its corresponding R.sup.1 is
optionally substituted phenyl, while the other Y is --NH--, and its
corresponding R.sup.1 is --C(R.sup.2).sub.2--COOR.sup.3. When
R.sup.1 is --CHR.sup.3COOR.sup.3, then the corresponding
--NR.sup.6--*CHR.sup.3COOR.sup.3, preferably has L
stereochemistry.
[0667] Also more preferred are such compounds wherein one Y is
--O--, and its corresponding R.sup.1 is -phenyl, while the other Y
is --NH-- and its corresponding R.sup.1 is --CH(Me)CO.sub.2Et.
[0668] In compounds of formula I, II, III, IV, V-1, V-2, VI, or X,
preferably both Y groups are --O--; or one Y is --O-- and one Y is
--NR.sup.6--. When only one Y is --NR.sup.6--, preferably the Y
closest to W and W' is --O--. Most preferred are prodrugs where
both Y groups are --O--;
[0669] In another particularly preferred aspect, both Y groups are
--O--, and R.sup.1 and R.sup.1 together are ##STR88## and V is
phenyl substituted with 1-3 halogens. Especially preferred are such
3-bromo-4-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, and
3,5-dichlorophenyl.
[0670] In another particularly preferred aspect, one Y is --O-- and
its corresponding R.sup.1 is phenyl, or phenyl substituted with 1-2
substituents selected from --NHC(O)CH.sub.3, --F, --Cl, --Br,
--C(O)OCH.sub.2CH.sub.3, and --CH.sub.3; while the other Y is
--NR.sup.6-- and its corresponding R.sup.1 is
--C(R.sup.2)COOR.sup.3; each R.sup.2 is independently selected from
--H, --CH.sub.3, and --CH.sub.2CH.sub.3. More preferred R.sup.6 is
--H, and R.sup.1 attached to --NH-- is --CH(Me)CO.sub.2Et.
[0671] In general, preferred substituents, V, Z, W, and W' of
formulae I, II, III, IV, V-1, V-2, VI or X are chosen such that
they exhibit one or more of the following properties:
[0672] (1) enhance the oxidation reaction since this reaction is
likely to be the rate determining step and therefore must compete
with drug elimination processes.
[0673] (2) enhance stability in aqueous solution and in the
presence of other non-p450 enzymes;
[0674] (3) enhance cell penetration, e.g. substituents are not
charged or of high molecular weight since both properties can limit
oral bioavailability as well as cell penetration;
[0675] (4) promote the .beta.-elimination reaction following the
initial oxidation by producing ring-opened products that have one
or more of the following properties:
[0676] a) fail to recyclize;
[0677] b) undergo limited covalent hydration;
[0678] c) promote .beta.-elimination by assisting in the proton
abstraction;
[0679] d) impede addition reactions that form stable adducts, e.g.
thiols to the initial hydroxylated product or nucleophilic addition
to the carbonyl generated after ring opening; and
[0680] e) limit metabolism of reaction intermediates (e.g.
ring-opened ketone);
[0681] (5) lead to a non-toxic and non-mutagenic by-product with
one or more of the following characteristics. Both properties can
be minimized by using substituents that limit Michael additions,
reactions, e.g.
[0682] a) electron donating Z groups that decrease double bond
polarization;
[0683] b) W groups that sterically block nucleophilic addition to
P-carbon;
[0684] c) Z groups that eliminate the double bond after the
elimination reaction either through retautomerization
(enol->keto) or hydrolysis (e.g. enamine);
[0685] d) V groups that contain groups that add to the
.alpha.,.beta.-unsaturated ketone to form a ring;
[0686] e) Z groups that form a stable ring via Michael addition to
double bond; and
[0687] f) groups that enhance detoxification of the by-product by
one or more of the following characteristics:
[0688] (i) confine to liver; and
[0689] (ii) make susceptible to detoxification reactions (e.g.
ketone reduction); and
[0690] (6) capable of generating a pharmacologically active
product.
[0691] In another aspect, it is preferred when Y is --O--, then
R.sup.1 attached to --O-- is independently selected from the group
consisting of --H, optionally substituted aryl, optionally
substituted alicyclic where the cyclic moiety contains a carbonate
or thiocarbonate, optionally substituted -alkylaryl,
--C(R.sup.2).sub.2OC(O)R.sup.3,
--C(R.sup.2).sub.2--O--C(O)OR.sup.3,
--C(R.sup.2).sub.2OC(O)SR.sup.3, -alkyl-S--C(O)R.sup.3, and
-alkyl-S--S-alkylhydroxy;
[0692] when Y is then R.sup.6 attached to --NR.sup.6-- is
independently selected from the group consisting of --H,
--[C(R.sup.2).sub.2].sub.q--COOR.sup.3,
[C(R.sup.2).sub.2].sub.q--C(O)SR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, and -cycloalkylene-COOR.sup.3;
[0693] or when either Y is independently selected from --O-- and
--N then together R.sup.1 and R.sup.1 are ##STR89## wherein
[0694] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl,
or
[0695] together V and W are connected via an additional 3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0696] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0697] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0698] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2, --R.sup.2,
--NHCOR.sup.2, --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.2,
and --(CH.sub.2).sub.p--SR.sup.2;
[0699] p is an integer 2 or 3;
[0700] q is an integer 1 or 2;
[0701] with the provisos that:
[0702] a) V, Z, W, W' are not all --H;
[0703] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic; and
[0704] c) both Y groups are not --NR.sup.6--;
[0705] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0706] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0707] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0708] More preferred are such compounds wherein when both Y groups
are --O--, then R.sup.1 is independently selected from the group
consisting of optionally substituted aryl, optionally substituted
benzyl, --C(R.sup.2).sub.2OC(O)R.sup.3,
--C(R.sup.2).sub.2OC(O)OR.sup.3, and --H; and
[0709] when Y is --NR.sup.6--, then the R.sup.1 attached to said
--NR.sup.6-- group is selected from the group consisting of
--C(R.sup.4).sub.2--COOR.sup.3, and --C(R.sup.2).sub.2COOR.sup.3;
and the other Y group is --O-- and then R.sup.1 attached to said
--O-- is selected from the group consisting of optionally
substituted aryl,
--C(R.sup.2).sub.2OC(O)R.sup.3, and
--C(R.sup.2).sub.2OC(O)OR.sup.3.
[0710] In another aspect, when one Y is --O--, then its
corresponding R.sup.1 is phenyl, and the other Y is --NH--, and its
corresponding R.sup.1 is --CH.sub.2CO.sub.2Et.
[0711] In another preferred aspect, when one Y is --O--, its
corresponding R.sup.1 is phenyl, and the other Y is --NH-- and its
corresponding R.sup.1 is --C(Me).sub.2CO.sub.2Et.
[0712] In another preferred aspect, when one Y is --O--, its
corresponding R.sup.1 is 4--NHC(O)CH.sub.3-phenyl, and the other Y
is --NH--, and its corresponding R.sup.1 is --CH.sub.2COOEt.
[0713] In another preferred aspect, when one Y is --O--, its
corresponding R.sup.1 is 2-CO.sub.2Et-phenyl, and the other Y is
--NH-- and its corresponding R.sup.1 is --CH.sub.2CO.sub.2Et.
[0714] In another preferred aspect, when one Y is --O--, then its
corresponding R.sup.1 is 2-CH.sub.3-phenyl, and the other Y is
--NH, and its corresponding, R.sup.1 is --CH.sub.2CO.sub.2Et.
[0715] In another aspect, preferred are compounds wherein both Y
groups are --O--, and R.sup.1 is aryl, or
--C(R.sup.2).sub.2-aryl.
[0716] Also preferred are compounds wherein both Y groups are O--,
and at least one R.sup.1 is selected from the group consisting of
--C(R.sup.2).sub.2--OC(O)R.sup.3, and
--C(R.sup.2).sub.2--OC(O)OR.sup.3.
[0717] In another aspect, preferred are compounds wherein both Y
groups are --O-- and at least one R.sup.1 is
-alkyl-S--S-alkylhydroxyl, -alkyl-S--C(O)R.sup.3, and
-alkyl-S--S--S-alkylhydroxy, or together R.sup.1 and R.sup.1 are
-alkyl-S--S-alkyl- to form a cyclic group.
[0718] In one aspect, particularly preferred are compounds wherein
both Y groups are --O-- and R.sup.1 is H.
[0719] In another aspect, particularly preferred are compounds
where both Y groups are --O--, and R.sup.1 is
--CH.sub.2OC(O)OEt.
[0720] More preferred are compounds wherein at least one Y is
--O--, and together R.sup.1 and R.sup.1 are ##STR90## wherein
[0721] V, W, and W' are independently selected from the group
consisting of --H, alkyl, aralkyl, alicyclic, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl,
or
[0722] together V and W are connected via an additional-3 carbon
atoms to form an optionally substituted cyclic group containing 6
carbon atoms and substituted with one substituent selected from the
group consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of
said carbon atoms that is three atoms from a Y attached to the
phosphorus;
[0723] together Z and W are connected via an additional 3-5 atoms
to form a cyclic group, optionally containing one heteroatom, and V
must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0724] together W and W' are connected via an additional 2-5 atoms
to form a cyclic group, optionally containing 0-2 heteroatoms, and
V must be aryl, substituted aryl, heteroaryl, or substituted
heteroaryl;
[0725] Z is selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OC(O)R.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OC(S)OR.sup.3, --CHR.sup.2OC(O)SR.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --OR.sup.2, --SR.sup.2, --R.sup.2,
--NHCOR.sup.2; --NHCO.sub.2R.sup.3, --(CH.sub.2).sub.p--OR.sup.2,
and --(CH.sub.2).sub.p--SR.sup.2;
[0726] p is an integer 2 or 3;
[0727] with the provisos that:
[0728] a) V, Z, W, W' are not all --H;
[0729] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic; and
[0730] c) both Y groups are not --NR.sup.6--;
[0731] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0732] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0733] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0734] In an other aspect, more preferred are compounds wherein one
Y is --O--, and R.sup.1 is optionally substituted aryl; and the
other Y is --NR.sup.6, where R.sup.1 on said NR.sup.6-- is selected
from the group consisting of --C(R.sup.4).sub.2COOR.sup.3, and
--C(R.sup.2).sub.2C(O)OR.sup.3. Particularly preferred are such
compounds where R.sup.1 attached to --O-- is -phenyl, and R1 to
--NH-- is --CH(Me)CO.sub.2Et, and
--NH*CH(Me)CO.sub.2Et is in the L configuration.
[0735] Especially preferred are such compounds where R.sup.1
attached to --O-- is selected from the group consisting of phenyl
and phenyl substituted with 1-2 substituents selected from the
group consisting of --NHAc, --F, --Cl, --Br, --COOEt, and
--CH.sub.3; and R.sup.1 attached to --NR.sup.6, is
--C(R.sup.2).sub.2COOR.sup.3 where R.sup.2 and R.sup.3
independently is --H, --CH.sub.3, and -Et. Of such compounds, when
R.sup.1 attached to --O-- is phenyl substituted with --NHAc or
--COOEt, then preferably any --NHAc is at the 4-position, and any
--COOEt is at the 2-position. More preferred are such compounds
where the substituents on the substituted phenyl is
4--NHC(O)CH.sub.3, --Cl, --Br, 2-C(O)OCH.sub.3CH.sub.3, or
--CH.sub.3.
[0736] More preferred V groups of formula 6-i are aryl, substituted
aryl, heteroaryl, and substituted heteroaryl. Preferably Y is
--O--. Particularly preferred aryl and substituted aryl groups
include phenyl, and phenyl substituted with 1-3 halogens.
Especially preferred are 3,5-dichlorophenyl,
3-bromo-4-fluorophenyl, 3-chlorophenyl, and 3-bromophenyl.
[0737] It is also especially preferred when V is selected from the
group consisting of monocyclic heteroaryl and monocyclic
substituted heteroaryl containing at least one nitrogen atom. Most
preferred is when such heteroaryl and substituted heteroaryl is
4-pyridyl, and 3-bromopyridyl, respectively.
[0738] It is also preferred when together V and Z are connected via
an additional 3-5 atoms to form a cyclic group, optionally
containing 1 heteroatom, that is fused to an aryl group at the beta
and gamma positions to the Y attached to phosphorus. In such
compounds preferably said aryl group is an optionally substituted
monocyclic aryl group and the connection between Z and the gamma
position of the aryl group is selected from the group consisting of
O, CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2 or CH.sub.2O,
[0739] In another aspect, it is preferred when together V and W are
connected via an additional 3 carbon atoms to form an optionally
substituted cyclic group containing 6 carbon atoms and
monosubstituted with one substituent selected from the group
consisting of hydroxy, acyloxy, alkoxycarbonyloxy,
alkylthiocarbonyloxy, and aryloxycarbonyloxy attached to one of
said additional carbon atoms that is three atoms from a Y attached
to the phosphorus. In such compounds, it is more preferred when
together V and W form a cyclic group selected from the group
consisting of --CH.sub.2--CH(OH)--CH.sub.2--,
CH.sub.2CH(OCOR.sup.3)--CH.sub.2--, and
--CH.sub.2CH(OCO.sub.2)R.sup.3)--CH.sub.2--.
[0740] Another preferred V group is 1-alkene. Oxidation by p450
enzymes is known to occur at benzylic and allylic carbons.
[0741] In one aspect, a preferred V group is --H, when Z is
selected from the group consisting of --CHR.sup.2OH,
--CHR.sup.2OCOR.sup.3, and --CHR.sup.2OCO.sub.2R.sup.3.
[0742] In another aspect, when V is aryl, substituted aryl,
heteroaryl, or substituted heteroaryl, preferred Z groups include
--OR.sup.2, --SR.sup.2, --CHR.sup.2N.sub.3, --R.sup.2,
--NR.sup.2.sub.2, --OCOR.sup.2, --OCO.sub.2R.sup.3, --SCOR.sup.3,
--SCO.sub.2R.sup.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--CH.sub.2NHaryl, --(CH.sub.2).sub.pOR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2. More preferred Z groups include
--OR.sup.2, --R.sup.2, --OCOR.sup.2, --OCO.sub.2R.sup.3,
--CH.sub.3, --NHCOR.sup.2, --NHCO.sub.2R.sup.3,
--(CH.sub.2).sub.p--OR.sup.2, and, --(CH.sub.2).sub.p--SR.sup.2.
Most preferred Z groups include OR.sup.2, --H, --OCOR.sup.2,
--OCO.sub.2R.sup.3, and --NHCOR.sup.2.
[0743] Preferred W and W' groups include H, R.sup.3, aryl,
substituted aryl, heteroaryl, and substituted aryl. Preferably, W
and W' are the same group. More preferred is when W and W' are
H.
[0744] In one aspect, prodrugs of formula 6-i are preferred:
##STR91## wherein
[0745] V is selected from the group consisting of aryl, substituted
aryl, heteroaryl, and substituted heteroaryl, 1-alkenyl, and
1-alkynyl. More preferred V groups of formula VI are aryl,
substituted, heteroaryl, and substituted heteroaryl. Preferably Y
is --O--. Particularly preferred aryl and substituted aryl groups
include phenyl and substituted phenyl. Particularly preferred
heteroaryl groups include monocyclic substituted and unsubstituted
heteroaryl groups. Especially preferred are 4-pyridyl and
3-bromopyridyl.
[0746] In one aspect, the compounds of formula VI preferably have a
group Z which is H, alkyl, alicyclic, hydroxy, alkoxy, ##STR92## or
NHCOR. Preferred are such groups in which Z decreases the
propensity of the byproduct, vinyl aryl ketone to undergo Michael
additions. Preferred Z groups are groups that donate electrons to
the vinyl group which is a known strategy for decreasing the
propensity of .alpha.,.beta.-unsaturated carbonyl compounds to
undergo a Michael addition. For example, a methyl group in a
similar position on acrylamide results in no mutagenic activity
whereas the unsubstituted vinyl analog is highly mutagenic. Other
groups could serve a similar function, e.g. Z=OR, NHAc, etc. Other
groups may also prevent the Michael addition especially groups that
result in removal of the double bond altogether such as Z=OH,
--OC(O)R, --OCO.sub.2R, and NH.sub.2, which will rapidly undergo
retautomerization after the elimination reaction. Certain W and W'
groups are also advantageous in this role since the group(s) impede
the addition reaction to the P-carbon or destabilize the product.
Another preferred Z group is one that contains a nucleophilic group
capable of adding to the .alpha.,.beta.-unsaturated double bond
after the elimination reaction i.e. (CH.sub.2).sub.pSH or
(CH.sub.2).sub.nOH where p is 2 or 3. Yet another preferred group
is a group attached to V which is capable of adding to the
.alpha.,.beta.-unsaturated double bond after the elimination
reaction: ##STR93##
[0747] In another aspect, prodrugs of formula 7-i are preferred:
##STR94## wherein
[0748] Z is selected from the group consisting of:
--CHR.sup.2OH, --CHR.sup.2OCOR.sup.3, --CHR.sup.2OC(S)R.sup.3,
--CHR.sup.2OCO.sub.2R.sup.3, --CHR.sup.2OC(O)SR.sup.3, and
--CHR.sup.2OC(S)OR.sup.3. Preferably Y is --O--. More preferred
groups include
--CHR.sup.2OH, --CHR.sup.2OC(O)R.sup.3, and
--CHR.sup.2OCO.sub.2R.sup.3.
[0749] In another aspect, prodrugs of formula 8-i are preferred:
##STR95## wherein
[0750] Z' is selected from the group consisting of --OH,
--OC(O)R.sup.3, --OCO.sub.2 R.sup.3, and --OC(O)SR.sup.3;
[0751] D.sup.4 and D.sup.3 are independently selected from the
group consisting of --H, alkyl, OR.sup.2, --OH, and --OC(O)R.sup.3;
with the proviso that at least one of D.sup.4 and D.sup.3 are --H.
Preferably Y is --O--.
[0752] In one preferred embodiment, W' and Z are --H, W and V are
both the same aryl, substituted aryl, heteroaryl, or substituted
heteroaryl such that the phosphonate prodrug moiety: ##STR96## has
a plane of symmetry. Preferably Y is --O--.
[0753] In another preferred embodiment, W and W' are H, V is
selected from the group consisting of aryl, substituted aryl,
heteroaryl, substituted heteroaryl, and Z is selected from the
group consisting of --H, OR.sup.2, and --NHCOR.sup.2. More
preferred are such compounds where Z is --H.
[0754] p450 oxidation can be sensitive to stereochemistry which
might either be at phosphorus or at the carbon bearing the aromatic
group. The prodrugs of the present invention have two isomeric
forms around the phosphorus. Preferred is the stereochemistry that
enables both oxidation and the elimination reaction. Preferred is
the cis-stereochemistry.
[0755] The preferred compounds of formula 8-i utilize a Z' group
that is capable of undergoing an oxidative reaction that yields an
unstable intermediate which via elimination reactions breaks down
to the corresponding R.sup.5--X--PO.sub.3.sup.2-,
R.sup.5--X--P(O)(NHR.sup.6).sub.2, or
R.sup.5--X--P(O)(O.sup.-)(NHR.sup.6). Especially preferred Z'
groups is OH. Groups D.sup.4 and D.sup.3 are preferably hydrogen,
alkyl, and --OR.sup.2, --OC(O)R.sup.3, but at least one of D.sup.4
or D.sup.3 must be H.
[0756] The following prodrugs of formulae I, II, III, IV, V-1, V-2,
VI, and X are preferred: [0757] Acyloxyalkyl esters; [0758]
Alkoxycarbonyloxyalkyl esters; [0759] Aryl esters; [0760] Benzyl
and substituted benzyl esters; [0761] Disulfide containing esters;
[0762] Substituted (1,3-dioxolen-2-one)methyl esters; [0763]
Substituted 3-phthalidyl esters; [0764]
Cyclic-[5-hydroxycyclohexan-1,3-diyl) diesters and hydroxy
protected forms; [0765]
Cyclic-[2-hydroxymethylpropan-1,3-diyl]diesters and hydroxy
protected forms; [0766] Cyclic-(1-arylpropan-1,3-diyl); [0767] Bis
Omega substituted lactone esters; and all mixed esters resulted
from possible combinations of above esters;
[0768] More preferred are the following: [0769]
Bis-pivaloyloxymethyl esters; [0770] Bis-isobutyryloxymethyl
esters; [0771] Cyclic-[2-hydroxymethylpropan-1,3-diyl]diester;
[0772] Cyclic-[2-acetoxymethylpropan-1,3-diyl]diester; [0773]
Cyclic-[2-methyloxycarbonyloxymethylpropan-1,3-diyl]diester; [0774]
Cyclic-[1-phenylpropan-1,3-diyl]diesters; [0775]
Cyclic-[1-(2-pyridyl)propan-1,3-diyl)]diesters; [0776]
Cyclic-[1-(3-pyridyl)propan-1,3-diyl]diesters; [0777]
Cyclic-[1-(4-pyridyl)propan-1,3-diyl]diesters; [0778]
Cyclic-[5-hydroxycyclohexan-1,3-diyl]diesters and hydroxy protected
forms; [0779] Bis-benzoylthiomethyl esters; [0780]
Bis-benzoylthioethyl esters; [0781] Bis-benzoyloxymethyl esters;
[0782] Bis-p-fluorobenzoyloxymethyl esters; [0783]
Bis-6-chloronicotinoyloxymethyl esters; [0784]
Bis-5-bromonicotinoyloxymethyl esters; [0785]
Bis-thiophenecarbonyloxymethyl esters; [0786] Bis-2-furoyloxymethyl
esters; [0787] Bis-3-furoyloxymethyl esters; [0788] Diphenyl
esters; [0789] Bis-(4-methoxyphenyl)esters; [0790]
Bis-(2-methoxyphenyl)esters; [0791] Bis-(2-ethoxyphenyl)esters;
[0792] Mono-(2-ethoxyphenyl)esters; [0793]
Bis-(4-acetamidophenyl)esters; [0794] Bis-(4-acetoxyphenyl)esters;
[0795] Bis-(4-hydroxyphenyl)esters; [0796]
Bis-(2-acetoxyphenyl)esters; [0797] Bis-(3-acetoxyphenyl)esters;
[0798] Bis-(4-morpholinophenyl)esters; [0799]
Bis-[4-(1-triazolophenyl)esters; [0800]
Bis-(3-N,N-dimethylaminophenyl)esters; [0801]
Bis-(1,2,3,4-tetrahydronapthalen-2-yl)esters; [0802]
Bis-(3-chloro-4-methoxy)benzyl esters; [0803]
Bis-(3-bromo-4-methoxy)benzyl esters; [0804]
Bis-(3-cyano-4-methoxy)benzyl esters; [0805]
Bis-(3-chloro-4-acetoxy)benzyl esters; [0806]
Bis-(3-bromo-4-acetoxy)benzyl esters; [0807]
Bis-(3-cyano-4-acetoxy)benzyl esters; [0808] Bis-(4-chloro)benzyl
esters; [0809] Bis-(4-acetoxy)benzyl esters; [0810]
Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters; [0811]
Bis-(3-methyl-4-acetoxy)benzyl esters; [0812] Bis-(benzyl)esters;
[0813] Bis-(3-methoxy-4-acetoxy)benzyl esters; [0814]
Bis-(6'-hydroxy-3',4'-dithia)hexyl esters; [0815]
Bis-(6'-acetoxy-3',4'-dithia)hexyl esters; [0816]
(3,4-dithiahexan-1,6-diyl)esters; [0817]
Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters; [0818]
Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters; [0819]
Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters; [0820]
Bis-3-(5,6,7-trimethoxy)phthalidyl esters; [0821]
Bis-(cyclohexyloxycarbonyloxymethyl)esters; [0822]
Bis-(isopropyloxycarbonyloxymethyl)esters; [0823]
Bis-(ethyloxycarbonyloxymethyl)esters; [0824]
Bis-(methyloxycarbonyloxymethyl)esters; [0825]
Bis-(isopropylthiocarbonyloxymethyl)esters; [0826]
Bis-(phenyloxycarbonyloxymethyl)esters; [0827]
Bis-(benzyloxycarbonyloxymethyl)esters; [0828]
Bis-(phenylthiocarbonyloxymethyl)esters; [0829]
Bis-(p-methoxyphenoxycarbonyloxymethyl)esters; [0830]
Bis-(m-methoxyphenoxycarbonyloxymethyl)esters; [0831]
Bis-(o-methoxyphenoxycarbonyloxymethyl)esters; [0832]
Bis-(o-methylphenoxycarbonyloxymethyl)esters; [0833]
Bis-(p-chlorophenoxycarbonyloxymethyl)esters; [0834]
Bis-(1,4-biphenoxycarbonyloxymethyl)esters; [0835]
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters; [0836]
Bis-(N-phenyl-N-methylcarbamoyloxymethyl)esters; [0837]
Bis-(2,2,2-trichloroethyl)esters; [0838] Bis-(2-bromoethyl)esters;
[0839] Bis-(2-iodoethyl)esters; [0840] Bis-(2-azidoethyl)esters;
[0841] Bis-(2-acetoxyethyl)esters; [0842] Bis-(2-aminoethyl)esters;
[0843] Bis-(2-N,N-dimethylaminoethyl)esters; [0844]
Bis-(2-aminoethyl)esters; [0845] Bis-(methoxycarbonylmethyl)esters;
[0846] Bis-(2-aminoethyl)esters; [0847]
Bis-[N,N-di(2-hydroxyethyl)]carbamoylmethylesters; [0848]
Bis-(2-aminoethyl)esters; [0849]
Bis-(2-methyl-5-thiazolomethyl)esters; [0850]
Bis-(bis-2-hydroxyethylcarbarnoylmethyl)esters. [0851]
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(N(H)--CH(Me)CO.sub.2Et) [0852]
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(N(H)--CH(Me)CO.sub.2Me) [0853]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-3-Cl)(NH--CH(Me)CO.sub.2Et) [0854]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2--Cl)(NH--CH(Me)CO.sub.2Et) [0855]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4--Cl)(NH--CH(Me)CO.sub.2Et) [0856]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4--NHAc)(NH--CH(Me)CO.sub.2Et) [0857]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--CH(Me)CO.sub.2Et) [0858]
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Et) [0859]
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Me) [0860]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-3--Cl)(NH--C(Me).sub.2CO.sub.2Et) [0861]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-2--Cl)(NH--C(Me).sub.2CO.sub.2Et) [0862]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-4--Cl)(NH--C(Me).sub.2CO.sub.2Et) [0863]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidate-
s (--P(O)(OPh-4--NHAc)(NH--C(Me).sub.2CO.sub.2Et) [0864]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoram-
idates (--P(O)(OPh-2-CO.sub.2Et)(NH--C(Me).sub.2CO.sub.2Et) [0865]
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Et) [0866]
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Me) [0867]
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-3-C1)(NH--CH.sub.2CO.sub.2Et) [0868]
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--CH.sub.2CO.sub.2Et) [0869]
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4--Cl)(NH--CH.sub.2CO.sub.2Et) [0870]
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4--NHAc)(NH--CH.sub.2CO.sub.2Et) [0871]
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--CH.sub.2CO.sub.2Et)
[0872] Most preferred are the following: [0873]
Bis-pivaloyloxymethyl esters; [0874] Bis-isobutyryloxymethyl
esters; [0875] Cyclic-(2-hydroxymethylpropan-1,3-diyl)ester; [0876]
Cyclic-(2-acetoxymethylpropan-1,3-diyl)ester; [0877]
Cyclic-(2-methyloxycarbonyloxymethylpropan-1,3-diyl)ester; [0878]
Cyclic-(2-cyclohexylcarbonyloxymethylpropan-1,3-diyl)ester; [0879]
Cyclic-[phenylpropan-1,3-diyl]diesters; [0880]
Cyclic-[1-(2-pyridyl)propan-1,3-diyl)]diesters; [0881]
Cyclic-[1-(3-pyridyl)propan-1,3-diyl]diesters; [0882]
Cyclic-[1-(4-pyridyl)propan-1,3-diyl]diesters; [0883]
Cyclic-[5-hydroxycyclohexan-1,3-diyl]diesters and hydroxy protected
forms; [0884] Bis-benzoylthiomethyl esters; [0885]
Bis-benzoylthioethylesters; [0886] Bis-benzoyloxymethyl esters;
[0887] Bis-p-fluorobenzoyloxymethyl esters; [0888]
Bis-6-chloronicotinoyloxymethyl esters; [0889]
Bis-5-bromonicotinoyloxymethyl esters; [0890]
Bis-thiophenecarbonyloxymethyl esters; [0891] Bis-2-furoyloxymethyl
esters; [0892] Bis-3-furoyloxymethyl esters; [0893] Diphenyl
esters; [0894] Bis-(2-methylphenyl)esters; [0895]
Bis-(2-methoxyphenyl)esters; [0896] Bis-(2-ethoxyphenyl)esters;
[0897] Bis-(4-methoxyphenyl)esters; [0898]
Bis-(3-bromo-4-methoxybenzyl)esters; [0899]
Bis-(4-acetoxybenzyl)esters; [0900]
Bis-(3,5-dimethoxy-4-acetoxybenzyl)esters; [0901]
Bis-(3-methyl-4-acetoxybenzyl)esters; [0902]
Bis-(3-methoxy-4-acetoxybenzyl)esters; [0903]
Bis-(3-chloro-4-acetoxybenzyl)esters; [0904]
Bis-(cyclohexyloxycarbonyloxymethyl)esters; [0905]
Bis-(isopropyloxycarbonyloxymethyl)esters; [0906]
Bis-(ethyloxycarbonyloxymethyl)esters; [0907]
Bis-(methyloxycarbonyloxymethyl)esters; [0908]
Bis-(isopropylthiocarbonyloxymethyl)esters; [0909]
Bis-(phenyloxycarbonyloxymethyl)esters; [0910]
Bis-(benzyloxycarbonyloxymethyl)esters; [0911]
Bis-(phenylthiocarbonyloxymethyl)esters; [0912]
Bis-(p-methoxyphenoxycarbonyloxymethyl)esters; [0913]
Bis-(m-methoxyphenoxycarbonyloxymethyl)esters; [0914]
Bis-(o-methoxyphenoxycarbonyloxymethyl)esters; [0915]
Bis-(o-methylphenoxycarbonyloxymethyl)esters; [0916]
Bis-(p-chlorophenoxycarbonyloxymethyl)esters; [0917]
Bis-(1,4-biphenoxycarbonyloxymethyl)esters; [0918]
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters; [0919]
Bis-(6-hydroxy-3,4-dithia)hexyl esters; [0920]
Cyclic-(3,4-dithiahexan-1,6-diyl)esters; [0921]
Bis-(2-bromoethyl)esters; [0922] Bis-(2-aminoethyl)esters; [0923]
Bis-(2-N,N-diaminoethyl)esters; [0924]
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--*CH(Me)CO.sub.2Et) [0925]
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--*CH(Me)CO.sub.2Me) [0926]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-3-C1)(NH--*CH(Me)CO.sub.2Et) [0927]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2--Cl)(NH--*CH(Me)CO.sub.2Et) [0928]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4-C1)(NH--*CH(Me)CO.sub.2Et) [0929]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4--NHAc)(NH--*CH(Me)CO.sub.2Et) [0930]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--*CH(Me)CO.sub.2Et) [0931]
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Et) [0932]
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Me) [0933]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-3--Cl)(NH--C(Me).sub.2CO.sub.2Et) [0934]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-2--Cl)(NH--C(Me).sub.2CO.sub.2Et) [0935]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-4--Cl)(NH--C(Me).sub.2CO.sub.2Et) [0936]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidate-
s (--P(O)(OPh-4--NHAc)(--C(Me).sub.2CO.sub.2Et) [0937]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoram-
idates (--P(O)(OPh-2-CO.sub.2Et)(NH--C(Me).sub.2CO.sub.2Et)
[0938] In the above prodrugs an asterisk (*) on a carbon refers to
the L-configuration. [0939]
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Et) [0940]
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Me) [0941]
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-3--Cl)(NH--CH.sub.2CO.sub.2Et) [0942]
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2--Cl)(NH--CH.sub.2CO.sub.2Et) [0943]
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4--Cl)(NH--CH.sub.2CO.sub.2Et) [0944]
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4--NHAc)(--CH.sub.2CO.sub.2Et) [0945]
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--CH.sub.2CO.sub.2Et)
[0946] The compounds designated in Table 1 refer to preferred
compounds of formula I-A where M is R.sup.5--X-- as defined in the
following formulae: formula i, formula ii, and formula iii.
##STR97##
[0947] In the above formulae i, ii, and iii, R.sup.5 may be
substituted by A and B. The preferred compounds of formulae i, ii,
and iii are listed in Table 1 by designated numbers assigned to
R.sup.5, A, B, Q.sup.1, and Q.sup.2 in the above formulae i, ii,
and iii according to the following convention:
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.5, A, B,
Q.sup.1 and Q.sup.2.
[0948] Variable R.sup.5 is divided into two groups, each listing
four different structures.
[0949] Compounds named in Table 1 of formulae i, ii, and iii
wherein the R.sup.5 moieties are assigned the following
numbers:
[0950] Group 1: TABLE-US-00001 1 2 3 4 R.sup.5 ##STR98## ##STR99##
##STR100## ##STR101##
[0951] Group 2: TABLE-US-00002 1 2 3 4 R.sup.5 = ##STR102##
##STR103## ##STR104## ##STR105##
[0952] Variable A moieties are assigned the following numbers:
TABLE-US-00003 1 2 3 4 A = NH2 H Me Cl
[0953] Variable B moieties are assigned the following numbers:
TABLE-US-00004 1 2 3 4 5 6 7 8 B = --SCH3 -iBu -cPr -S-nPr -SEt
-iPr -nPr --CH2cPr
[0954] Variables Q.sup.1 and Q.sup.2 are divided into three groups,
each listing eight different substituents.
[0955] Q.sup.1 and Q.sup.2 moieties are assigned the following
numbers:
Group 1:
Q.sup.1 and Q.sup.2
1. --NH--CH2--C(O)R14
2. --NH--CH(CH3)--C(O)R14
3. --NH--C(CH3)2--C(O)R14
4. --NH--C(CH3)2CH2--C(O)R14
5. --NH--CH(CH(CH3)2))-C(O)R14
6. --NH--CH(CH2(CH(CH3)2)))-C(O)R14
7. --NH--CH(CH2CH2SCH3)--C(O)R14
8. --NH--CH(CH2SCH2Ph)--C(O)R14
Group 2:
Q.sup.1 and Q.sup.2
1. --NH--CH2CH2--C(O)R14
2. --NH--CH(CH2CH2COR14)--C(O)R14
3. --NH--CH(CH2COR14)--C(O)R14
4. --NH--CH(CH2CONH2)--C(O)R14
5. --NH--CH(COR14)CH2-C(O)R14
6. --NH--CH(CH2OR17)--C(O)R14
7. --NH--CH(CH2CH2COR14)--C(O)R14
8. --NH--CH(CH20H)--C(O)R14
Group 3:
Q.sup.1 and Q.sup.2
1. --NH--CH(CH2--C6H5OH)--C(O)R14
2. --NH--C(c-propyl)-C(O)R14
3. --NH--C(c-pentyl)-C(O)R14
4. --NH--C(c-hexyl)-C(O)R14
5. --NH--CH(CH2Ph)--C(O)R14
6. --N(CH3)--CH2--C(O)R14
[0956] 7. ##STR106## 8. --NR18R19 where R.sup.4 is selected from
the groups consisting of OMe, OEt, OBn, O-tBu, O-nPr, OPh,
--N(Me).sub.2, morpholine, SMe, SEt; R.sup.17 is methyl, ethyl,
benzyl, and propyl; R.sup.18 is H, Me, Et, Bn, Pr and Ph and R19 is
Me, Et, Bn, Pr and Ph; R18 and R19 is morpholinyl and
pyrrolidinyl.
[0957] Thus, the compound 3.3.1.2.1 in Group 1 corresponds to the
structure below for formula i: ##STR107## and when R4 is ethoxy the
structure would be ##STR108##
[0958] The numbers designated in Table 1 also refer to preferred
benzothiazole and benzoxazole compounds of formula X. These
preferred compounds are shown in formulae iv and v. ##STR109##
[0959] The preferred 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.
[0960] Variables Q.sup.1 and Q.sup.2 are divided into three groups,
each listing eight different substituents.
Group 1:
Q.sup.1 and Q.sup.2 moieties are assigned the following
numbers:
Q.sup.1 and Q.sup.2
1. --NH--CH2--C(O)R14
2. --NH--CH(CH3)--C(O)R14
3. --NH--C(CH3)2--C(O)R14
4. --NH--C(CH3)2CH2--C(O)R14
5. --NH--CH(CH(CH3)2))-C(O)R14
6. --NH--CH(CH2(CH(CH3)2)))-C(O)R14
7. --NH--CH(CH2CH2SCH3)--C(O)R14
8. --NH--CH(CH2SCH2Ph)--C(O)R14
Group 2:
Q.sup.1 and Q.sup.2
1. --NH--CH2CH2--C(O)R14
2. --NH--CH(CH2CH2COR14)--C(O)R14
3. --NH--CH(CH2COR14)--C(O)R14
4. --NH--CH(CH2CONH2)--C(O)R14
5. --NH--CH(COR14)CH2--C(O)R14
6. --NH--CH(CH2OR17)--C(O)R14
7. --NH--CH(CH2CH2COR14)--C(O)R14
8. --NH--CH(CH20H)--C(O)R14
Group 3:
Q.sup.1 and Q.sup.2
1. --NH--CH(CH2--C6H5OH)--C(O)R14
2. --NH--C(c-propyl)-C(O)R14
3. --NH--C(c-pentyl)-C(O)R14
4. --NH--C(c-hexyl)-C(O)R14
5. --NH--CH(CH2Ph)-C(O)R14
6. --N(CH3)--CH2--C(O)R14
[0961] 7. ##STR110## 8. --NR18R19
[0962] Variable B is divided into three groups, each listing eight
different substituents.
Group 1:
[0963] B moieties are assigned the following numbers:
TABLE-US-00005 1 2 3 4 5 6 7 8 B = H Me Et nPr Br iPr Cl cPr
[0964] Group 2: TABLE-US-00006 1 2 3 4 5 6 7 8 B = CN F OMe OEt SMe
SEt 2-furanyl C(O)OEt
[0965] Group 3: TABLE-US-00007 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)
[0966] Group 3 for Variable B can only be combined with Group 3
variable for D.
[0967] Variable D is divided into three groups, each listing four
different substituents.
[0968] Group 1: TABLE-US-00008 1 2 3 4 D = H Me Et SCN
Group 2:
[0969] Variable D is replaced with the moieties assigned in the
following numbers: TABLE-US-00009 1 2 3 4 D = SMe SEt CH2OMe
OMe
[0970] Group 3: TABLE-US-00010 1 2 3 4 D = null null null null
[0971] Compounds named in Table 1 of formulae iv and v wherein the
A moieties are assigned the following numbers: TABLE-US-00011 1 2 3
4 A = NH2 H Me Cl
where R4 is selected from the groups consisting of OMe, OEt, OBn,
O-tBu, O-nPr, OPh, --N(Me).sub.2, morpholine, SMe, SEt; R17 is
methyl, ethyl, benzyl, and propyl; R18 is H, Me, Et, Bn, Pr and Ph
and R19 is Me, Et, Bn, Pr and Ph; R18 and R19 is morpholinyl and
pyrrolidinyl
[0972] 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
##STR111## and when R4 is ethoxy the structure would be
##STR112##
[0973] Similarly, in group 3 for variable B, the compound 2.2.1.7.4
corresponds to the structure below for formula iv ##STR113##
[0974] and when R4 is ethoxy the structure would be TABLE-US-00012
TABLE 1 ##STR114## 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.L.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
5.4.3.3.1 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 5.7.2.5.4 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
7.6.2.5.4 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 7.8.4.4.3 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
[0975] The best mode of practicing the claimed invention is with
compounds of Example numbers 48.6, 48.9, 48.15, and 48.20.
[0976] Preferred insulin sensitizers are compounds disclosed in the
following publications and patents: [0977] (1) Tamura et al.
W09737688 [0978] (2) Nagao et al., Eur. Pat. Appl. EP-787727 [0979]
(3) Kallam et al. Can. Pat. Appl. CA2173660 AA [0980] (4) Inman et
al. W09639401 A1 [0981] (5) Yanagisawa et al. W09638427 [0982] (6)
Fujita et al., EP-745600 A1 [0983] (7) Ohara et al., W09626207 A1
[0984] (8) Ohara et al. W09611196 A1 [0985] (9) Malamas et al.,
U.S. Pat. No. 5,532,256 A [0986] (10) Yanagisawa et al., EP-708098
A1 [0987] (11) Regnier et al., U.S. Pat. No. 5,478,853 A [0988]
(12) U.S. Pat. No. 5,468,762 A [0989] (13) Ohara et al., W0952637
A1 [0990] (14) Antonucci et al. U.S. Pat. No. 5,457,109 A [0991]
(15) Yoshioka et al. JP07002852 A2 [0992] (16) Shibata et al.,
W09401433 A1 [0993] (17) Fujita et al., EP-543662 A2 [0994] (18) De
Nanteuil et al., EP-559571 A1 [0995] (19) Zask et al., U.S. Pat.
No. 5,236,941 A [0996] (20) Ohnota et al., W09214719 [0997] (21)
Miyaoka et al., EP-489663 A1 [0998] (22) Arita et al., EP-506273 A2
[0999] (23) Hulin et al., J. Med. Chem. 35, 1853 (1992) [1000] (24)
Zask et al., J. Med. Chem. 33: 1418-1423 (1990) [1001] (25) Clark
U.S. Pat. No. 4,791,125A [1002] (26) Iijima et al., EP-283035 A1
[1003] (27) Kees et al., U.S. Pat. No. 4,728,739 A [1004] (28)
Meguro et al., EP-177353 A2 [1005] (29) Hasler et al., EP-129747 A2
[1006] (30) Kawamatsu et al., EP-91761 A2 [1007] (31) Tontonez et
al. Gene & Develop 8: 1224-1234 (1994) [1008] (32) Tontonez et
al. Cell 79: 1147-1156 [1009] (33) Lehmann et al., J. Biol. Chem.
270, 1-4 (1994) [1010] (34) Amri et al. J. Lipid Res. 32: 1449-1456
(1991) [1011] (35) Grimaldi et al. Proc. Natl. Acad. Sci. USA 89:
10930 (1992) [1012] (36) EP0745600
[1013] All references are incorporated by reference. While such
disclosures constitute a large number of the insulin sensitizers,
the instant invention is not so limited and can utilize any insulin
sensitizer compound. The insulin sensitizers encompassed by the
invention are compounds that improve insulin sensitivity as
measured, for instance, by conducting standard assays such as those
described in Examples H through M.
[1014] More preferred are the following insulin sensitizers:
##STR115## ##STR116##
[1015] Especially preferred PPAR .gamma. agonists are Troglitazone,
Pioglitazone, ciglitazone, WAY-120,744, englitazone, AD 5075,
SB219994, SB219993, BRL49653, G1-262570, darglitazone and analogs
thereof.
[1016] Preferred RXR ligands are described in e.g. Heyman et al.,
WO9710819 A1; Especially preferred RXR ligands are LG100268, LGD
1069, ALRT 1057 and analogs thereof.
[1017] Other classes of insulin sensitizers are within the scope of
the invention and include non-thiazolidinediones) such as SB 236636
and SB 219994, which are 3-aryl-2-alkoxy propanoic acids, PKC
inhibitors, angiotensin II antagonists, and angiotensin converting
enzyme inhibitors.
[1018] As expected from their mechanism of action,
insulin-sensitizers are primarily effective in the
hyperinsulinemic, early stages of type 2 diabetes. Efficacy is
considerably reduced in advanced diabetes which is associated with
severely disturbed beta-cell function and hence diminished insulin
levels. This drug profile has been observed both in animal models
of the disease as well as in the clinic. Hyperglycemia in young,
hyperinsulinemic ZDF rats, for instance, is completely reversed by
treatment with Troglitazone. Sreenan et al. Am. J. Physiol. 271:
E742-747. ZDF rats in a more advanced, hypoinsulinemic phase of the
disease, however, respond poorly to insulin sensitizer treatment.
Brown et al. Diabetes 48: 1415-1424 (1999). In addition,
hypoinsulinemic, streptozotocin induced diabetic mice do not
respond to Troglitazone treatment. Fujiwara et al. Diabetes 37:
1549-1558 (1988). Clinical trials with Troglitazone have brought to
light similarly variable responses in type 2 diabetics, with the
non-response rate ranging from 35-62%. Valiquett T. et al. Diabetes
44-(Suppl. 1): 406A (1995). In these trials it was found that the
best predictor of efficacy was fasting insulin C peptide levels;
the higher the C-peptide level, the greater the glucose-lowering
effect in patients. Maggs D G et al. Ann. Intern. Med. 128:176-185
(1998). Patients with sufficient pancreatic insulin secretory
function thus respond well to therapy, whereas patients with
decreased pancreatic function, characteristic of more advanced
diabetes, respond poorly or are non-responders to therapy.
[1019] Insulin sensitizer treatment in general falls short of
restoring euglycemia or normalizing HbA1c levels in patients. In
clinical trials with Pioglitazone, for example, average blood
glucose lowering and HbA1c reductions were .about.50 mg/dl and
0.6%, respectively. Mathisen et al. Diabetes 48 (Suppl. 1): 441A
(1998). In the patient populations treated, average reductions of
>140 mg/dl and >3% would have been necessary to restore these
parameters to normal values. A high rate of non-response and
overall modest reductions in blood glucose levels have also been
observed in clinical trials with Rosiglitazone. Patel et al.
Diabetes, Obesity, and Metabolism 1: 165-172 (1999). There thus
appears ample opportunity for agents such as the FBPase inhibitors
to provide a benefit in combination with insulin sensitizers in the
clinic.
[1020] FBPase inhibitors are likely to be efficacious both in early
and advanced stages of type 2 diabetes. In animal studies they
significantly lowered blood glucose in the hyperinsulinemic db/db
mouse (a model of early type 2 diabetes, Examples S and T) as well
as in a model of advanced type 2 diabetes: the insulinopenic
streptozotocin-induced diabetic rat. In the ZDF rat, FBPase
inhibitors were effective both in early diabetes (8-9 weeks of age,
Examples N-R) as well as in advanced diabetes (16 weeks of age).
Based on the pharmacological profile described above, the
combination of FBPase inhibitors and insulin sensitizers will be
effective across a broad patient population. In early stage
diabetics, the insulin sensitizer and FBPase inhibitor are both
likely to be fully effective, whereas in advanced diabetics, the
response to insulin sensitizers may be partial whereas the FBPase
inhibitor will maintain robust efficacy. The benefit of the
combination in advanced diabetes will be a significant reduction in
the number of non-responders to therapy (Example R). While the
initial response of the combination may in large part be due to
treatment with the FBPase inhibitor, blood glucose lowering may
improve pancreatic function (Example P) and allow the insulin
sensitizer to become more fully effective over time and in the long
term provide enhanced glycemic control. In some cases, insulin
sensitizers are best used in combination with agents that improve
the actions of the insulin sensitizer, such as insulin, insulin
analogs, RXR ligands, or insulin secretagogues (eg. the
sulfonylureas). With the actions of the insulin sensitizer thus
enhanced, combination treatment with an FBPase inhibitor will
result in more effective glycemic control. Moreover, long term
treatment will diminish the need for agents that enhance insulin
levels.
[1021] FBPase inhibitors lower blood glucose both in the fasted
(example T) and the fed state (examples N-S). This provides a broad
opportunity for therapy in combination with insulin sensitizers.
The combination could, for instance, be administered at mealtime
and provide enhanced glycemic control over either agent alone by
simultaneously enhancing glucose disposal and reducing the
contribution of gluconeogenesis to hyperglycemia during the
postprandial period. Meal time administration has the additional
benefit of reducing the potential risk of hypoglycemia that could
ensue from treatment with an FBPase inhibitor. Another possible
dosing regimen may be the administration of the insulin sensitizer
during the daytime, and administration of the FBPase inhibitor
separately at bedtime. The insulin sensitizer will thus provide
glycemic control by enhancing glucose disposal following daytime
meals, whereas the FBPase inhibitor will control excessive glucose
production by the liver known to occur to a greater extent during
the overnight fast. There is precedent for the use of a hepatic
glucose production suppressor during the overnight fast; insulin
has been widely used in this application. Riddle, The Lancet
192-195 (1985).
[1022] An additional benefit of combination treatment is that it
will allow a reduction in dose of both agents thereby reducing
potential side effects. The most common side-effect of
Troglitazone, for example, is hepatotoxicity which manifests itself
as the elevation of liver enzymes (1% of patients). This
side-effect has resulted in a recommendation for liver function
monitoring every month for the first six months of treatment. In
addition, an association between Troglitazone and increased heart
weight in animals has led to recommendations that this drug be used
cautiously in patients with congestive heart failure. Rosiglitazone
treatment, although not reported to cause liver enzyme elevations,
is known to significantly decrease haematocrit. All insulin
sensitizers cause weight gain. As discussed above, in some cases
efficacy with an insulin sensitizer can only be achieved with
supplemental insulin or sulfonylurea administrations. Insulin has
the undesirable side-effects of promoting weight gain, of
exacerbating insulin resistance, and predisposing to hypoglycemia.
Sulfonylureas also promote weight gain, increase the risk of
hypoglycemia, and by overstimulating the pancreas can promote
beta-cell degeneration. In certain animal models, FBPase inhibitors
are known to elevate blood lactate and triglycerides and could
therefore predispose to systemic acidosis and the vascular
complication associated with hypertriglyceridemia. Combination
treatment with an insulin sensitizer may suppress the potential
lactate and triglyceride elevations associated with FBPase
inhibitor treatment (Examples O and Q). Other side effects of
FBPase inhibitors may manifest themselves in man. By treating
patients with the combination of an insulin sensitizer and an
FBPase inhibitor, the reduced dosages feasible are likely to
significantly decrease the risks of the (potential) side-effects
associated with the individual therapies.
[1023] While an insulin sensitizer-FBPase inhibitor combination is
primarily envisaged for the treatment of type 2 diabetes and the
associated renal, neuronal, retinal, micro- and macro-vascular and
metabolic complications, treatment of other diseases that respond
to improved glycemic control and improved insulin sensitivity is
also possible. Patients with impaired glucose tolerance (IGT) are
minimally hyperglycemic under ordinary circumstances but can become
hyperglycemic following the ingestion of large glucose loads. IGT
is a predictor of future diabetes and patients with this condition
have become the target of diabetes prevention trials in recent
years. Combination treatment of these patients, particularly at
mealtime, restores a normal glucose response and reduces the risk
of the development of diabetes. Another distinct group of subjects
at high risk for the development of type 2 diabetes are women who
suffer from polycystic ovary syndrome (POCS). Combination treatment
is of benefit in these patients as well since they are typically,
hyperinsulinemic, insulin resistant, and can suffer from IGT.
Combination treatment is also useful for treating renal dysfunction
and hypertension particularly in obese, insulin resistant,
hyperinsulinemic patients with IGT. Other applications of
combination treatment include gestational diabetes, poorly
controlled type 1 diabetes, obesity and dyslipidemia.
Formulations
[1024] 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.
[1025] Intraarterial and intravenous injection as used herein
includes administration through catheters. Oral administration is
generally preferred.
[1026] 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.
[1027] 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.
[1028] 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.
[1029] 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.
[1030] 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.
[1031] 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.
[1032] 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.
[1033] 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.
[1034] Compounds of the invention may be administered as a daily
dose or an appropriate fraction of the daily dose (e.g. bid).
Administration of the FBPase inhibitor may occur at or near the
time in which the insulin sensitizer active ingredient is
administered or at a different time. Simultaneous administration of
the active ingredients is achieved either by administration of the
active ingredients in the same or different formulations.
Formulations include time-release formulations intended to release
either both of the active ingredients simultaneously or to stage
the release of the active ingredients such that release, absorption
and systemic exposure occurs with one of the ingredients before the
other.
[1035] 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 formulation intended for oral
administration to humans may contain 20 to 2000 .mu.mol
(approximately 10 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.
[1036] 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 nonaqueous
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.
[1037] 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.
[1038] 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.
[1039] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[1040] 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.
[1041] 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. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and
tablets of the kind previously described.
[1042] Preferred unit dosage formulations are those containing a
daily dose or unit, daily sub-dose, or an appropriate fraction
thereof, a fructose-1,6-bisphosphatase inhibitor compound and an
insulin sensitizer.
[1043] 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.
[1044] Capsules comprising FBPase inhibitors suitable for oral
administration according to the methods of the present invention
may be prepared as follows: (1) for a 10,000 capsule preparation:
up to 5000 g of FBPase inhibitor is blended with other ingredients
(as described above) and filled into capsules which are suitable
for administration depending on dose, from about 1 capsules per day
to about 8 capsules per day (2 capsules per 6 hours), to an adult
human.
[1045] Capsules comprising insulin sensitizers suitable for oral
administration according to the methods of the present invention
may be prepared as follows: (1) for a 10,000 capsule preparation:
up to 5600 g of insulin sensitizer is blended with other
ingredients (as described above) and filled into capsules which are
suitable for administration depending on dose, from about 1
capsules per day to about 8 capsules per day (2 capsules per 6
hours), to an adult human.
[1046] Capsules comprising FBPase inhibitors and insulin
sensitizers suitable for oral administration according to the
methods of the present invention may be prepared as follows: (1)
for a 10,000 capsule preparation: up to 2500 g of FBPase inhibitor
and up to 2500 g of insulin sensitizer are blended with other
ingredients (as described above) and filled into capsules which are
suitable for administration depending on dose, from about 1
capsules per day to about 8 capsules per day (2 capsules per 6
hours), to an adult human.
EXAMPLES
[1047] Compounds of formula VI are prepared according to the
literature procedures with modifications and additions well
understood by those skilled in the art. In general, these compounds
are synthesized by the method of Srivastava, J. Med. Chem. (1976).
Other methodology is described by Wood et al. J. Med. Chem. 28:
1198-1203 (1985); Sagi et al., J. Med. Chem. 35: 4549-4556 (1992);
Paul, Jr. J. Med. Chem. 28: 1704-1716 (1985); Cohen et al., J. Am.
Chem. Soc. 95: 4619-4624 (1973).
[1048] Compounds of formulae II-IV are prepared according to the
procedures described in PCT publication numbers WO 98/39344, WO
98/39343, and WO 98/39342.
Section 1.
Synthesis of Compounds of Formula I
[1049] 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 2 wherein R.sup.5 is a 5-membered
heteroaromatic ring. Compounds of formula 2 wherein R.sup.5 is a
6-member heteroaromatic ring or other heteroaromatic rings are
prepared in an analogous manner. ##STR117## (1a) Preparation of a
Phosphonate Prodrug
[1050] Prodrugs can be introduced at different stages of the
synthesis. Most often these prodrugs are made from the phosphonic
acids of formula 2, because of their lability. Advantageously,
these prodrugs can be introduced at an earlier stage, provided that
it can withstand the reaction conditions of the subsequent
steps.
[1051] Compounds of formula 2, can be alkylated with electrophiles
(such as alkyl halides, alkyl sulfonates, etc) under nucleophilic
substitution reaction conditions to give phosphonate esters. For
example, compounds of formula I, wherein R.sup.1 is an acyloxyalkyl
group can be synthesized through direct alkylation of compounds of
formula 2 with an appropriate acyloxyalkyl halide (e.g. Cl, Br, I;
Elhaddadi, et al Phosphorus Sulfur, 1990, 54(1-4): 143; Hoffmann,
Synthesis, 1988, 62) in the presence of a base (e.g.
N,N'-dicyclohexyl-4-morpholinecarboxamidine, Hunigs base, etc.) in
suitable solvents such as 1,1-dimethyl formamide ("DMF") (Starrett,
et al, J. Med. Chem., 1994, 1857). The carboxylate component of
these acyloxyalkyl halides includes but is not limited to acetate,
propionate, isobutyrate, pivalate, benzoate, and other
carboxylates. When appropriate, further modification are envisioned
after the formation of these acyloxyalkyl phosphonate esters such
as reduction of a nitro group. For example, compounds of formula 3
wherein A is a NO.sub.2 group can be converted to compounds of
formula 3 wherein A is an H.sub.2N-- group under suitable reduction
conditions (Dickson, et al, J. Med. Chem., 1996, 39: 661; Iyer, et
al, Tetrahedron Lett., 1989, 30: 7141; Srivastva, et al, Bioorg.
Chem., 1984, 12: 118). These methods can be extended to the
synthesis of other types of prodrugs, such as compounds of formula
I where R.sup.1 is a 3-phthalidyl, a
2-oxo-4,5-didehydro-1,3-dioxolanemethyl, or a
2-oxotetrahydrofuran-5-yl group (Biller et al., U.S. Pat. No.
5,157,027; Serafinowska et al., J. Med. Chem. 1995, 38: 1372;
Starrett et al., J. Med. Chem. 1994, 37: 1857; Martin et al., J.
Pharm. Sci. 1987, 76: 180; Alexander et al., Collect. Czech. Chem.
Commun, 1994, 59: 1853; EPO 0632048A1). N,N-Dimethylformamide
dialkyl acetals can also be used to alkylate phosphonic acids
(Alexander, P., et al Collect. Czech. Chem. Commun., 1994, 59,
1853).
[1052] Alternatively, these phosphonate prodrugs can also be
synthesized by reactions of the corresponding dichlorophosphonates
with an alcohol (Alexander et al, Collect. Czech. Chem. Commun.,
1994, 59: 1853). For example, reactions of a dichlorophosphonate
with substituted phenols and aralkyl alcohols in the presence of
base (e.g. pyridine, triethylamine, etc) yield compounds of formula
V where R.sup.1 is an aryl group (Khamnei et al., J. Med. Chem.,
1996, 39: 4109; Serafinowska et al., J. Med. Chem., 1995, 38: 1372;
De Lombaert et al., J. Med. Chem., 1994, 37: 498) or an arylalkyl
group (Mitchell et al., J. Chem. Soc. Perkin Trans. 1, 1992, 38:
2345). The disulfide-containing prodrugs (Puech et al., Antiviral
Res., 1993, 22: 155) can also be prepared from a
dichlorophosphonate and 2-hydroxyethyl disulfide under standard
conditions.
[1053] Such reactive dichlorophosphonates can be generated from the
corresponding phosphonic acids with a chlorinating agent (e.g.
thionyl chloride: Starrett et al., J. Med. Chem., 1994, 1857,
oxalyl chloride: Stowell et al., Tetrahedron Lett., 1990, 31: 3261,
and phosphorus pentachloride: Quast et al., Synthesis, 1974, 490).
Alternatively, a dichlorophosphonate can also be generated from its
corresponding disilyl phosphonate esters (Bhongle et al., Synth.
Commun., 1987, 17: 1071) or dialkyl phosphonate esters (Still et
al., Tetrahedron Lett., 1983, 24: 4405; Patois et al., Bull. Soc.
Chim. Fr., 1993, 130: 485).
[1054] Furthermore, these prodrugs can be prepared using Mitsunobu
reactions (Mitsunobu, Synthesis, 1981, 1; Campbell, J. Org. Chem.,
1992, 52: 6331), and other coupling reactions (e.g. using
carbodiimides: Alexander et al., Collect. Czech. Chem. Commun.,
1994, 59: 1853; Casara et al., Bioorg. Med. Chem. Lett., 1992, 2:
145; Ohashi et al., Tetrahedron Lett., 1988, 29: 1189, and
benzotriazolyloxytris-(dimethylamino)phosphonium salts: Campagne et
al., Tetrahedron Lett., 1993, 34: 6743). Compounds of formula I
wherein R.sup.1 is a cyclic carbonate, a lactone or a phthalidyl
group can also be synthesized via direct alkylation of the free
phosphonic acid with appropriate halides in the presence of a
suitable base (e.g. NaH or diisopropylethylamine, Biller et al.,
U.S. Pat. No. 5,157,027; Serafinowska et al., J. Med. Chem. 1995,
38: 1372; Starrett et al., J. Med. Chem. 1994, 37: 1857; Martin et
al., J. Pharm. Sci. 1987, 76: 180; Alexander et al., Collect.
Czech. Chem. Commun, 1994, 59: 1853; EPO 0632048A1).
[1055] R.sup.1 can also be introduced at an early stage of the
synthesis provided that it is compatible with the subsequent
reaction steps. For example, compounds of formula I where R.sup.1
is an aryl group can be prepared by metalation of a 2-furanyl
heterocycle (e.g. using LDA) followed by trapping the anion with a
diaryl chlorophosphate.
[1056] It is envisioned that compounds of formula V can be mixed
phosphonate esters (e.g. phenyl and benzyl esters, or phenyl and
acyloxyalkyl esters) including the chemically combined mixed esters
such as the phenyl and benzyl combined prodrugs reported by Meier,
et al. Bioorg. Med. Chem. Lett., 1997, 7: 99.
(1b) Preparation of a Bisamidate Phosphonate
General Synthesis of Bis-Phosphoroamidate Prodrugs:
[1057] 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
aminoacid ester for example, glycine ethylester with or without
base for example, N-methylimidazole. The reactive dichloridates,
can be prepared as described above in the general prodrug
section
[1058] Alternatively, these bis-phosphoroamidates can be prepared
by reacting the corresponding phosphonic acid with an aminoacid
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.
[1059] Synthesis of mixed bis-phosphoroamidates of formula IA,
where --NR.sup.15R.sup.16 and
--N(R.sup.18)--(CR.sup.12R.sup.13).sub.nC(O)--R.sup.14 are
different aminoacid esters or a combination of an aminoacid ester
and a substituted amine can be prepared by direct conversion via
dichloridate as described above (sequential addition) followed by
separation of the required product by column chromatography or
HPLC. Alternatively, these mixed 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 bis-amide 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).
[1060] The substituted cyclic propyl phosphonate esters can be
synthesized by reactions of the corresponding dichlorophosphonate
with a substituted 1,3-propanediol. Some of the methods useful for
the preparation of a substituted 1,3-propanediol are discussed
below.
Synthesis of a 1,3-propanediol
[1061] Various synthetic methods can be used to prepare numerous
types of 1,3-propanediols: (i) 1-substituted, (ii) 2-substituted,
(iii) 1,2- or 1,3-annulated 1,3-propanediols. Substituents on the
prodrug moiety of compounds of formula I (i.e. substituents on the
1,3-propanediol moiety) can be introduced or modified either during
the synthesis of these diols or after the coupling of these diols
to compounds of formula 2.
(i) 1-Substituted 1,3-propanediols
[1062] 1,3-Propanediols useful in the synthesis of compounds in the
present invention can be prepared using various synthetic methods.
Additions of a aryl Grignard to a 1-hydroxypropan-3-al give
1-aryl-substituted 1,3-propanediols (path a). This method is
suitable for the conversion of various aryl halides to
1-arylsubstituted-1,3-propanediols (Coppi et. al., J. Org. Chem.,
1988, 53, 911). Conversions of aryl halides to 1-substituted
1,3-propanediols can also be achieved using Heck reactions (e.g.
couplings with a 1,3-diox-4-ene) followed by reductions and
subsequent hydrolysis reactions (Sakamoto et. al., Tetrahedron
Lett., 1992, 33, 6845). Various aromatic aldehydes can also be
converted to 1-substituted-1,3-propanediols using alkenyl Grignard
addition reactions followed by hydroboration reactions (path b).
Additions of a metallated t-butyl acetate to aromatic aldehydes
followed by reduction of the ester (path e) are also useful for the
synthesis of 1,3-propanediols (Turner., J. Org. Chem., 1990, 55
4744). In another method, epoxidations of cinnamyl alcohols using
known methods (e.g. Sharpless epoxidations and other asymmetric
epoxidation reactions) followed by a reduction reaction (e.g. using
Red-Al) give various 1,3-propanediols (path c). Alternatively,
enantiomerically pure 1,3-propanediols can be obtained using chiral
borane reduction reactions of hydroxyethyl aryl ketone derivatives
(Ramachandran et. al., Tetrahedron Lett., 1997, 38 761).
Propan-3-ols with a 1-heteroaryl substituent (e.g. a pyridyl, a
quinolinyl or an isoquinolinyl) can be oxygenated to give
1-substituted 1,3-propanediols using N-oxide formation reactions
followed by a rearrangement reaction in acetic anhydride conditions
(path d) (Yamamoto et. al., Tetrahedron, 1981, 37, 1871).
##STR118## (ii) 2-Substituted 1,3-propanediols
[1063] A variety of 2-substituted 1,3-propanediols useful for the
synthesis of compounds of formula I can be prepared from
2-(hydroxymethyl)-1,3-propanediols using known chemistry (Larock,
Comprehensive Organic Transformations, VCH, New York, 1989). For
example, reductions of a trialkoxycarbonylmethane under known
conditions give a triol via complete reduction (path a) or a
bis(hydroxymethyl)acetic acid via selective hydrolysis of one of
the ester groups followed by reduction of the remaining two other
ester groups. Nitrotriols are also known to give triols via
reductive elimination (path b) (Latour et. al., Synthesis, 1987, 8,
742). Furthermore, a 2-(hydroxymethyl)-1,3-propanediol can be
converted to a mono acylated derivative (e.g. acetyl,
methoxycarbonyl) using an acyl chloride or an alkyl chloroformate
(e.g. acetyl chloride or methyl chloroformate) (path d) using known
chemistry (Greene et al., Protective Groups In Organic Synthesis;
Wiley, New York, 1990). Other functional group manipulations can
also be used to prepare 1,3-propanediols such as oxidation of one
the hydroxylmethyl groups in a 2-(hydroxymethyl)-1,3-propanediol to
an aldehyde followed by addition reactions with an aryl Grignard
(path c). Aldehydes can also be converted to alkyl amines via
reductive amination reactions (path e). ##STR119## (iii) Annulated
1,3-propane Diols
[1064] Compounds of formula I wherein V and Z or V and W are
connected by four carbons to form a ring can be prepared from a
1,3-cyclohexanediol. For example, cis, cis-1,3,5-cyclohexanetriol
can be modified as described for 2-substituted 1,3-propanediols. It
is envisioned that these modifications can be performed either
before or after formation of a cyclic phosphonate 1,3-propanediol
ester. Various 1,3-cyclohexanediols can also be prepared using
Diels-Alder reactions (e.g. using a pyrone as the diene: Posner et.
al., Tetrahedron Lett., 1991, 32, 5295). 1,3-Cyclohexanediol
derivatives are also prepared via other cycloaddition reaction
methodologies. For example, cycloadditon of a nitrile oxide to an
olefin followed by conversion of the resulting cycloadduct to a
2-ketoethanol derivative can be converted to a 1,3-cylohexanediol
using known chemistry (Curran, et. al., J. Am. Chem. Soc., 1985,
107, 6023). Alternatively, precursors to 1,3-cyclohexanediol can be
made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32,
547.)
2) Deprotection of a Phosphonate Ester
[1065] Compounds of formula I wherein R.sup.1 is H 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
[1066] 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.
[1067] 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
[1068] When feasible compounds disclosed in the present invention
are advantageously prepared via a convergent synthetic route
entailing the coupling of a heterocycle with a phosphonate diester
component.
[1069] 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 V wherein X is an alkynyl group (Heck
Palladium Reagents in Organic Synthesis; 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.
[1070] 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 2 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).
[1071] 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 4
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 4 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 4 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 4 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--.
[1072] Rearrangement reactions can also be used to prepare
compounds covered in the present invention. For example, the
Curtius's rearrangement of a thiazole-4-carboxylic acid in the
presence of a dialkyl hydroxyalkylphosphonate or a dialkyl
aminoalkylphosphonate lead to compounds of formula 4 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's
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--.
[1073] For compounds of formula V 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).
[1074] 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 3 wherein R5
is a pyridyl, X is a 1-(2-phosphono)ethynyl group.
(5) Construction of a Heterocycle
[1075] Although existing heterocycles are useful for the synthesis
of compounds of formula V, when required, heterocycles can also be
constructed leading to compounds in the current invention, and in
some cases may be preferred for the preparations of certain
compounds. 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: Synthesis,
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
[1076] 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 2 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 2 wherein R5 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
[1077] 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 2 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
[1078] 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, Mariella, 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
[1079] Pyrimidine ring systems useful for the synthesis of
compounds of formula V-2 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 (Sherman 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 V-2 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
[1080] Imidazoles useful for the synthesis of compounds of formula
V-1 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
[1081] Isoxazoles useful for the synthesis of compounds of formula
V-1 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 2 wherein R.sup.5 is an
isoxazole and X is a furan-2,5-diyl group.
(vii) Construction of a Pyrazole Ring System
[1082] Pyrazoles useful for the synthesis of compounds of formula
V-1 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 (Dorn 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
[1083] 1,2,4-Triazoles useful for the synthesis of compounds of
formula V-1 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
[1084] 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 2 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 2 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 2 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
[1085] 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.
[1086] Various aryl phosphonate dialkyl esters are particularly
useful for the synthesis of compounds of formula I. For example,
compounds of formula 3 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. CIPO.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).
[1087] 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,
nitriles, 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 it may be advantageous to protect some of
these functional groups using a number of well-known methods (e.g.
protection of aldehydes as acetals, aminals; 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). It is
advantageous to have the phosphonate moiety 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.
[1088] 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-alkylacryloyl)-5-dialkylphosphonofuran (e.g.
2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).
[1089] 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).
[1090] 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
[1091] 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. ##STR120## (3) Construction of a Heterocycle (i)
Benzothiazole Ring System
[1092] Compounds of formula 3 wherein G''=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''=S, A=NH.sub.2, L.sup.2, E.sup.2, J.sup.2=H,
X.sup.2=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.
[1093] 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.sup.2=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).
[1094] 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=NH.sub.2, L.sup.2,
E.sup.2, J.sup.2=H, X.sup.2=CH.sub.2O and R'=Et with bromine in
polar solvents such as AcOH gave compound of formula 3 wherein
E.sup.2=Br.
[1095] 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
[1096] 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
[1097] Compounds of formula 4 (wherein X.sup.2=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
preferably 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 (wherein a halo group, preferably a fluoro or a
chloro, is present ortho to a nitro group). For example, a compound
of formula 4 (wherein X.sup.2=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
[1098] 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)).
EXAMPLES
Example 1
Preparation of 5-diethylphosphono-2-furaldehyde (1)
[1099] 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.
[1100] 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.
[1101] 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.
[1102] 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.
[1103] 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).
[1104] Step F. A solution of furan-2-(N,N'-dimethylimidazolidine)
(1 mmole) and TMEDA (1 mmole) in TH 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.
[1105] 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-oxo)alkyl]furans and
6-diethylphosphono-2-[(1-oxo)alkyl]pyridines
[1106] 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 mmHg).
[1107] 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.
[1108] 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.
[1109] 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 mmHg).
[1110] The following compounds were prepared according to this
procedure:
[1111] (2.2) 5-diethylphosphono-2-acetylfuran: bp 125-136.degree.
C., 0.1 mmHg.
[1112] (2.3) 5-diethylphosphono-2-[(1-oxo)butyl]furan: bp
130-145.degree. C., 0.08 mmHg.
[1113] Alternatively these compounds can be prepared using the
following procedures:
[1114] 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.
[1115] 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.
[1116] Some of 5-diethylphosphono-2-[(1-oxo)alkyl]furans are
prepared using the following procedures:
[1117] 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.
[1118] 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.
[1119] 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.
[1120] The following compounds were prepared according to this
procedure:
[1121] (2.4) 5-Diethylphosphono-2-(2-ethoxycarbonylacetyl)furan
[1122] (2.5) 5-Diethylphosphono-2-(2-methylthioacetyl)furan
[1123] (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
[1124] Step A. A solution of compound 2.1 (1 mmole) in ethanol was
treated with copper (II) 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.
[1125] 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.
[1126] 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.
[1127] According to the above procedures or in some cases with
minor modifications of these procedures using conventional
chemistry the following compounds were prepared:
[1128] (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.
[1129] (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.
[1130] (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.
[1131] (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.
[1132] (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.
[1133] (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.
[1134] (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.
[1135] (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.
[1136] (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.
[1137] (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.
[1138] (3.12)
2-Acetamido-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp
179-181.degree. C. Anal. calcd. for
C.sub.13H.sub.11N.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.
[1139] (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.
[1140] (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.
[1141] (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.
[1142] (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+0.65 HBr: C, 30.72; H, 3.11; N,
8.96. Found: C, 30.86; H, 3.33; N, 8.85.
[1143] (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.
[1144] (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+0.1HBr+0.3EtOAc: C, 41.62;
H, 4.63; N, 7.35. Found: C, 41.72; H, 4.30; N, 7.17.
[1145] (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.
[1146] (3.20)
2-Amino-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.10H.sub.13N.sub.2O.sub.4PS+1 HBr: C, 32.53; H,
3.82; N, 7.59. Found: C, 32.90; H, 3.78; N, 7.65.
[1147] (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.
[1148] (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.
[1149] (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.
[1150] (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.
[1151] (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+0.1HBr: C, 36.81; H, 3.43; N,
8.58. Found: C, 36.99; H, 3.35; N, 8.84.
[1152] (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.
[1153] (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.
[1154] (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.
[1155] (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.
[1156] (3.30)
2-Amino-5-cyclobutyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.11H.sub.13N.sub.2O.sub.4PS+0.15HBr+0.15H.sub.2O: C,
41.93; H, 4.30; N, 8.89. Found: C, 42.18; H, 4.49; N, 8.53.
[1157] (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.
[1158] (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.
[1159] (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.
[1160] (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.
[1161] (3.35)
2-Amino-5-propyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp
245.degree. C. (decomp). Anal. calcd for C,
1H.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.
[1162] (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.
[1163] (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.
[1164] (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.
[1165] (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.
[1166] (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.
[1167] (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.
[1168] (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.
[1169] (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.
[1170] (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.
[1171] (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.
[1172] (3.46)
2-Amino-5-cyclopropylmethoxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole.
Mp 238.degree. C. (decomp). 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.
[1173] (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.
[1174] (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.
[1175] (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.
[1176] (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.
[1177] (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.
[1178] (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.
[1179] (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.
[1180] (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.
[1181] (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.
[1182] (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.
[1183] (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.
[1184] (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.
[1185] (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.
[1186] (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.
[1187] (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.
[1188] (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.
[1189] (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.
[1190] (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.
[1191] (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.
[1192] (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.
[1193] (3.67) 2-Amino-4-[2-(6-phosphono)pyridyl]thiazole
hydrobromide.
[1194] (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.
[1195] (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.
[1196] (3.70)
2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]selenazole. Anal.
calcd for C.sub.11H.sub.15N.sub.2O.sub.4PSe+0.14 HBr+0.6 EtOAc: C,
38.93; H, 4.86; N, 6.78. Found: C, 39.18; H, 4.53; N, 6.61.
[1197] (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.
[1198] (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
[1199] 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.
[1200] 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.
Found: C, 25.93; H, 1.64; N, 8.53.
[1201] The following compounds were prepared according to this
procedure:
[1202] (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.
[1203] (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.
[1204] (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.
Examples 5
Preparation of 2-halo-4-[2-(5-phosphono)furanyl]thiazoles
[1205] 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 nitrite
(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.
[1206] 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.
[1207] The following compound was prepared according to this
procedure:
[1208] (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.
[1209] (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
[1210] 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.
[1211] Step B.
2-Vinyl-5-isobutyl-4-[2-(5-diethylphosphano)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.
[1212] This method can also be used to prepare various
5-substituted 4-[2-(5-phosphono)furanyl]thiazoles from their
corresponding halides.
[1213] 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.
[1214] 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.
[1215] The following compound was prepared according to this
procedure:
[1216] (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
[1217] 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.
[1218] 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
[1219] 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.
[1220] 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.
[1221] 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.
[1222] 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.
[1223] 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
[1224] (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.
[1225] Step F.
2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole was
subjected to Step C of Example 3 to give
2-amino-4-phosphonomethoxymethylthiazole
[1226] (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
[1227] 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.
[1228] 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.
[1229] The following compound was prepared according to this
procedure:
[1230] (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.
[1231] 2-Ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazoles
can also be converted to other 2-substituted
4-[2-(5-phosphono)furanyl]thiazoles.
[1232] 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.
[1233] 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.
[1234] The following compound was prepared according to this
procedure:
[1235] (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.
[1236] 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.
[1237] 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.
[1238] The following compound was prepared according to this
procedure:
[1239] (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.
[1240] 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.
[1241] 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.
[1242] 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.
[1243] 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.
[1244] 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
C.sub.12H.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.
[1245] According to the above procedures or in some cases with some
minor modifications of the above procedures, the following
compounds were prepared:
[1246] (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.
[1247] (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
[1248] Step A. A solution of
5-diethylphosphono-2-[(2-bromo-4-methyl-1-oxo)pentyl]furan (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.
[1249] 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.
[1250] 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.
[1251] Alternatively 4-[2-(5-phosphono)furanyl]oxazoles and
4-[2-(5-phosphono)furanyl]imidazoles can be prepared as
following:
[1252] 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.
[1253] 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:
[1254] (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.
[1255] (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.
[1256] (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.
[1257] Alternatively 4-[2-(5-phosphono)furanyl]imidazoles can be
prepared as following:
[1258] 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.
[1259] 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.
[1260] Alternatively
4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]-imidazole can be
prepared as following:
[1261] 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.
[1262] 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.
[1263] According to the above procedures or in some cases with some
minor modifications of the above procedures, the following
compounds were prepared:
[1264] (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.
[1265] (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.
[1266] (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.
[1267] (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.
[1268] (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.
[1269] (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.
[1270] (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.
[1271] (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.
[1272] (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.
[1273] (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.degree.; N,
5.16. Found: C, 48.67; H, 5.02; N, 5.10.
[1274] (10.12) 2-Amino-5-butyl-4-[2-(5-phosphono)furanyl]oxazole.
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, 45.32; H, 5.29; N, 9.50.
[1275] (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.
[1276] (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.
[1277] (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.
[1278] (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.
[1279] (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.
[1280] (10.24)
2-Amino-5-(2-thienylmethyl)-4-[2-(5-phosphono)furanyl]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.
[1281] (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
[1282] (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.
[1283] (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
[1284] (10.28)
2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. Calcd for
C.sub.12H.sub.11BrN.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.
[1285] (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.
[1286] (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.
[1287] (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.
[1288] (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.
[1289] (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.
[1290] (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.
[1291] (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.
[1292] (10.36)
2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole.
mp 221.degree. C. (decomp). Anal. calcd for C,
1H.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.
[1293] (10.37)
2-Amino-5-methoxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole. mp
240.degree. C. (decomp). Anal. calcd for
C.sub.9H.sub.9N.sub.2O.sub.7P+0.3H.sub.2O+0.1Acetone: C, 37.31; H,
3.43; N, 9.36. Found: C, 37.37; H, 3.19; N, 9.01.
[1294] (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.
[1295] (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.
[1296] (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.
[1297] (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.
[1298] (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.
[1299] (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.
[1300] (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.
[1301] (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
[1302] 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)-furanyl]imidazole
and
1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)-furanyl]imidazole.
[1303] 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:
[1304] (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-(6phosphono)pyridyl]pyridine
[1305] 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.
[1306] 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.
[1307] 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+0.1HBr:
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
[1308] 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.
[1309] 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.
[1310] 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+1.0H2O+0.5HBr: C, 37.32; H, 5.74; N, 4.84.
Found: C, 37.18; H, 5.38; N, 4.67.
[1311] The following compound was prepared similarly:
[1312] (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
(14)
[1313] 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
[1314] 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.
[1315] Step B. A solution of 2-amino-6-chloropyridine (1 mmole) and
compound 14 (1 mmole) in p-xylene was treated with
tetrakis(triphenylohosphine) 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.
[1316] 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.
[1317] 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.
[1318] 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:
[1319] (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.
[1320] (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.
[1321] 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.
[1322] 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.
[1323] 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.
[1324] Step I. 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.
[1325] 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.
[1326] Following compounds were prepared according to the above
described procedures or with some minor modifications of these
procedures using conventional chemistry.
[1327] (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.
[1328] (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.
[1329] (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.
[1330] (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.
[1331] (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.
[1332] (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.
[1333] (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.
[1334] (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.
[1335] (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.
[1336] (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.11BrNO.sub.4P+0.45HBr: C, 35.85; H, 3.13; N, 3.80.
Found: C, 35.98; H, 3.10; N, 3.71.
[1337] (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.
[1338] (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.
[1339] (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.
[1340] (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:
[1341] (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.
[1342] (15.22) 2-Methyl-5-cyano-6-[2-(5-phosphono)furanyl]pyridine.
Anal. Calcd. for C.sub.11H9N.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.
[1343] (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.
[1344] (15.24) 2-Chloro-4-cyano-6-[2-(5-phosphono)furanyl]pyridine.
Anal. Calcd. for C.sub.10H6N.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
[1345] 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.
[1346] 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.
[1347] 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.
[1348] 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.
[1349] The following compound was prepared according to this
procedure:
[1350] (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.
[1351] Alternatively other 4-[2-(5-phosphono)furanyl]pyrimidines
can be prepared according to the following procedures:
[1352] 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.
[1353] 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.
[1354] 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]-pyridine (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.
[1355] 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.
[1356] 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.
[1357] The following compounds were prepared according to the above
described procedures or with some minor modifications using
conventional chemistry:
[1358] (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.
[1359] (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.
[1360] (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.
[1361] (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.
[1362] (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.
[1363] (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.
[1364] (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.
[1365] (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.
[1366] (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.
[1367] (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
[1368] 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. The following compounds were prepared
accordingly:
[1369] (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.
[1370] (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.
[1371] (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.
[1372] (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.
[1373] (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.
[1374] (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.
[1375] (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.
[1376] (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.
[1377] (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.
[1378] (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.
[1379] (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
[1380] 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.
[1381] 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 .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.
[1382] 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.
[1383] Alternatively the ester linkage can be formed using a mixed
anhydride method as exemplified in the following procedures:
[1384] 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.
[1385] 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.
[1386] 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.
[1387] 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.
[1388] 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.
[1389] 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 H2 (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.
[1390] 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.
I. Preparation of 4-phosphonomethylthiocarbonylthiazole
[1391] 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.
[1392] 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
[1393] 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
[1394] 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.
[1395] 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:
[1396] (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.
[1397] (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.
[1398] (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.
[1399] (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.
[1400] (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.
[1401] (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.
[1402] (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.
[1403] (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.
[1404] (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.
[1405] (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.
[1406] (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.
[1407] (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.
[1408] (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.
[1409] (18.21) 2-Amino-5-phenyl-4-phosphonomethoxycarbonylthiazole.
Mp>230.degree. C. Anal. Calcd. for C.sub.11Hi N.sub.2O.sub.5PS:
C, 42.04; H, 3.53; N, 8.91. Found: C, 42.04; H, 3.40; N, 8.72.
[1410] (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.
[1411] (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.
[1412] (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.
[1413] (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.
[1414] (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.
[1415] (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.
[1416] (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.
[1417] (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.
[1418] (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.
[1419] (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.
[1420] (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.
[1421] (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.
[1422] (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.
[1423] (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.
[1424] (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.
[1425] (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.
[1426] (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.
[1427] (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.
[1428] (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.
[1429] (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.
[1430] (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.
[1431] (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.
[1432] (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.
[1433] (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.
[1434] (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 Various Phosphonate Diesters as Prodrugs
[1435] A suspension of
2-methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (1 mmole) in
thionyl chloride (5 mL) was warmed at reflux for 4 h. The cooled
reaction mixture was evaporated to dryness and the resulting yellow
residue was dissolved in methylene chloride and treated with a
solution of the corresponding benzyl alcohol (4 mmole) and pyridine
(2.5 mmole) in methylene chloride. After stirring at 25.degree. C.
for 24 h the reaction mixture was subjected to extraction and
chromatography to give the titled compounds. The following
compounds were prepared according to this procedure:
[1436] (19.1)
2-Methyl-5-isobutyl-4-{2-[5-bis(4-pivaloyloxybenzyl)phosphono]furanyl}thi-
azole. Anal. Calcd. for C.sub.36H.sub.44NO.sub.8PS+0.4H.sub.2O: C,
62.76; H, 6.55; N, 2.03. Found: C, 62.45; H, 6.44; N, 2.04.
[1437] (19.2)
2-Methyl-5-isobutyl-4-{2-[5-bis(3,4-diacetoxybenzyl)phosphono]furanyl}thi-
azole. Anal. Calcd. for C.sub.34H.sub.36NO.sub.12PS+0.8H.sub.2O: C,
56.09; H, 5.21; N, 1.92. Found: C, 55.90; H, 4.98; N, 1.94.
[1438] (19.3)
2-Methyl-5-isobutyl-4-{2-[S-bis(4-acetoxy-3-methoxybenzyl)phosphono]furan-
yl}thiazole. Anal. Calcd. for C.sub.32H.sub.36NO.sub.10PS: C,
58.44; H, 5.52; N, 2.13. Found: C, 58.16; H, 5.34; N, 2.13.
[1439] (19.4)
2-Methyl-5-isobutyl-4-{2-[5-bis(4-acetoxy-3-methylbenzyl)phosphono]furany-
l}thiazole. Anal. Calcd. for C.sub.32H.sub.36NO.sub.8PS: C, 61.43;
H, 5.80; N, 2.24. Found: C, 61.34; H, 5.89; N, 2.25.
[1440] (19.5)
2-Amino-5-isobutyl-4-{2-[5-bis(3,4-diacetoxybenzyl)phosphono]furanyl}thia-
zole. Anal. Calcd. for C.sub.33H.sub.35N.sub.2O.sub.12PS: C, 55.46;
H, 4.94; N, 3.92. Found: C, 55.06; H, 4.96; N, 3.79.
[1441] (19.6)
2-Amino-5-isobutyl-4-{2-[5-bis(4-acetoxybenzyl)phosphono]furanyl}thiazole-
. Anal. Calcd. for C.sub.29H.sub.31N.sub.2O.sub.8PS: C, 58.19; H,
5.22; N, 4.68. Found: C, 57.82; H, 4.83; N, 4.50.
[1442] This method is also useful for the preparation of phenyl
phosphonate esters as prodrugs, and the following compound was
prepared:
[1443] (19.7)
2-Methyl-5-isobutyl-4-[2-(5-diphenylphosphono)furanyl]thiazole.
Anal. Calcd. for C.sub.24H.sub.24NO.sub.4PS+0.1H.sub.2O: C, 63.31;
H, 5.36; N, 3.08. Found: C, 63.22; H, 5.34; N, 3.14.
[1444] (19.63)
2-Amino-5-isobutyl-4-[2-(5-diphenylphosphono)furanyl]thiazole. Mp
128-129 0.degree. C. Anal. Calcd. for
C.sub.23H.sub.23N.sub.2O.sub.4PS: C, 60.78; H, 5.10; N, 6.16.
Found: C, 60.68; H, 4.83; N, 6.17.
[1445] (19.64)
2-Amino-5-isobutyl-4-[2-(5-phenylphosphono)furanyl]thiazole.
Mp>250.degree. C. Anal. Calcd. for
C.sub.17H.sub.19N.sub.2O.sub.4PS: C, 53.96; H, 5.06; N, 7.40.
Found: C, 53.81; H, 4.87; N, 7.41.
[1446] (19.65)
2-Amino-5-isobutyl-4-[2-(5-bis(3-chlorophenyl)phosphono)furanyl]thiazole.
Anal. Calcd. for
C.sub.23H.sub.21N.sub.2O.sub.4PSCl.sub.2+0.5H.sub.2O: C, 51.89; H,
4.17; N, 5.26. Found C, 51.55; H, 3.99; N, 5.22.
[1447] (19.67)
2-Amino-5-isobutyl-4-[2-(5-bis(4-methoxyphenyl)phosphono)furanyl]thiazole-
. Anal. Calc. for C.sub.25H.sub.27N.sub.2O.sub.6PS+0.5H.sub.2O: C,
57.35; H, 5.39; N, 5.35. Found C, 57.11; H, 5.36; N, 5.75.
[1448] This method is also useful for the preparation of some
thio-containing phosphonate esters as prodrugs, and the following
compounds were prepared:
[1449] (19.8)
2-Methyl-5-isobutyl-4-{2-[5-bis(2-methylcarbonylthioethyl)phosphono]furan-
yl}thiazole. Anal. Calcd. for C.sub.20H.sub.28NO.sub.6PS.sub.3: C,
47.51; H, 5.58; N, 2.77. Found: C, 47.32; H, 5.56; N, 2.77.
[1450] (19.9)
2-Methyl-5-isobutyl-4-{2-[5-bis(thiobenzoylmethyl)phosphono]furanyl}thiaz-
ole. Anal. Calcd. for C.sub.28H.sub.28NO.sub.6PS.sub.3: C, 55.89;
H, 4.69; N, 2.33. Found: C, 55.73; H, 4.72; N, 2.28.
[1451] This method is also useful for the preparation of cyclic
phosphonate esters (e.g. cyclic 1,3-propanediol phosphonate esters)
as prodrugs by coupling of phosphoric acids with various diols
(e.g. 1,3-propanediols see Example 21 for the synthesis of some
1,3-propanediols), and the following compounds were made:
[1452] (19.10)
5-Isobutyl-2-methyl-4-{2-[5-(1-hydroxy-3,5-cyclohexyl)phosphono]furanyl}t-
hiazole (minor isomer). Anal. Calcd. for
C.sub.18H.sub.24NO.sub.5PS+0.33H.sub.2O: C, 53.60; H, 6.16; N,
3.47. Found: C, 53.75; H, 6.53; N, 3.45.
[1453] (19.11)
5-Isobutyl-2-methyl-4-{2-[5-(1-hydroxy-3,5-cyclohexyl)phosphono]furanyl}t-
hiazole (major isomer). Anal. Calcd. for
C.sub.18H.sub.24NO.sub.5PS: C, 54.40; H, 6.09; N, 3.52. Found: C,
54.44; H, 6.11; N, 3.63.
[1454] (19.12)
5-Isobutyl-2-methyl-4-{2-[5-(2-hydroxymethyl-1,3-propyl)phosphono]furanyl-
}thiazole. Anal. Calcd. for
C.sub.16H.sub.22NO.sub.5PS+0.3CH.sub.2Cl.sub.2+0.5H.sub.2O: C,
48.24; H, 5.86; N, 3.45. Found: C, 47.94; H, 5.59; N, 3.57.
[1455] (19.13)
5-Isobutyl-2-methyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazo-
le, (minor isomer). Anal. Calcd. for
C.sub.21H.sub.24NO.sub.4PS+0.25H.sub.2O: C, 59.77; H, 5.85; N,
3.32. Found: C, 59.76; H, 5.69; N, 3.38.
[1456] (19.14)
5-Isobutyl-2-methyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazo-
le, (major isomer). Anal. Calcd. for
C.sub.21H.sub.24NO.sub.4PS+0.5H.sub.2O: C, 59.14; H, 5.91; N, 3.28.
Found: C, 59.27; H, 5.85; N, 3.38.
[1457] (19.15)
2-Amino-5-isobutyl-4-[2-(5-[2-(methoxycarbonyloxymethyl)-propan-1,3-yl]ph-
osphono)furanyl]thiazole (minor isomer). mp 170-173.degree. C.
Anal. Calcd. for C.sub.17H.sub.23N.sub.2O.sub.7PS: C, 47.44; H,
5.39; N, 6.51. Found: C, 47.28; H, 5.27; N, 6.47.
[1458] (19.16)
2-Amino-5-isobutyl-4-[2-(5-[2-(methoxycarbonyloxymethyl)-propan-1,3-yl]ph-
osphono)furanyl]thiazole (major isomer). Anal. Calcd. for
C.sub.17H.sub.23N.sub.2O.sub.7PS+0.5H.sub.2O: C, 46.47; H, 5.51; N,
6.38. Found: C, 46.38; H, 5.29; N, 6.20.
[1459] (19.17)
5-Isobutyl-2-methyl-4-{2-[5-(1-(4-pyridyl)-1,3-propyl)phosphono]furanyl}--
thiazole. Anal. Calcd. for
C.sub.20H.sub.23N.sub.2O.sub.4PS+2H.sub.2O+0.4CH.sub.2Cl.sub.2: C,
50.16; H, 5.74; N, 5.74. Found: C, 50.36; H, 5.36; N, 5.80.
[1460] (19.18)
2-Amino-5-isobutyl-4-(2-{5-[1-(4-pyridyl)-propan-1,3-yl]phosphono}furanyl-
)thiazole. mp 101-106.degree. C. Anal. Calcd. for
C.sub.19H.sub.22N.sub.3O.sub.4PS+0.75H.sub.2O: C, 52.71; H, 5.47;
N, 9.71. Found: C, 52.59; H, 5.49; N, 9.65.
[1461] (19.20)
2-Amino-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazol-
e (minor isomer). Anal. Calcd. for
C.sub.20H.sub.23N.sub.2O.sub.4PS+0.33HCl: C, 55.80; H, 5.46; N,
6.51. Found: C, 55.95; H, 5.36; N, 6.46.
[1462] (19.21)
2-Amino-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazol-
e (major isomer). Anal. Calcd. for
C.sub.20H.sub.23N.sub.2O.sub.4PS+0.33HCl: C, 55.80; H, 5.46; N,
6.51. Found: C, 55.77; H, 5.19; N, 6.44.
[1463] (19.22)
2-Amino-5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazole
(less polar isomer). Anal. Calcd. for
C.sub.18H.sub.19N.sub.2O.sub.4PS+0.2HCl+0.25H.sub.2O: C, 53.75; H,
4.94; N, 6.97. Found: C, 53.86; H, 4.70; N, 6.87.
[1464] (19.23)
2-Amino-5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}-thiazole
(more polar isomer). Anal. Calcd. for
C.sub.18H.sub.19N.sub.2O.sub.4PS+0.2HCl+0.25H.sub.2O: C, 53.75; H,
4.94; N, 6.97. Found: C, 53.92; H, 4.82; N, 6.92.
[1465] (19.24)
2-Amino-5-ethyl-4-{2-[5-(1-{4-pyridyl}-1,3-propyl)phosphono]furanyl}thiaz-
ole. Anal. Calcd. for
C.sub.17H.sub.18N.sub.3O.sub.4PS+0.1HCl+0.5H.sub.2O: C, 50.54; H,
4.76; N, 10.40. Found: C, 50.38; H, 4.53; N, 10.25.
[1466] (19.25)
2-Methyl-4-{2-[5-(2-acetoxymethylpropan-1,3-diyl)phosphono]furanyl}thiazo-
le. Anal. calcd. for C.sub.14H.sub.16NO.sub.6PS+0.5H.sub.2O: C,
45.90; H, 4.68; N, 3.82. Found C, 45.50; H, 4.55; N, 3.45.
[1467] (19.26)
2-Methyl-4-(2-{5-[1-(4-pyridyl)propan-1,3-diyl]phosphono}furanyl)thiazole-
. Anal. calcd. for C.sub.16H.sub.15N.sub.2O.sub.4PS+0.75H.sub.2O:
C, 51.13; H, 4.42; N, 7.45. Found: C, 50.86; H, 4.72; N, 7.11.
[1468] (19.27)
2-Amino-5-methylthio-4-(2-{5-[1-(4-pyridyl)propan-1,3-diyl]phosphono}fura-
nyl)thiazole. Anal. calcd. for
C.sub.16H.sub.16N.sub.3O.sub.4PS.sub.2+0.4HCl: C, 45.32; H, 3.90;
N, 9.91. Found: C, 45.29; H, 3.80; N, 9.83.
[1469] (19.28)
2-Amino-5-isobutyl-4-{2-[5-(1-(3-bromophenyl)propan-1,3-diyl)phosphono]fu-
ranyl}thiazole, major isomer. Anal. calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PBrS: C, 48.30; H, 4.46; N, 5.63.
Found: C, 48.51; H, 4.21; N, 5.33.
[1470] (19.29)
2-Amino-5-methylthio-4-{2-[5-(1-(R)-phenyl-1,3-propyl)phosphono]furanyl}t-
hiazole. Anal. Calcd. for C.sub.17H.sub.17N.sub.2O.sub.4PS+HCl: C,
49.46; H, 4.39; N, 6.79. Found: C, 49.77; H, 4.13; N, 6.54.
[1471] (19.30)
2-Amino-5-isobutyl-4-{2-[5-(1-(3-bromophenyl)-1,3-propyl)phosphono]furany-
l}thiazole, minor isomer. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSBr+0.25HCl: C, 47.43; H, 4.43; N,
5.53. Found: C, 47.58; H, 4.16; N, 5.31.
[1472] (19.31)
2-Amino-5-isobutyl-4-{2-[5-(2-benzyl-1,3-propyl)phosphono]furanyl}thiazol-
e. Anal. Calcd. for C.sub.21H.sub.25N.sub.2O.sub.4PS: C, 58.32; H,
5.83; N, 6.48. Found: C, 57.98; H, 5.65; N, 6.47.
[1473] (19.32)
2-Amino-5-cyclopropyl-4-{2-[5-(1-(4-pyridyl)-1,3-propyl)phosphono]furanyl-
}thiazole. Anal. Calcd. for
C.sub.18H.sub.18N.sub.3O.sub.4PS+0.5H.sub.2O: C, 52.42; H, 4.64; N,
10.19. Found: C, 52.62; H, 4.51; N, 9.89.
[1474] (19.33)
2-Methyl-5-isobutyl-4-{2-[5-(1-(S)-phenyl-1,3-propyl)phosphono]furanyl}th-
iazole, minor isomer. Anal. Calcd. for C.sub.21H.sub.24NO.sub.4PS:
C, 60.42; H, 5.79; N, 3.36. Found: C, 60.10; H, 5.58; N, 3.32.
[1475] (19.34)
2-Methyl-5-isobutyl-4-{2-[5-(1-(S)-phenyl-1,3-propyl)phosphono]furanyl}th-
iazole, major isomer. Anal. Calcd. for
C.sub.21H.sub.24NO.sub.4PS+0.33H.sub.2O: C, 59.57; H, 5.87; N,
3.31. Found: C, 59.45; H, 5.83; N, 3.30.
[1476] (19.35)
2-Azido-5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazole,
major isomer. Anal. Calcd. for
C.sub.18H.sub.17N.sub.4O.sub.4PS+0.25H.sub.2O+0.1 isoamyl alcohol
(C.sub.5H.sub.12O): C, 51.71; H, 4.39; N, 13.04. Found: C, 51.80;
H, 4.20; N, 12.78.
[1477] (19.36)
2-Azido-5-ethyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphono]furanyl}thiazole,
minor isomer. Anal. Calcd. for
C.sub.18H.sub.17N.sub.4O.sub.4PS+0.15 isoamyl alcohol
(C.sub.5H.sub.12O): C, 52.42; H, 4.41; N, 13.04. Found: C, 52.27;
H, 4.47; N, 12.76.
[1478] (19.37)
2-Amino-5-isobutyl-4-{2-[5-(1-(1-naphthyl)-1,3-propyl)phosphono]furanyl}t-
hiazole. Anal. Calcd. for C.sub.24H.sub.25N.sub.2O.sub.4PS: C,
61.53; H, 5.38; N, 5.98. Found: C, 61.40; H, 5.12; N, 6.11.
[1479] (19.38)
2-Amino-5-isobutyl-4-{2-[5-(1-(2-bromophenyl)-1,3-propyl)phosphono]furany-
l}thiazole. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSBr+0.1C.sub.5H.sub.5N: C, 48.73; H,
4.49; N, 5.82. Found: C, 48.63; H, 4.26; N, 5.70.
[1480] (19.39)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-bromophenyl)-1,3-propyl)phosphono]furany-
l}thiazole, minor isomer. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSBr: C, 48.30; H, 4.46; N, 5.63.
Found: C, 48.23; H, 4.30; N, 5.77.
[1481] (19.40)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-bromophenyl)-1,3-propyl)phosphono]furany-
l}thiazole, major isomer. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSBr: C, 48.30; H, 4.46; N, 5.63.
Found: C, 48.20; H, 4.63; N, 5.41.
[1482] (19.41)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-fluoro-3-bromophenyl)-1,3-propyl)phospho-
no]furanyl}thiazole, minor isomer. Anal. Calcd. for
C.sub.20H.sub.21N.sub.2O.sub.4PSBrF+0.1C.sub.5H.sub.5N: C, 47.06;
H, 4.14; N, 5.62. Found: C, 47.00; H, 3.84; N, 5.48.
[1483] (19.42)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-fluoro-3-bromophenyl)-1,3-propyl)phospho-
no]furanyl}thiazole, major isomer. Anal. Calcd. for
C.sub.20H.sub.21N.sub.2O.sub.4PSBrF: C, 46.61; H, 4.11; N, 5.44; P:
6.01. Found: C, 46.81; H, 4.23; N, 5.65; P: 5.65.
[1484] (19.43)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-trifluoromethylphenyl)-1,3-propyl)phosph-
ono]furanyl}thiazole, minor isomer. Anal. Calcd. for
C.sub.21H.sub.22N.sub.2O.sub.4PSF.sub.3+0.1H.sub.2O: C, 51.66; H,
4.58; N, 5.74. Found: C, 51.54; H, 4.28; N, 5.46.
[1485] (19.44)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-trifluoromethylphenyl)-1,3-propyl)phosph-
ono]furanyl}thiazole, major isomer. Anal. Calcd. for
C.sub.21H.sub.22N.sub.2O.sub.4PSF.sub.3+0.1H.sub.2O: C, 51.66; H,
4.58; N, 5.74. Found: C, 51.48; H, 4.62; N, 5.81.
[1486] (19.45)
2-Amino-5-isobutyl-4-{2-[5-(1-(3-chlorophenyl)-1,3-propyl)phosphono]furan-
yl}thiazole, minor isomer. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSCl+0.5H.sub.2O: C, 52.01; H, 5.02;
N, 6.06. Found: C, 52.10; H, 4.92; N, 5.82.
[1487] (19.46)
2-Amino-5-isobutyl-4-{2-[5-(1-(3-chlorophenyl)-1,3-propyl)phosphono]furan-
yl}thiazole, major isomer. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSCl+0.25H.sub.2O: C, 52.52; H, 4.96;
N, 6.12. Found: C, 52.70; H, 4.79; N, 5.91.
[1488] (19.47)
2-Amino-5-isobutyl-4-{2-[5-(1-(3,5-dichlorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, minor isomer. Anal. Calcd. for
C.sub.20H.sub.21N.sub.2O.sub.4PSCl.sub.2: C, 49.29; H, 4.34; N,
5.75. Found: C, 49.47; H, 4.60; N, 5.89.
[1489] (19.48)
2-Amino-5-isobutyl-4-{2-[5-(1-(3,5-dichlorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, major isomer. Anal. Calcd. for
C.sub.20H.sub.21N.sub.2O.sub.4PSCl.sub.2: C, 49.29; H, 4.34; N,
5.75; Cl: 14.55. Found: C, 49.26; H, 4.36; N, 5.71; Cl: 14.66.
[1490] (19.49)
2-Amino-5-isobutyl-4-{2-[5-(2-(4-methoxybenzyl)-1,3-propyl)phosphono]fura-
nyl}thiazole. Mp 185-188.degree. C. Anal. Calcd. for
C.sub.22H.sub.27N.sub.2O.sub.5PS: C, 57.13; H, 5.88; N, 6.06.
Found: C, 56.86; H, 5.71; N, 5.73.
[1491] (19.50)
2-Amino-5-isobutyl-4-{2-[5-(2-methanesulfonyloxymethyl-1,3-propyl)phospho-
no]furanyl}thiazole. Anal. Calcd. for
C.sub.16H.sub.23N.sub.2O.sub.7PS.sub.2+0.2H.sub.2O: C, 42.32; H,
5.19; N, 6.17. Found: C, 42.15; H, 4.94; N, 5.95.
[1492] (19.51)
2-Amino-5-isobutyl-4-{2-[5-(2-azidomethyl-1,3-propyl)phosphono]furanyl}th-
iazole. Mp 187-189.degree. C. Anal. Calcd. for
C.sub.15H.sub.20N.sub.5O.sub.4PS: C, 45.34; H, 5.07; N, 17.62.
Found: C, 45.09; H, 4.82; N, 17.72.
[1493] (19.52)
2-Amino-5-isobutyl-4-{2-[5-(2-aminomethyl-1,3-propyl)phosphono]furanyl}th-
iazole. Anal. Calcd. for
C.sub.15H.sub.22N.sub.3O.sub.4PS+0.3H.sub.2O+0.1HCl: C, 47.36; H,
6.01; N, 11.04. Found: C, 47.55; H, 5.62; N, 10.64.
[1494] (19.53)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-tert-butylphenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, minor isomer. Mp 141-143.degree. C. Anal. Calcd.
for C.sub.24H.sub.31N.sub.2O.sub.4PS+1.5HCl: C, 54.47; H, 6.19; N,
5.29. Found: C, 54.44; H, 5.85; N, 4.92.
[1495] (19.54)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-tert-butylphenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, major isomer. Mp 178.degree. C. (decomp). Anal.
Calcd. for C.sub.24H.sub.31N.sub.2O.sub.4PS+H.sub.2O: C, 58.52; H,
6.75; N, 5.69. Found: C, 58.20; H, 6.31; N, 5.29.
[1496] (19.55)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-chlorophenyl)-1,3-propyl)phosphono]furan-
yl}thiazole, major isomer. Mp 102-104.degree. C. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSCl+H.sub.2O+0.2EtOAc: C, 51.14; H,
5.28; N, 5.73. Found: C, 50.86; H, 5.09; N, 5.34.
[1497] (19.56)
2-Amino-5-isobutyl-4-{2-[5-(1-(2,4-dichlorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, major isomer. Mp 173-174.degree. C. Anal. Calcd.
for C.sub.20H.sub.21N.sub.2O.sub.4PSCl.sub.2: C, 49.29; H, 4.34; N,
5.75. Found: C, 49.55; H, 4.32; N, 5.46.
[1498] (19.57)
2-Amino-5-isobutyl-4-{2-[5-(1,3-(S,S)-diphenyl)-1,3-propyl)phosphono]fura-
nyl}thiazole. Mp 105-107.degree. C. Anal. Calcd. for
C.sub.26H.sub.27N.sub.2O.sub.4PS+0.5H.sub.2O+0.5HCl: C, 59.85; H,
5.51; N, 5.37. Found: C, 59.83; H, 5.18; N, 5.27.
[1499] (19.58)
2-Amino-5-isobutyl-4-{2-[5-(1-(4-chlorophenyl)-1,3-propyl)phosphono]furan-
yl}thiazole, minor isomer. Mp 102-104.degree. C. Anal. Calcd. for
C.sub.20H.sub.22N.sub.2O.sub.4PSCl: C, 53.04; H, 4.90; N, 6.19.
Found: C, 52.80; H, 4.70; N, 6.07.
[1500] (19.59)
2-Amino-5-isobutyl-4-{2-[5-(1-(3,5-difluorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, minor isomer. Mp 152-154.degree. C. Anal. Calcd.
for C.sub.20H.sub.21N.sub.2O.sub.4PSF.sub.2+0.5H.sub.2O+0.3 EtOAc:
C, 51.98; H, 5.02; N, 5.72. Found: C, 51.67; H, 4.77; N, 5.42.
[1501] (19.60)
2-Amino-5-isobutyl-4-{2-[5-(1-(3,5-difluorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, major isomer. Mp 94-95.degree. C. Anal. Calcd. for
C.sub.20H.sub.21N.sub.2O.sub.4PSF.sub.2: C, 52.86; H, 4.66; N,
6.16. Found: C, 52.68; H, 4.73; N, 5.90.
[1502] (19.61)
2-Amino-5-isobutyl-4-{2-[5-(1-(3,5-dibromophenyl)-1,3-propyl)phosphono]fu-
ranyl}thiazole, major isomer. Mp 113-115.degree. C. Anal. Calcd.
for C.sub.20H.sub.21N.sub.2O.sub.4PSBr.sub.2+0.3 EtOAc: C, 42.25;
H, 3.91; N, 4.65. Found: C, 42.52; H, 3.91; N, 4.96.
[1503] (19.62)
2-Amino-5-isobutyl-4-{2-[5-(1-(3,5-dibromophenyl)-1,3-propyl)phosphono]fu-
ranyl}thiazole, minor isomer. Mp 209-210.degree. C. Anal. Calcd.
for C.sub.20H.sub.21N.sub.2O.sub.4PSBr.sub.2: C, 41.69; H, 3.67; N,
4.86. Found: C, 41.93; H, 3.71; N, 4.74.
[1504] (19.66)
2-Amino-5-isobutyl-4-{2-[5-(1-(3-pyridyl)-1,3-propyl)phosphono]furanyl}th-
iazole dihydrochloride. Anal. Calcd. for
C.sub.19H.sub.22N.sub.3O.sub.4PS+2HCl+2H.sub.2O: C, 43.19; H, 5.34;
N, 7.95. Found: C, 43.10; H, 5.25; N, 7.85.
[1505] (19.68)
2-Amino-5-isobutyl-4-{2-[5-(1-oxo-1-phospha-2,5,8-trioxa-3,4-benzo)cycloo-
ctan-1-yl]furanyl}thiazole. Anal. Calcd. for
C.sub.19H.sub.21N.sub.2O.sub.5PS+0.75H.sub.2O: C, 52.59; H, 5.23;
N, 6.46. Found: C, 52.38; H, 4.85; N, 6.08.
[1506] Preferably the cyclic 1,3-propanediol phosphonate esters
were prepared using 1,3-dicyclohexylcarbodiimide (DCC) coupling
reaction conditions as following.
[1507] A suspension of
2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (1 mmole) in
DMF:pyridine (5:1, 10 mL) was treated with DCC (2=mole) followed by
3-(3,5-dichloro)phenyl-1,3-propanediol (1.1 mmole). The resulting
mixture was heated at 80.degree. C. for 8 h. Evaporation followed
by column chromatography gave
2-amino-5-isobutyl-4-{2-[5-(1-(3,5-dichlorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, major isomer. (19.48) as a solid.
[1508] This method is also useful for the preparation of
(5-substituted 2-oxo-1,3-dioxolen-4-yl)methyl and (5-substituted
2-thiocarbonyl-1,3-dioxolen-4-yl)methyl phosphonate prodrugs by
coupling of phosphonic acids with
5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene and
5-methyl-4-hydroxymethyl-2-thiocarbonyl-1,3-dioxolene (prepared
from 4,5-dimethyl-2-oxo-1,3-dioxolene as described in Example 23).
The following compound was made using this method:
[1509] (19.19)
2-Methyl-5-isobutyl-4-{2-[5-(bis(5-methyl-2-thioxo-1,3-dioxolen-4-yl)meth-
yl)phosphono]furanyl}thiazole. Anal. Calcd. for
C.sub.22H.sub.24NO.sub.8PS.sub.3: C, 47.39; H, 4.34; N, 2.51.
Found: C, 47.42; H, 4.30; N, 2.52.
[1510] Alternatively, these compounds can be prepared according to
reported procedures (Chem. Pharm. Bull. 1984, 32(6), 2241) by
reaction of phosphonic acids with
5-methyl-4-bromomethyl-2-oxo-1,3-dioxolene in DMF in the presence
of sodium hydride at 25.degree. C.
[1511]
2-Amino-5-isobutyl-{2-[5-bis(3-phthalidyl-2-ethyl)phosphono]furany-
l}-thiazole is also prepared following the above described
procedures using 2-(3-phthalidyl)ethanol which was prepared from
phthalide-3-acetic acid in Example 22.
Example 20
Preparation of Acyloxyalkyl and Alkyloxycarbonyloxyalkyl
Phosphonate Diesters as Prodrugs
[1512] A solution of 2-methyl-4-[2-(5-phosphono)furanyl]thiazole (1
mmole) in acetonitrile and N,N,N-diisopropylethylamine (5 mmole)
was treated with pivaloyloxymethyl iodide (4 mmole) at 0.degree. C.
for 24 h. Extraction and chromatography gave
2-methyl-4-[2-(5-dipivaloyloxymethylphosphono)furanyl]-thiazole
(20.1). Anal. Calcd. for C.sub.20H.sub.28NO.sub.8PS: C, 50.59; H,
6.03; N, 2.65. Found: C, 50.73; H, 5.96; N, 2.96.
[1513] The following compounds were prepared according to this
procedure:
[1514] (20.2)
2-Methyl-5-isobutyl-4-{2-[5-(O-isobutyryloxymethyl-O-pivaloyloxymethyl)-p-
hosphono]furanyl}thiazole. Anal. Calcd. for
C.sub.23H.sub.34NO.sub.8PS: C, 53.58; H, 6.65; N, 2.72. Found: C:
53.&1; H, 6.83; N, 2.60.
[1515] (20.3)
2-Methyl-5-isobutyl-4-{2-[5-(dipivaloyloxymethyl)phosphono]furanyl}thiazo-
le. Anal. Calcd. for C.sub.24H.sub.36NO.sub.8PS: C, 54.43; H, 6.85;
N, 2.64. Found: C, 54.46; H, 7.04; N, 2.55.
[1516] (20.4)
2-Amino-5-isobutyl-4-{2-[5-(dipivaloyloxymethyl)phosphono]furanyl}thiazol-
e. Anal. Calcd. for C.sub.23H.sub.35N.sub.2O.sub.8PS: C, 52.07; H,
6.65; N, 5.28. Found: C, 52.45; H, 6.78; N, 5.01.
[1517] (20.5)
2-Bromo-5-isobutyl-4-{2-[5-(dipivaloyloxymethyl)phosphono]furanyl}thiazol-
e. Anal. Calcd. for C.sub.23H.sub.33NO.sub.8PSBr: C, 47.00; H,
5.75; N, 2.32. Found: C, 47.18; H, 5.46; N, 2.30.
[1518] The cyclic acyloxyalkyl phosphonate esters can also be
prepared in a similar manner according to Farquhar's procedure
(Farquhar, D. et al, Tetrahedron Lett. 1995, 36, 655).
[1519] (20.13)
2-Amino-5-isobutyl-4-{2-[5-(1-benzoyloxypropane-1,3-diyl)phosphono]furany-
l}thiazole, more polar isomer. MS calcd for
C.sub.21H.sub.23N.sub.2O.sub.6PS+H, 463, found 463.
[1520] (20.14)
2-Amino-5-isobutyl-4-{2-[5-(1-benzoyloxypropane-1,3-diyl)phosphono]furany-
l}thiazole, less polar isomer. MS calcd for
C.sub.21H.sub.23N.sub.2O.sub.6PS+H, 463, found 463.
[1521] Alkyloxycarbonyloxyalkyl phosphonate esters were also
prepared according to the above procedures with slight
modifications described below:
[1522] A solution of
2-methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (1 mmole) in
DMF was treated with N,N'-dicyclohexyl-4-morpholinecarboxamidine (5
mmole) and ethylpropyloxycarbonyloxymethyl iodide (5 mmole) which
was prepared from chloromethyl chloroformate according to the
reported procedure (Nishimura et al. J. Antibiotics, 1987, 40(1),
81-90). The reaction mixture was stirred at 25.degree. C. for 24 h,
and evaporation followed by chromatography gave
2-methyl-5-isobutyl-4-{-2-[5-bis(ethoxycarbonyloxymethyl)phosphono]furany-
l}thiazole (20.6). Anal. Calcd. for C.sub.20H.sub.28NO.sub.10PS: C,
47.52; H, 5.58; N, 2.77. Found: C, 47.52; H, 5.67; N, 2.80.
[1523] The following compounds were prepared according to this
procedure:
[1524] (20.7)
2-Methyl-5-isobutyl-4-{-2-[5-bis(isopropyloxycarbonyloxymethyl)phosphono]-
-furanyl}thiazole. Anal. Calcd. for C.sub.22H.sub.32NO.sub.10PS: C,
49.53; H, 6.05; N, 2.63. Found: C, 49.58; H, 6.14; N, 2.75.
[1525] (20.8)
2-Amino-5-isobutyl-4-{-2-[5-bis(phenoxycarbonyloxymethyl)phosphono]-furan-
yl}thiazole. Anal. Calcd. for C.sub.27H.sub.27N.sub.2O.sub.10PS: C,
53.82; H, 4.52; N, 4.65. Found: C, 54.03; H, 4.16; N, 4.30.
[1526] (20.9)
2-Amino-5-isobutyl-4-{-2-[5-bis(ethoxycarbonyloxymethyl)phosphono]-furany-
l}thiazole. Anal. Calcd. for C.sub.19H.sub.27N.sub.2O.sub.10PS: C,
45.06; H, 5.37; N, 5.53. Found: C, 45.11; H, 5.30; N, 5.43.
[1527] (20.10)
2-Methyl-5-isobutyl-4-{-2-[5-bis(isopropylthiocarbonyloxymethyl)-phosphon-
o]furanyl}thiazole. Anal. Calcd. for
C.sub.22H.sub.32NO.sub.8PS.sub.3+0.2 EtOAc: C, 46.95; H, 5.81; N,
2.40. Found: C, 47.06; H, 5.86; N, 2.73.
[1528] (20.11)
2-Amino-5-isobutyl-4-(2-[5-bis(isopropyloxycarbonyloxymethyl)phosphono]fu-
ranyl}thiazole. Anal. calcd. for C.sub.21H.sub.31N.sub.2O.sub.1PS:
C, 47.19; H, 5.85; N, 5.24. Found: C, 47.33; H, 5.66; N, 5.57.
[1529] (20.12)
2-Methyl-5-isobutyl-4-{2-[5-bis(benzoyloxymethyl)phosphono]furanyl}thiazo-
le. Anal. calcd. for
C.sub.28H.sub.28NO.sub.8PS+0.2CH.sub.2Cl.sub.2: C, 59.31; H, 5.40;
N, 2.64. Found: C, 59.25; H, 5.27; N, 2.44.
[1530] (20.15)
2-Amino-5-isobutyl-4-{2-[5-bis(1-(1-ethoxycarbonyloxy)ethyl)phosphono]-fu-
ranyl}thiazole. Mp 76-78.degree. C. Anal. calcd. for
C.sub.21H.sub.31N.sub.2O.sub.10PS: C, 47.19; H, 5.85; N, 5.42.
Found C, 48.06; H, 5.80; N, 5.16.
[1531]
2-Amino-5-isobutyl-4-{2-[5-bis(3-(5,6,7-trimethoxy)phthalidyl)phos-
phono]furanyl}thiazole is also synthesized following this procedure
using 3-bromo-5,6,7-trimethoxyphthalide as the alkylating
reagent
Example 21
Preparation of 3-(2-pyridyl)propan-1,3-diol
[1532] Step A. (J. Org. Chem., 1957, 22, 589) A solution of
3-(2-pyridyl)propanol in acetic acid was treated with 30% hydrogen
peroxide at 80.degree. C. for 16 h. The reaction was concentrated
under vacuum and the residue was dissolved in acetic anhydride and
heated at 110.degree. C. for 12 h. Evaporation and chromatography
gave 3-(2-pyridyl)-1,3-propanediol diacetate.
[1533] Step B. A solution of 3-(2-pyridyl)-1,3-propanediol
diacetate (1 mmole) in methanol-water (3:1) was treated with
potassium carbonate (5 mmole) at 25.degree. C. for 3 h. Evaporation
and chromatography gave 3-(2-pyridyl)-1,3-propanediol as a
solid.
Example 22
Preparation of 3-(2-hydroxyethyl)phthalide
[1534] A solution of phthalide-3-acetic acid (1 mmole) in THF was
treated with borane dimethylsulfide (1.5 mmole) at 0.degree. C. for
1 h, and at 25.degree. C. for 24 h. Extraction and chromatography
gave 2-(3-phthalidyl)ethanol as a light yellow oil: Rf=0.25, 50%
EtOAc-hexane.
Example 23
Preparation of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene
[1535] A solution of 4,5-dimethyl-2-oxo-1,3-dioxolene (1 mmole) and
selenium dioxide (2.5 mmole) in dioxane was heated at reflux for 1
h. Evaporation, extraction and chromatography gave
5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC:
Rf=0.5, 5% MeOH-dichloromethane.
[1536] A solution of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene
(1 mmole) in DMF was treated with tert-butyldimethylsilane (1.2
mmole) and imidazole (2.2 mmole) at 25.degree. C. for 24 h.
Extraction and chromatography gave
5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene.
[1537] A solution of
5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene (1
mmole) and Lawesson's reagent (1.2 mmole) in toluene was heated to
120.degree. C. for 12 h. Extraction and chromatography gave
5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolene.
[1538] A solution of
5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolene in
methanolic hydrogen chloride was stirred at 0.degree. C. for 1 h
and 25.degree. C. for 12 h. Extraction and chromatography gave
5-methyl-4-hydroxymethyl-2-thio-1,3-dioxolene.
Example 24
Preparation of Hydroxyethyldisulfidylethylphosphonate Diester
[1539] A suspension of
2-methyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (1 mmole) in
thionyl chloride (5 mL) is warmed at reflux for 4 h. The cooled
reaction mixture is evaporated to dryness and the resulting yellow
residue is treated with a solution of 2-hydroxyethyl disulfide (4
mmole), pyridine (2.5 mmole) in methylene chloride. After stirring
at 25.degree. C. for 4 h. the reaction is subjected to extraction
and chromatography to give two compounds:
2-methyl-5-isobutyl-4-(2-[5-bis(6'-hydroxy-3',4'-disulfide)hexylphosphono-
]furanyl}thiazole and
2-methyl-5-isobutyl-4-{2-[5-(3',4'-disulfide)nonacyclicphosphono]-furanyl-
}thiazole.
Example 25
Preparation of 3-[2-(5-phosphono)furanyl]pyrazoles
[1540] 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.
[1541] 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 (25.1). 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.
[1542] 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.
[1543] 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 (25.2).
Anal. Calcd. for
C.sub.12H.sub.17N.sub.2O.sub.4P+0.85HBr+0.75H.sub.2O: C, 39.32; H,
5.32; N, 7.64. Found: C, 39.59; H, 5.30; N, 7.47.
Example 26
Preparation of 3-[2-(5-phosphono)furanyl]isoxazoles
[1544] 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.
[1545] 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.
[1546] 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.
[1547] 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 (26.1). 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.
[1548] The following compound was prepared according to this
procedure:
[1549] (26.2)
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.
[1550] (26.3)
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.
[1551] (26.4)
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.
[1552] (26.5)
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.
[1553] (26.6)
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.
[1554] (26.7)
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.
[1555] (26.8) 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.
[1556] (26.9) 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 27
Preparation of 2-[2-(5-phosphono)furanyl]thiazoles
[1557] 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.
[1558] 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 (27.1). 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 28
Preparation of 4-(3,3-difluoro-3-phosphono-1-propyl)thiazoles
[1559] 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.
[1560] Step B. A solution of LDA (1.06 mmole) in THF was treated
with absolution 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.
[1561] Step C. A solution of diethyl
4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutyl-
phosphonate (11 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)-2,2-difluorobutylphosphonate as a
clear oil.
[1562] 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.
[1563] 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.
[1564] 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 (28.1) 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.
[1565] The following compound was prepared in a similar manner:
[1566]
2-Amino-5-methylthio-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazol-
e (28.2). MS m/e 305 (M+H).
Example 29
Preparation of 2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole
and 2-phosphonomethylthiopyridine
[1567] 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.
[1568] 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 (29.1) 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.
[1569] Alternatively, phosphonomethylthio substituted
heteroaromatics are made using the following method as exemplified
by the synthesis of 2-phosphonomethylthiopyridine:
[1570] 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.
[1571] Step D. 2-Diethylphosphonomethylthiopyridine was subjected
to Step C of Example 3 to give 2-phosphonomethylthiopyridine (29.2)
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 30
Preparation of 2-[(2-phosphono)ethynyl]pyridine
[1572] 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.
[1573] Step B. 2-[(2-Diethylphosphono)ethynyl]pyridine was
subjected to Step C of Example 3 to give
2-[1-(2-phosphono)ethynyl]pyridine (30.1) as a brown solid. Mp
160.degree. C. (decomp). MS m/e 184 (M+H).
Example 31
A. Preparation of Various Phosphoramides as Prodrugs
[1574] Step A. A solution of
2-methyl-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole
dichloridate (generated as in Example 19) (1 mmole) in
dichloromethane (5 mL) was cooled to 0.degree. C. and treated with
a solution of benzyl alcohol (0.9 mmole) in dichloromethane (0.5
mL) and pyridine (0.3 mL). The resulting reaction solution was
stirred at 0.degree. C. for 1 h, and then added a solution of
ammonia (excess) in THF. After stirring at room temperature for 16
h, the reaction was evaporated to dryness and the residue was
purified by chromatography to give
2-methyl-5-isopropyl-4-[2-(5-phosphonomonoamido)furanyl]thiazole
(31.1) as a yellow hard gum and
2-methyl-5-isopropyl-4-[2-(5-phosphorodiamido)furanyl]thiazole
(31.2) as a yellow hard gum.
[1575] (31.1)
2-Methyl-5-isopropyl-4-[2-(5-phosphonomonoamido)furanyl]thiazole:
MS m/e 299 (M-H).
[1576] (31.2)
2-Methyl-5-isopropyl-4-[2-(5-phosphorodiamido)furanyl]thiazole: MS
m/e 298 (M-H).
[1577] Alternatively, a different method was used to prepare other
phosphoramides as exemplified in the following procedure:
[1578] Step B. A suspension of
2-amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole
dichloridate (generated as in Example 19) (1 mmole) in
dichloromethane (5 mL) was cooled to 0.degree. C. and ammonia
(excess) was bubbled through the reaction for 10 min. After
stirring at room temperature for 16 h, the reaction was evaporated
to dryness and the residue was purified by chromatography to give
2-amino-5-methylthio-4-[2-(5-phosphorodiamido)furanyl]thiazole
(31.3) as a foam. Anal. Calcd for
C.sub.8H.sub.11N.sub.4O.sub.2PS.sub.2+1.5HCl+0.2 EtOH: C, 28.48; H,
3.90; N, 15.82. Found: C, 28.32; H, 3.76; N, 14.21.
[1579] The following compounds were prepared according to the above
described procedures or in some cases with minor modifications of
these procedures:
[1580] (31.4)
2-Amino-5-isobutyl-4-[2-(5-phosphonomonoamido)furanyl]thiazole. Mp
77-81.degree. C. Anal. Calcd for
C.sub.11H.sub.16N.sub.3O.sub.3PS+H.sub.2O+0.8 Et.sub.3N: C, 47.41;
H, 7.55; N, 13.30. Found: C, 47.04; H, 7.55; N, 13.67.
[1581] (31.5)
2-Amino-5-isobutyl-4-[2-(5-phosphorodiamido)furanyl]thiazole. Anal.
Calcd for C.sub.11H.sub.17N.sub.4O.sub.2PS+0.5H.sub.2O+0.75HCl: C,
39.24; H, 5.61; N, 16.64. Found: C, 39.05; H, 5.43; N, 15.82.
[1582] (31.28)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-diisobutyl)phosphoroadiamido]furanyl}-th-
iazole. Mp 182-183.degree. C. Anal. Calcd. for
C.sub.19H.sub.33N.sub.4O.sub.2PS: C, 55.32; H, 8.06; N, 13.58.
Found: C, 54.93; H, 7.75; N, 13.20.
[1583] (31.29)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-(1,3-bis(ethoxycarbonyl)-1-propyl)phosph-
oro)diamido]furanyl}thiazole. Anal. Calcd for
C.sub.29H.sub.45N.sub.4O.sub.6PS: C, 51.78: H, 6.74; N, 8.33.
Found: C, 51.70; H, 6.64; N, 8.15.
[1584] (31.30)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-(1-benzyloxycarbonyl)-1-ethyl)phosphorod-
iamido]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.
[1585] (31.31)
2-Amino-5-isobutyl-4-{2-[5-bis(2-methoxycarbonyl-1-azirdinyl)phosphorodia-
mido]furanyl}thiazole. Anal. Calcd for
C.sub.19H.sub.25N.sub.4O.sub.6PS+0.3CH.sub.2Cl.sub.2: C, 46.93; H,
5.22; N, 11.34. Found: C, 58.20; H, 5.26; N, 9.25.
[1586] (31.39)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-2-(1-ethoxycarbonyl)propyl)phosphorodiam-
ido]furanyl}thiazole. Anal. Calcd for
C.sub.23H.sub.37N.sub.4O.sub.6PS+0.6EtOAc+0.1 CH.sub.2Cl.sub.2: C,
51.91; H, 7.18; N, 9.50. Found: C, 51.78; H, 7.17; N, 9.26.
[1587] The monophenyl-monophosphonamide derivatives of compounds of
formula I can also be prepared according to the above described
procedures:
[1588] Step C. A solution of
2-amino-5-isobutyl-4-[2-(5-diphenylphosphono)furanyl]thiazole
(prepared according to the procedures of Example 19) (1 mmole) in
acetonitrile (9 .mu.L) and water (4 mL) was treated with lithium
hydroxide (1N, 1.5 mmole) at room temperature for 4 h. The reaction
solution was evaporated to dryness, and the residue was dissolved
in water (10 mL), cooled to 0.degree. C. and the pH of the solution
was adjusted to 4 by addition of 6 N HCl. The resulting white solid
was collected through filtration to give
2-amino-5-isobutyl-4-[2-(5-phenylphosphono)furanyl]thiazole
(19.64).
[1589] Step D. A suspension of
2-amino-5-isobutyl-4-[2-(5-phenylphosphono)furanyl]thiazole (1
mmole) in thionyl chloride (3 mL) was heated to reflux for 2 h. The
reaction solution was evaporated to dryness, and the residue was
dissolved in anhydrous dichloromethane (2 mL) and the resulting
solution was added to a solution of L-alanine methyl ester
hydrochloride (1.2 mmole) in pyridine (0.8 mL) and dichloromethane
(3 mL) at 0.degree. C. The resulting reaction solution was stirred
at room temperature for 14 h. Evaporation and chromatography gave
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-methoxycarbonyl)ethyl)phosphona-
mido]furanyl}thiazole (31.6) as an oil. Anal. calcd. for
C.sub.21H.sub.26N.sub.3O.sub.5PS: C, 54.42; H, 5.65; N, 9.07.
Found: C, 54.40; H, 6.02; N, 8.87.
[1590] The following compounds were prepared according to the above
described procedures:
[1591] (31.7)
2-amino-5-isobutyl-4-{2-[5-(O-phenylphosphonamido)]furanyl}thiazole.
mp 205.degree. C. (decomp). Anal. calcd. for
C.sub.17H.sub.20N.sub.3O.sub.3PS+0.3H.sub.2O+0.3HCl: C, 51.86; H,
5.35; N, 10.67. Found: C, 51.58; H, 4.93; N, 11.08.
[1592] (31.8)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-ethoxycarbonylmethyl)phosphonamido-
]furanyl}thiazole. Anal. calcd. for
C.sub.21H.sub.26N.sub.3O.sub.5PS: C, 54.42; H, 5.65; N, 9.07.
Found: C, 54.78; H, 5.83; N, 8.67.
[1593] (31.9)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-isobutyl)phosphonamido]furanyl}thi-
azole. mp 151-152.degree. C. Anal. calcd. for
C.sub.21H.sub.28N.sub.3O.sub.3PS: C, 58.18; H, 6.51; N, 9.69.
Found: C, 58.12; H, 6.54; N, 9.59.
[1594] (31.18)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-ethoxycarbonyl-2-phenyl)ethy-
l)phosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.28H.sub.32N.sub.3O.sub.5PS: C, 60.75; H, 5.83; N, 7.59.
Found: C, 60.35; H, 5.77; N, 7.37.
[1595] (31.19)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-ethoxycarbonyl-2-methyl)prop-
yl)phosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.23H.sub.30N.sub.3O.sub.5PS: C, 56.20; H, 6.15; N, 8.55.
Found: C, 55.95; H, 5.80; N, 8.35.
[1596] (31.20)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1,3-bis(ethoxycarbonyl)propyl)-
phosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.26H.sub.34N.sub.3O.sub.7PS+0.2 CH.sub.2Cl.sub.2: C, 54.20; H,
5.97; N, 7.24. Found C, 54.06; H, 5.68; N, 7.05.
[1597] (31.21)
2-amino-5-isobutyl-4-{2-[5-(O-(3-chlorophenyl)-N-(1-(1-methoxycarbonyl)et-
hyl)propyl)phosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.21H.sub.25N.sub.3O.sub.5PSCl: C, 50.65; H, 5.06; N, 8.44.
Found: C, 50.56; H, 4.78; N, 8.56.
[1598] (31.22)
2-amino-5-isobutyl-4-{2-[5-(O-(4-chlorophenyl)-N-(1-(1-methoxycarbonyl)et-
hyl)phosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.21H.sub.25N.sub.3O.sub.5PSCl+1HCl+0.2H.sub.2O: C, 46.88; H,
4.95; N, 7.81. Found: C, 47.33; H, 4.71; N, 7.36.
[1599] (31.23)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-bis(ethoxycarbonyl)methyl)ph-
osphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.24H.sub.30N.sub.3O.sub.7PS: C, 53.83; H, 5.65; N, 7.85.
Found: C, 53.54; H, 5.63; N, 7.77
[1600] (31.24)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-morpholinyl)phosphonamido)]fura-
nyl}thiazole. Anal. calcd. for C.sub.21H.sub.26N.sub.3O.sub.4PS: C,
56.37; H, 5.86; N, 9.39. Found: C, 56.36; H, 5.80; N, 9.20.
[1601] (31.25)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-benzyloxycarbonyl)ethyl)phos-
phonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.27H.sub.30N.sub.3O.sub.5PS: C, 60.10; H, 5.60; N, 7.79.
Found: C, 59.80; H, 5.23; N, 7.53.
[1602] (31.32)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-benzyloxycarbonylmethyl)phosphonam-
ido)]furanyl}thiazole. Anal. calcd. for
C.sub.26H.sub.28N.sub.3O.sub.5PS: C, 59.42; H, 5.37; N, 8.00.
Found: C, 59.60; H, 5.05; N, 7.91.
[1603] (31.36)
2-amino-5-isobutyl-4-{2-[5-(O-(4-methyoxyphenyl)-N-(1-(1-methoxycarbonyl)-
ethyl)phosphonamido)]furanyl}thiazole. Anal. calcd. for
C.sub.22H.sub.28N.sub.3O.sub.6PS+0.1 CHCl.sub.3+0.1 MeCN: C, 52.56;
H, 5.62; N, 8.52. Found: C, 52.77; H, 5.23: N, 8.87.
[1604] (31.37)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-2-methoxycarbonyl)propyl)phosphona-
mido)]furanyl}thiazole. Anal. calcd. for
C.sub.22H.sub.28N.sub.3O.sub.5PS+0.6H.sub.2O: C, 54.11; H, 6.03; N,
8.60. Found: C, 53.86; H, 5.97; N, 8.61.
[1605] (31.38)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(2-(1-ethoxycarbonyl)propyl)phosph-
onamido)]furanyl}thiazole. Anal. calcd. for
C.sub.23H.sub.30N.sub.3O.sub.5PS: C, 56.20; H, 6.15; N, 8.55.
Found: C, 55.90; H, 6.29; N, 8.46.
[1606] The reaction of a dichlorophosphonate with a
1-amino-3-propanol in the presence of a suitable base (e.g.
pyridine, triethylamine) can also be used to prepare cyclic
phosphoramidates as prodrugs of phosphonates. The following
compounds were prepared in this manner:
[1607] (31.10)
2-Methyl-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]furanyl}th-
iazole minor isomer. Anal. calcd. for
C.sub.21H.sub.25N.sub.2O.sub.3PS+0.25H.sub.2O+0.1HCl: C, 59.40; H,
6.08; N, 6.60. Found: C, 59.42; H, 5.72; N, 6.44.
[1608] (31.11)
2-Methyl-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]furanyl}th-
iazole major isomer. Anal. calcd. for
C.sub.21H.sub.2SN.sub.2O.sub.3PS+0.25H.sub.2O: C, 59.91; H, 6.11;
N, 6.65. Found: C, 60.17; H, 5.81; N, 6.52.
[1609] (31.12)
2-Amino-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]furanyl}thi-
azole major isomer. Anal. calcd. for
C.sub.20H.sub.24N.sub.3O.sub.3PS+0.25H.sub.2O+0.1 CH.sub.2Cl.sub.2:
C, 55.27; H, 5.72; N, 9.57. Found: C, 55.03; H, 5.42; N, 9.37.
[1610] (31.13)
2-Amino-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]furanyl}thi-
azole minor isomer. Anal. calcd. for
C.sub.20H.sub.24N.sub.3O.sub.3PS+0.15 CH.sub.2Cl.sub.2: C, 56.26;
H, 5.69; N, 9.77. Found: C, 56.36; H, 5.46; N, 9.59.
[1611] (31.14)
2-Amino-5-methylthio-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]furanyl}t-
hiazole less polar isomer. Anal. calcd. for
C.sub.17H.sub.18N.sub.3O.sub.3PS.sub.2+0.4HCl: C, 48.38; H, 4.39;
N, 9.96. Found: C, 48.47; H, 4.21; N, 9.96.
[1612] (31.15)
2-Amino-5-methylthio-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]furanyl}t-
hiazole more polar isomer. Anal. calcd. for
C.sub.17H.sub.18N.sub.3O.sub.3PS.sub.2: C, 50.11; H, 4.45; N,
10.31. Found: C, 49.84; H, 4.19; N, 10.13.
[1613] (31.16)
2-Amino-5-methylthio-4-{2-[5-(N-methyl-1-phenyl-1,3-propyl)phosphonamido]-
furanyl}thiazole. Anal. calcd. for
C.sub.18H.sub.20N.sub.3O.sub.3PS.sub.2+0.25HCl: C, 50.21; H, 4.74;
N, 9.76. Found: C, 50.31; H, 4.46; N, 9.79.
[1614] (31.17)
2-Amino-5-methylthio-4-{2-[5-(1-phenyl-1,3-propyl)-N-acetylphosphonamido]-
furanyl}thiazole. Anal. calcd. for
C.sub.22H.sub.26N.sub.3O.sub.4PS+1.25H.sub.2O: C, 54.82; H, 5.96;
N, 8.72. Found: C, 55.09; H, 5.99; N, 8.39.
[1615] (31.26)
2-amino-5-isobutyl-4-{2-[5-(1-oxo-1-phospha-2-oxa-7-aza-3,4-benocyclohept-
an-1-yl)]furanyl}thiazole, major isomer. Mp 233-234.degree. C.
Anal. calcd. for C.sub.21H.sub.24N.sub.3O.sub.5PS+0.2 CHCl.sub.3:
C, 52.46; H, 5.03; N, 8.66. Found C, 52.08; H, 4.65; N, 8.58.
[1616] (31.27)
2-amino-5-isobutyl-4-{2-[5-(1-oxo-1-phospha-2-oxa-7-aza-3,4-benocyclohept-
an-1-yl)]furanyl}thiazole, minor isomer. MS calcd. for
C.sub.21H.sub.24N.sub.3O.sub.5PS+H: 462, found 462.
[1617] (31.34)
2-amino-5-isobutyl-4-{2-[5-(3-(3,5-dichlorophenyl)-1,3-propyl)phosphonami-
do]furanyl}thiazole. Anal. calcd. for
C.sub.20H.sub.22N.sub.3O.sub.3PSCl.sub.2: C, 49.39; H, 4.56; N,
8.64. Found: C, 49.04; H, 4.51; N, 8.37.
[1618] (31.35)
2-amino-5-isobutyl-4-{2-[5-(4,5-benzo-1-oxo-1-phospha-2-oxa-6-aza)cyclohe-
xan-1-yl]furanyl}thiazole. Anal. calcd. for
C.sub.18H.sub.20N.sub.3O.sub.3PS+0.7H.sub.2O: C, 53.78; H, 5.37; N,
10.45. Found C, 53.63; H, 5.13; N, 10.36.
Example 32
Preparation of 5-[2-(5-phosphono)furanyl]tetrazole
[1619] 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.
[1620] 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.
[1621] Step C. A mixture of 5-iodo-2-diethylphosphonofuran (1
mmole), 2-benzyloxymethyl-5-(tributylstannyl)tetrazole (1.05
mmole), tetrakis(triphenylphosphine) palladium(0) (0.03 mmole) and
copper(I) iodide (0.07 mmole) in 3 mL of toluene was refluxed at
110.degree. C. for 20 h. Evaporation and chromatography provided
2-benzyloxymethyl-5-[2-(5-diethylphosphono)furanyl]tetrazole as an
oil.
[1622] 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 (32.1) 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.
[1623] Step E.
[1624] 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.2Cl.sub.2 layer was evaporated and combined with the
product of the following reaction for chromatography.
[1625] 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.
[1626] 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 (32.2) 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.
[1627] 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.
[1628] (32.3) 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 33
High Throughput Synthesis of Various 2-(5-phosphono)furanyl
Substituted Heteroaromatic Compounds
[1629] 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.
[1630] 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.
[1631] 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.
[1632] 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 10 min),
CH.sub.3CN (2 10 min) and then 9:1 CH.sub.3CN:water (1 1 0 min).
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.
[1633] 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 10 min), CH.sub.3CN (2 10 min) and
then 9:1 CH.sub.3CN:water (1 10 min). 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.
[1634] 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
[1635] 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.
[1636] 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.
[1637] Step I. To coupled phosphonate resin (2.41 mmol) in THF (100
mL) was added 1M 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
[1638] 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 L), combined with TMSBr (100 L) and mixed for
6 h. The mixture was filtered, the resin washed with anhydrous
CH.sub.2Cl.sub.2 (500 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 L). After shaking for 30 min. the
solvents were removed to provide the desired
[{N-(phosphono)acetyl]amino} substituted heteroaromatic analogs.
Compounds 33.97-33.119 and 33.146-33.164 were synthesized according
to these procedures and they are listed in Table 33.1 and Table
33.2.
Preparation of the Aminomethylphosphonate Resin
[1639] 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.
[1640] Step L. As described above in Step H, monomethyl
phthalimidomethylphosphonate was coupled to
hydroxymethylpolystyrene to give the resin-coupled
phthalimidomethylphosphonate monomethyl ester.
[1641] 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.
[1642] 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 L), combined with TMSBr (50 L)
and mixed for 6 h. The mixture was filtered, the resin washed with
anhydrous CH.sub.2Cl.sub.2 (500 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 L). After shaking for 30 min the
solvents were evaporated to provide the desired
(N-phosphonomethyl)carbamoyl substituted heteroaromatic analogs.
Compounds 33.120-33.145 were synthesized according to these
procedures and they are listed in Table 33.2.
[1643] 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.
[1644] 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.
TABLE-US-00013 HPLC Elution Program: 1.5 mL/min flow rate Time
(min) % Acetonitrile (A) % Buffer.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
[1645] TABLE-US-00014 ##STR121## synthetic HPLC example Rt number A
B X Y' (min.) M-1 found 33.146 H Br NHC(O)CH2 S 6.58 299/301 33.147
H Ph NHC(O)CH2 S 6.57 297 33.148 Ph H NHC(O)CH2 S 6.06 297 33.149
Ph Et NHC(O)CH2 O 309 33.150 H H NHC(O)CH2 S 4.22 221 33.151
adamantyl Me NHC(O)CH2 S 6.59 369 33.152 Bu-t Br NHC(O)CH2 S 6.62
355/357 33.153 H Ph(-4-Br) NHC(O)CH2 S 6.62 375/377 ##STR122##
synthetic HPLC example Rt number A* B* X Y' (min.) M-1 found 33.154
H H NHC(O)CH2 O 6.68 205 33.155 null NH2 NHC(O)CH2 O 6.6 221 33.156
NHMe null NHC(O)CH2 S 3.82 251 33.157 Me H NHC(O)CH2 NH 33.158 H H
NHC(O)CH2 NH 33.159 OH H NHC(O)CH2 NH 33.160 Bu-t H NHC(O)CH2 O
6.62 261 33.161 null 3-pyridyl NHC(O)CH2 O 6.58 283 33.162
CH2Ph(2,6- null NHC(O)CH2 O dichloro) 33.163 Br null furan-2,5-diyl
NH 4.46 292/294 33.164 Br null furan-2,5-diyl S 5.96 309/311 *when
A or B is null, then the correspondimg G is N.
[1646] TABLE-US-00015 TABLE 33.2 ##STR123## synthetic HPLC example
Rt M-1 number A* B* X D* E* (min.) found 33.1 NH2 Cl furan-2,5-diyl
Me null 11.06 288 33.2 H OC(O)(Ph-2,6- furan-2,5-diyl H H 3.99 413
dichloro) 33.3 OMe H furan-2,5-diyl CH2OH H 8.34 284 33.4 OMe H
furan-2,5-diyl C(O)NH2 H 8.23 297 33.5 OMe H furan-2,5-diyl CO2H H
9.54 298 33.6 OH H furan-2,5-diyl CF3 C(O)NH2 3.91 351 33.7 OMe H
furan-2,5-diyl CF3 C(O)NH2 9.14 365 33.8 null H furan-2,5-diyl H
OMe 9.72 255 33.9 null H furan-2,5-diyl H OH 4.52 241 33.10 OH H
furan-2,5-diyl Me null 3.79 255 33.11 OMe H furan-2,5-diyl Me null
6.44 269 33.12 NH2 null furan-2,5-diyl OH H 3.96 256 33.13 NH2 null
furan-2,5-diyl OMe H 8.02 270 33.14 H OMe furan-2,5-diyl null H
7.22 255 33.15 H OH furan-2,5-diyl null H 4.82 241 33.16 OMe H
furan-2,5-diyl null H 7.48 255 33.17 OEt H furan-2,5-diyl H H 9.72
268 33.18 OEt H furan-2,5-diyl CH2OH H 5.26 298 33.19 null H
furan-2,5-diyl Me OEt 7.80 283 33.20 null H furan-2,5-diyl Me OH
3.80 255 33.21 OH H furan-2,5-diyl Me null 3.77 255 33.22 OEt H
furan-2,5-diyl Me null 7.33 283 33.23 NH2 null furan-2,5-diyl OH H
3.94 256 33.24 NH2 null furan-2,5-diyl OEt H 5.66 284 33.25 NH2 H
furan-2,5-diyl OEt null 5.90 284 33.26 NH2 H furan-2,5-diyl OH null
3.78 256 33.27 H OEt furan-2,5-diyl null H 9.74 269 33.28 H OH
furan-2,5-diyl null H 4.81 241 33.29 OEt H furan-2,5-diyl null H
9.78 269 33.30 Br H furan-2,5-diyl H NO2 7.78 347/ 33.31 Cl H
furan-2,5-diyl H C(O)OEt 9.69 330 33.32 Br H furan-2,5-diyl H
C(O)OEt 9.69 374/376 33.33 Cl H furan-2,5-diyl Me C(O)NH2 3.72 315
33.34 Cl CF3 furan-2,5-diyl H CF3 9.04 394 33.35 Cl H
furan-2,5-diyl NH2 H 4.89 273 33.36 Cl H furan-2,5-diyl CN H 7.93
283 33.37 Cl H furan-2,5-diyl CH2OH H 5.38 288 33.38 Cl H
furan-2,5-diyl C(O)NH2 H 5.57 301 33.39 Cl H furan-2,5-diyl C(O)OEt
H 8.54 330 33.40 Cl 1-triazinyl(3- furan-2,5-diyl H H 8.91 398
amino-5- methylthio) 33.41 Cl H furan-2,5-diyl Me CN 8.22 297 33.42
Cl H furan-2,5-diyl CF3 NH2 8.60 341 33.43 Cl H furan-2,5-diyl CF3
CN 8.66 351 33.44 null CH3 furan-2,5-diyl Me Br 9.25 331/333 33.45
null CH3 furan-2,5-diyl Me Cl 9.25 287 33.46 Br CH3 furan-2,5-diyl
H null 5.62 317/319 33.47 Br Br furan-2,5-diyl H null 3.54 381/383/
385 33.48 Br H furan-2,5-diyl Me null 5.55 317/ 319 33.49 H NH2
furan-2,5-diyl Br null 4.78 318/ 320 33.50 Br Cl furan-2,5-diyl Br
null 8.38 417/ 419 33.51 SMe Ph furan-2,5-diyl Br null 9.26 425/
427 33.52 NH2 H furan-2,5-diyl Br null 4.87 318/ 320 33.53 NH2 H
furan-2,5-diyl OH null 3.70 256 33.54 Br H furan-2,5-diyl Br null
9.64 381/383/ 385 33.55 Br H furan-2,5-diyl Cl null 9.64 337/339
33.56 H Br furan-2,5-diyl null H 5.08 303/ 305 33.57 NH2 Cl
furan-2,5-diyl null C(O)OMe 3.34 332 33.58 OPr-n H furan-2,5-diyl
Me null 8.14 297 33.59 H OPr-n furan-2,5-diyl null H 8.45 283 33.60
H O(CH2)2OEt furan-2,5-diyl null H 7.82 313 33.61 NH2 null
furan-2,5-diyl OH H 3.97 256 33.62 NH2 null furan-2,5-diyl OPr-n H
7.84 298 33.63 OPr-n H furan-2,5-diyl CH2OH H 4.36 312 33.64 OBu-n
H furan-2,5-diyl CH2OH H 8.58 326 33.65 O(CH2)2OEt H furan-2,5-diyl
CH2OH H 4.13 342 33.66 NH2 H furan-2,5-diyl OPr-n null 7.96 298
33.67 NH2 H furan-2,5-diyl OBu-n null 3.86 312 33.68 H OBu-i
furan-2,5-diyl null H 8.80 297 33.69 H O(CH2)2OEt furan-2,5-diyl
null H 7.14 299 33.70 H O(CH2)2NMe2 furan-2,5-diyl null H 4.57 312
33.71 NH2 null furan-2,5-diyl OBu-i H 8.06 312 33.72 NH2 null
furan-2,5-diyl O(CH2)2OMe H 4.84 314 33.73 NH2 H furan-2,5-diyl
OBu-i null 8.70 312 33.74 Br H furan-2,5-diyl C(O)NH2 H 7.68
346/348 33.75 NH2 null furan-2,5-diyl Cl H 4.77 274 33.76
NH(CH2)2OH H furan-2,5-diyl Me null 4.56 298 33.77 H NH(CH2)2OH
furan-2,5-diyl null H 4.55 284 33.78 NH2 null furan-2,5-diyl
NH(CH2)2OH H 4.58 299 33.79 NH(CH2)2OH H furan-2,5-diyl NH2 null
4.58 299 33.80 NH(CH2)2OH H furan-2,5-diyl CH2OH H 4.44 313 33.81
NH2 H furan-2,5-diyl NH(CH2)2OH null 4.33 299 33.82 NHCH2-- H
furan-2,5-diyl CH3 null 4.65 312 CH(OH)Me 33.83 NH2 null
furan-2,5-diyl NHCH2-- H 4.63 313 CH(OH)Me 33.84 NHCH2-- H
furan-2,5-diyl NH2 null 4.63 313 CH(OH)Me 33.85 NHCH2-- H
furan-2,5-diyl CH2OH H 4.52 327 CH(OH)Me 33.86 NH2 H furan-2,5-diyl
NHCH2-- null 4.65 313 CH(OH)Me 33.87 NH(CH2)3OH H furan-2,5-diyl Me
null 4.62 312 33.88 NH2 null furan-2,5-diyl NH(CH2)3OH H 4.48 313
33.89 NH(CH2)3OH H furan-2,5-diyl NH2 null 4.48 313 33.90 NH2
NH(CH2)3OH furan-2,5-diyl null C(O)NH-- 4.76 414 (CH2)3OH 33.91 H
4-morpholinyl furan-2,5-diyl null H 6.46 310 33.92 4-morpholinyl H
furan-2,5-diyl Me null 6.53 324 33.93 NH2 null furan-2,5-diyl
4-morpholinyl H 6.15 325 33.94 4-morpholinyl H furan-2,5-diyl NH2
null 4.84 325 33.95 NH2 4-morpholinyl furan-2,5-diyl null C(O)(4-
7.47 438 morpholinyl) 33.96 NH2 H furan-2,5-diyl 4-morpholinyl null
5.30 325 33.97 Me H NHC(O)CH2 H H 6.58 229 33.98 H Me NHC(O)CH2 H H
6.60 229 33.99 NH2 H NHC(O)CH2 H Cl 6.63 264 33.100 NH2 Cl
NHC(O)CH2 H H 6.63 264 33.101 H OH NHC(O)CH2 H H 6.54 231 33.102 Me
H NHC(O)CH2 Me H 6.59 243 33.103 H H NHC(O)CH2 H Cl 7.02 249 33.104
H H NHC(O)CH2 H Br 8.01 293/295 33.105 Me H NHC(O)CH2 H Br 6.64
307/309 33.106 H H NHC(O)CH2 H H 6.72 215 33.107 H H NHC(O)CH2 H Me
6.54 229 33.108 H H NHC(O)CH2 Me H 6.53 229 33.109 Me Cl NHC(O)CH2
Me null 3.93 279 33.110 Cl H NHC(O)CH2 null H 4.20 251 33.111 H Br
NHC(O)CH2 H Me 6.44 307/309 33.112 NH2 H NHC(O)CH2 NH(Ph-4-Br) null
4.42 401/403 33.113 NH2 Bn NHC(O)CH2 H Bn 6.49 410 33.114 H H
NHC(O)CH2 Et H 6.57 243 33.115 Me Et NHC(O)CH2 H H 6.54 257 33.116
Me H NHC(O)CH2 H Br 6.55 307/309 33.117 H Br NHC(O)CH2 H Me 6.51
307/309 33.118 H Me NHC(O)CH2 H Br 6.52 307/309 33.119 Me Br
NHC(O)CH2 H Br 6.19 385/387/ 389 33.120 H H C(O)NHCH2 H H 3.74 215
33.121 Me H C(O)NHCH2 H H 229 33.122 OH H C(O)NHCH2 H H 3.72 231
33.123 Br H C(O)NHCH2 H H 5.02 293/295 33.124 Cl H C(O)NHCH2 H H
4.60 249/251 33.125 H H C(O)NHCH2 Cl H 5.18 249/251 33.126 H Br
C(O)NHCH2 OH H 3.60 310/312 33.127 H H C(O)NHCH2 null H 3.70 216
33.128 H H C(O)NHCH2 NO2 H 5.00 260 33.129 H H C(O)NHCH2 H Bu-n
8.35 271 33.130 H OPr-n C(O)NHCH2 H H 7.46 273 33.131 Cl Cl
C(O)NHCH2 H H 4.23 283/285/ 287 33.132 Cl CF3 C(O)NHCH2 H H 8.05
317/319 33.133 H Cl C(O)NHCH2 H CF3 6.49 317/319 33.134 H Cl
C(O)NHCH2 Cl Cl 7.20 318/320/ 322 33.135 H C(O)Ph C(O)NHCH2 H H
7.00 319 33.136 H OEt C(O)NHCH2 H CF3 6.65 327 33.137 SMe Cl
C(O)NHCH2 H null 5.82 296/298 33.138 SMe Br C(O)NHCH2 H null 5.40
340/342 33.139 H O(Ph-3-CF3) C(O)NHCH2 null H 376 33.140 H H
C(O)NHCH2 null Me 3.75 230 33.141 H Me C(O)NHCH2 H H 4.96 229
33.142 Cl Cl C(O)NHCH2 Cl Cl 9.18 351/353/ 355/357 33.143 H F
C(O)NHCH2 OH null 250 33.144 Me F C(O)NHCH2 OH null 264 33.145 OH F
C(O)NHCH2 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 34
Preparation of
2-amino-4-phosphonomethyloxy-6-bromobenzothiazole
[1647] 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.
[1648] 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.
[1649] 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.
[1650] 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 (34.1) 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.
[1651] Similarly, the following compounds were prepared according
to the above described procedures:
[1652] (34.2) 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 35
Preparation of
2-amino-4-phosphonomethyloxy-6-bromo-7-chlorobenzothiazole
[1653] 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 34 to give
2-amino-4-phosphonomethoxy-6-bromo-7-chloro benzothiazole (35.1).
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.
[1654] Similarly, the following compounds were prepared according
to the above described procedures:
[1655] (35.2) 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: C, 30.25; H, 2.50; N, 7.77.
[1656] (35.3) 2-Amino-4-phosphonomethoxy-7-methylbenzothiazole.
mp>220.degree. C. (dec.). Anal. Calcd. for
C.sub.9H.sub.11N.sub.2O.sub.4PS+1.0H.sub.2O: C, 36.99; H, 4.48; N,
9.59. Found: C, 36.73; H, 4.23; N, 9.38.
[1657] (35.4) 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 36
Preparation of
2-Amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
[1658] Step A. 3-Amino-2-hydroxy-5,6,7,8-tetrahydronaphthalene was
subjected to Step B of Example 34 to give
3-amino-2-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphthalene.
[1659] 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.
[1660] Step C.
2-Amino-4-diethylphosphonomethyloxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiaz-
ole was subjected to Step D of Example 34 to give
2-Amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(36.1). mp>220.degree. C. (dec.). Anal. Calcd. for
C.sub.12H.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.
[1661] The following compounds were also prepared according to
above procedures:
[1662] (36.2) 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.
[1663] (36.3)
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.
Example 37
Preparation of
2-Amino-7-methoxy-6-thiocyanato-4-phosphonomethoxybenzothiazole
[1664] Step A. 2-Hydroxy-5-methoxynitrobenzene was subjected to
Step B of Example 34 to give
2-diethylphosphonomethyloxy-5-methoxynitrobenzene.
[1665] 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.
[1666] Step C. 2-Diethylphosphonomethyloxy-5-methoxyaniline was
subjected to Step B of Example 36 to give
2-amino-4-diethylphosphonomethyloxy-6-thiocyano-7-methoxybenzothiazole,
which was subjected to Step D of Example 34 to give
2-amino-7-methoxy-6-thiocyanato-4-phosphonomethoxybenzothiazole
(37.1). 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.
[1667] Similarly, the following compounds were prepared according
to above procedures:
[1668] (37.2) 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.
[1669] (37.3)
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.
[1670] (37.4)
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 38
Preparation of 2-Amino-7-bromo-6-thiocyanato-4-phosphonomethoxy
benzothiazole
[1671] 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.
[1672] Step B. 2-Diethylphosphonomethyloxy-5-bromonitrobenzene was
subjected to Step B of Example 37, Step B of Example 36, and Step D
of Example 34 to give
2-amino-7-bromo-6-thiocyanato-4-phosphonomethoxybenzothiazole
(38.1). 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.
[1673] Similarly, the following compound was prepared according to
above procedures:
[1674] (38.2)
2-Amino-7-fluoro-6-thiocyanato-4-phosphonomethoxybenzothiazole.
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.
Example 39
Preparation of
2-Amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethoxy
benzothiazole
[1675] Step A. 2-Chloro-5-formylnitrobenzene was subjected to Step
A of Example 38 to give
2-diethylphosphonomethyloxy-5-formylnitrobenzene.
[1676] 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 36 followed by Step D of Example 34
to give
2-amino-7-hydroxymethyl-6-thiocyanato-4-phosphonomethoxybenzothiazole
(39.1). 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; H,
3.05; N, 11.88. Found: C, 33.76; H, 2.66; N, 11.61.
Example 40
Preparation of
2-Amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole
[1677] 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 34 to give
2-amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole (40.1).
Anal. Calcd. for C.sub.8H.sub.7N.sub.2O.sub.4PSBrF+0.1HBr: C,
26.31; H, 1.96; N, 7.67. Found: C, 25.96; H, 1.94; N, 7.37.
Example 41
Preparation of 2-Amino-7-ethyl-6-thiocyano-4-phosphonomethoxy
benzothiazole
[1678] Step A. A solution of
2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared
as in Example 37, Step A) 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 38, Step B of
Example 36, and Step D of Example 34 to give
2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (41.1).
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.
Example 42
Preparation of
2-Amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxy
benzothiazole
[1679] Step A. A suspension of
2-diethylphosphonomethyloxy-5-vinylnitrobenzene (1 mmole, prepared
as in Step A of Example 40) 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 37, Step B of Example 36, and
Step D of Example 34 to give
2-amino-7-cyclopropyl-6-thiocyanato-4-phosphonomethoxybenzothiazo-
le hydrogen bromide (42.1). 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 43
Preparation of 2-Amino-4-phosphonomethoxy-6-chloro-7-methyl
benzothiazole
[1680] Step A. 2-Methoxy-4-chloro-5-methylaniline was subjected to
Steps A and B of Example 34, Step B of Example 36, and Step D of
Example 34 to give 2-amino-4-phosphonomethoxy-6-chloro-7-methyl
benzothiazole (43.1). 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.
[1681] Similarly, the following compounds were prepared according
to above procedures:
[1682] (43.2)
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 44
Preparation of
2-bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e
[1683] 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) dropwisely. 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.
[1684] Step B.
2-Bromo-4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazol-
e was subjected to Step D of Example 34 to give
2-bromo-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(44.1) 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.
Example 45
Preparation of
4-diethylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
[1685] 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 34 to give
4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (45.1)
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.
Example 46
Preparation of 2-Amino-4-phosphonomethythio benzothiazole
[1686] Step A. 2-Diethylphosphonomethylthioaniline, prepared
according to Step B of Example 34, was subjected to Step B of
Example 36 to give
2-amino-4-diethylphosphonomethythiobenzothiazole:
[1687] Step B. 2-Amino-4-diethylphosphonomethythiobenzothiazole was
subjected to Step D of Example 34 to give
2-amino-4-phosphonomethythiobenzothiazole (46.1) 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 47
Preparation of Various Prodrugs of Benzothiazoles
[1688] Step A. A suspension of
2-amino-4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(1 mmole) in DMF (10 mL) was treated with DCC (3 mmole) followed by
3-(3,5-dichloro)phenyl-1,3-propanediol (1.1 mmole). The resulting
mixture was heated at 80.degree. C. for 8 h. Evaporation followed
by column chromatography gave
2-amino-4-{[3-(3,5-dichlorophenyl)propane-1,3-diyl]phosphonomethoxy}-5,6,-
7,8-tetrahydronaphtho[1,2-d]thiazole (47.1) as solid.
mp>230.degree. C. Anal. Calcd. for
C.sub.21H.sub.21N.sub.2O.sub.4PSCl.sub.2: C, 50.51; H, 4.24; N,
5.61. Found: C, 50.83; H, 4.34; N, 5.25.
[1689] Step B. A solution of
4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
dichloridate (generated as in Example 19) (1 mmole) in
dichloromethane (5 mL) is cooled to 0.degree. C. and treated with a
solution of benzyl alcohol (0.9 mmole) in dichloromethane (0.5 mL)
and pyridine (0.3 mL). The resulting reaction solution is stirred
at 0.degree. C. for 1 h, and then added a solution of ammonia
(excess) in THF. After stirring at room temperature for 16 h, the
reaction is evaporated to dryness and the residue is purified by
chromatography to give of
4-phosphonomonoamidomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole.
[1690] Alternatively, a different method is used to prepare other
phosphoramides as exemplified in the following procedure:
[1691] Step C. A suspension of
4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
dichloridate (generated as in Example 19) (1 mmole) in
dichloromethane (5 mL) is cooled to 0.degree. C. and ammonia
(excess) is bubbled through the reaction for 10 min. After stirring
at room temperature for 16 h, the reaction is evaporated to dryness
and the residue is purified by chromatography to give
4-(phosphorodiamido)methoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole.
[1692] The monophenyl-monophosphonamide derivatives of compounds of
formula X can also be prepared according to the above described
procedures:
[1693] Step D. A solution of
4-diphenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(prepared according to the procedures of Example 19) (1 mmole) in
acetonitrile (9 mL) and water (4 mL) is treated with lithium
hydroxide (1N, 1.5 mmole) at room temperature for 24 h. The
reaction solution is evaporated to dryness, and the residue is
dissolved in water (10 mL), cooled to 0.degree. C. and the pH of
the solution is adjusted to 4 by addition of 6 N HCl. The resulting
white solid is collected through filtration to give
4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole.
[1694] Step E. A suspension of
4-phenylphosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole
(1 mmole) in thionyl chloride (3 mL) is heated to reflux for 2 h.
The reaction solution is evaporated to dryness, and the residue is
dissolved in anhydrous dichloromethane (2 mL) and the resulting
solution is added to a solution of L-alanine ethyl ester
hydrochloride (1.2 mmole) in pyridine (0.8 mL) and dichloromethane
(3 mL) at 0.degree. C. The resulting reaction solution is stirred
at room temperature for 14 h. Evaporation and chromatography give
4-[O-phenyl-N-(1-ethoxycarbonyl)ethylphosphonamido]methoxy-5,6,7,8-tetrah-
ydronaphtho[1,2-d]thiazole.
[1695] Step F. A solution of
4-phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2-d]thiazole (1
mmole) in DMF is treated with
N,N'-dicyclohexyl-4-morpholinecarboxamidine (5 mmole) and
ethylpropyloxycarbonyloxymethyl iodide (5 mmole) which was prepared
from chloromethyl chloroformate according to the reported procedure
(Nishimura et al. J Antibiotics, 1987, 40, 81). The reaction
mixture is stirred at 25 oC for 24 h. Evaporation and
chromatography give
4-bis(ethoxycarbonyloxymethyl)phosphonomethoxy-5,6,7,8-tetrahydronaphtho[-
1,2-d]thiazole.
[1696]
4-(Dipivaloyloxymethyl)phosphonomethoxy-5,6,7,8-tetrahydronaphtho[-
1,2-d]thiazole and
4-bis(isobutyryloxymethyl)phosphonomethoxy-5,6,7,8-tetrahydronaphtho[1,2--
d]thiazole are also prepared in a similar manner.
Example 48
General Procedure for Bis-Phosphoroamide Prodrugs
Dichloridate Formation
[1697] 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:
[1698] Method A: The crude dichloridate was taken into 5 mL of dry
CH.sub.2Cl.sub.2, and was added 8 mmol of aminoacid 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.
[1699] 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 aminoacid
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.
The following compounds were prepared in this manner.
[1700] (48.1) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-glutamic acid
diethylester) phosphonoamido)furanyl]thiazole. Anal. cald. 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.
[1701] (48.2) 2-Amino-5-isobutyl-4-[2-(5-N,N-bis(L-alanine acid
dibenzyl ester)phosphonoamido)furanyl]thiazole. Anal. cald. 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.
[1702] (48.3)
2-Amino-5-isobutyl-4-{2-[5-(N,Nbis(benzyloxycarbonylmethyl)phosphonodiami-
do]furanyl}thiazole. Anal. cald. 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.
[1703] (48.4)
2-Amino-5-isobutyl-4-{2-[5-(N,N-bis(benzyloxycarbonylmethyl)phosphonodiam-
ido]furanyl}thiazole. Anal. cald. 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.
[1704] (48.5)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((R)-1-methoxycarbonyl)ethyl)
phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1705] (48.6)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl)ethyl)phosphona-
mido]furanyl}thiazole. mp. 164-165.degree. C.: Anal. cald. 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.
[1706] (48.7)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((t-butoxycarbonyl)methyl)phosphonami-
do]furanyl}thiazole. Anal. cald. 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.
[1707] (48.8)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis(ethoxycarbonyl)methyl)phosphonamido)-
]furanyl}thiazole. Anal. cald. 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.
[1708] (48.9)
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. cald.
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.
[1709] (48.10)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis(ethoxycarbonylmethyl)-N,N'-dimethylp-
hosphonamido)]furanyl}thiazole. Anal. cald. 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.
[1710] (48.11)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-benzyloxycarbonyl-2-methyl)pro-
pyl)phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1711] (48.12)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-methoxycarbonyl-3-methyl)butyl-
)phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1712] (48.13)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((R)-1-ethoxycarbonyl-2-(S-benzyl))et-
hyl)phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1713] (48.14)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-3-(S-methyl))bu-
tyl)phosphonamido]furanyl}thiazole; Anal. cald. for
C.sub.23H.sub.37N.sub.4O.sub.6PS3: C, 46.61; H, 6.92; N, 9.45.
Found: C, 46.26; H, 6.55; N, 9.06.
[1714] (48.15)
2-Amino-5-propylthio-4-{2-[5-(N,N'-(1-(S)-ethoxycarbonyl)ethyl)phosphonam-
ido]furanyl}thiazole. Anal. cald. 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.
[1715] (48.16)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-benzyloxycarbonyl-2-methyl)iso-
butyl)phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1716] (48.17)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-3-methyl)butyl)-
phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1717] (48.18)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-2-methyl)propyl-
)phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1718] (48.19)
2-Amino-5-isobutyl-4-{2-[5-(N,N'-bis((S)-1-ethoxycarbonyl-2-phenyl)ethyl)-
phosphonamido]furanyl}thiazole. Anal. cald. 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.
[1719] (48.20)
2-Amino-5-propylthio-4-{2-[5-(N,N'-(1-methyl-1ethoxycarbonyl)ethyl)phosph-
onamido]furanyl}thiazole. mp. 110-115.degree. C.: Anal. cald. 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.
[1720] (48.21)
2-Amino-5-methylthio-4-{2-[5-(N,N-bis(1-methyl-1-ethoxycarbonyl)ethyl)pho-
sphonamido]furanyl}thiazole. Anal. cald. 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 49
General Procedure for Mixed Bis-Phosphoroamidate Prodrugs
[1721] To a solution of crude dichloridate (1 mmol, prepared as
described in Example 40) 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 aminoacid 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.
[1722] The following compounds were prepared in this manner.
[1723] (49.1)
2-Amino-5-isobutyl-4-{2-[5-(N-morpholino-N'-(1-methyl-1-ethoxycarbonyl)et-
hyl)phosphonamido]furanyl}thiazole. mp. 182-183.degree. C.: Anal.
cald. 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.
[1724] (49.2)
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.
cald. 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.
BIOLOGICAL EXAMPLES
[1725] The following examples may be useful for identifying
compounds which 1) inhibit FBPase and gluconeogenesis in cellular
and animal models of diabetes; or 2) enhance insulin sensitivity in
cell culture or animal models of diabetes; or 3) exhibit superior
pharmacological activity as combinations of FBPase inhibitors and
insulin sensitizers relative to either agent alone.
[1726] The following compounds A-K are used in some of the
Biological Examples which follow: ##STR124## ##STR125##
[1727] Compound F is prepared in Example 10.6, Compound G is
prepared in example 3.26, compound H is prepared in Example 3.68,
Compound I is prepared in Example 3.58, Compound J is prepared in
Example 48.6, and Compound K is prepared in Example 48.2.
Example A
Inhibition of Human Liver FBPase
[1728] 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. hlFBPase was
typically purified from 10 liters of E. coli culture as described
by M. Gidh-Jain et al. J. Biol. Chem. 269, 27732-27738 (1994).
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 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.).
[1729] The potencies of select compounds against human liver FBPase
are shown in the table below: TABLE-US-00016 TABLE 1 Compound IC50,
.mu.M AMP 1.3 E 0.055 D 1.0 B 5.0 C 30 F 0.12 G 0.015 H 0.025 I
0.018 Troglitazone >100
Example B
Inhibition of Rat Liver and Mouse Liver FBPase
[1730] 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, and purified as
described (El-Maghrabi, M. R., and Pilkis, S. J. (1991) Biochem.
Biophys. Res. Commun. 176: 137-144). Mouse liver FBPase was
obtained by homogenizing freshly isolated mouse liver in 100 mM
Tris-HCl buffer, pH 7.4, containing 1 mM EGTA, and 10% glycerol.
The homogenate was clarified by centrifugation, and the 45-75%
ammonium sulfate fraction prepared. This fraction was redissolved
in the homogenization buffer and desalted on a PD-10 gel filtration
column (Biorad) eluted with same. This partially purified fraction
was used for enzyme assays. Both rat liver and mouse liver FBPase
were assayed as described for human liver FBPase in Example A.
Generally, as reflected by higher IC.sub.50 values, the rat and
mouse liver enzymes are less sensitive to inhibition by the
compounds tested than the human liver enzyme.
[1731] The following Table depicts the IC.sub.50 values for several
compounds prepared in the Examples: TABLE-US-00017 TABLE 2 Compound
IC.sub.50 Rat Liver (.mu.M) IC.sub.50 Mouse Liver (.mu.M) AMP 25 15
B 140 33 D 1.25 55 C >100 >100 E 0.4 1.1 F 2.0 G 0.25 H 0.175
I 0.05
Example C
Inhibition of Gluconeogenesis in Rat Hepatocytes
[1732] Hepatocytes were prepared from fed 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/m) were incubated in 1 ml Krebs-bicarbonate buffer
containing 10 mM Lactate, 1 mM pyruvate, 1 mg/ml BSA, and test
compound concentrations from 0 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.
[1733] The following Table depicts the IC.sub.50 values for several
compounds prepared in the Examples: TABLE-US-00018 TABLE 3 Compound
IC50 (.mu.M) Compound A 50 Compound D 4.5 Compound E 2.5 Compound C
>100 Compound F 15 Compound G 10 Compound H 2.5 Compound I 2.0
Compound J 2.0 Compound K 2.1 Troglitazone >100
[1734] FBPase from rat liver is less sensitive to AMP than that
from human liver. IC.sub.50 values are consequently higher in rat
hepatocytes than would be expected in human hepatocytes.
[1735] It is particularly advantageous to screen compounds of
formula I on hepatocytes such as described in Examples C and D
because these compounds are phosphorylated by the hepatocytes and
thereby become FBPase inhibitors.
Example D
Inhibition of Glucose Production and Elevation of
Fructose-1,6-Bisphosphate Levels in Rat Hepatocytes Treated with
FBPase Inhibitors
[1736] Rat hepatocytes were isolated and incubated as described in
Example C. Cell extracts, were analyzed for glucose content as
described in Example C, and also for fructose 1,6-bisphosphate.
Fructose 1,6-bisphosphate was assayed spectrophotometrically by
coupling its enzymatic conversion to glycerol 3-phosphate to the
oxidation of NADH, which was monitored at 340 nm. Reaction mixtures
(1 ml) consisted 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 was
added and the change in absorbance measured until a stable value
was obtained. 2 moles of NADH are oxidized in this reaction per
mole of fructose 1,6-bisphosphate present in the cell extract.
[1737] Compound A and Compound E inhibited glucose production in a
dose-dependent manner with IC50's of 50 and 2.5 .mu.M,
respectively. Consistent with the inhibition of FBPase,
dose-dependent elevation of intracellular fructose 1,6-bisphosphate
was observed with both compounds.
Example E
Analysis of Hepatic and Plasma Drug Metabolite Levels, Blood
Glucose, and Hepatic Fructose 1,6-bisphosphate Levels After
Administration of Compound A p.o. to Normal Fasted Rats
[1738] Compound A was administered by oral gavage to freely-feeding
SpragueDawley rats (250-300 g). The compound was prepared as a
suspension in carboxymethylcellulose, and administered at a dose of
250 mg/kg. For the determination of liver metabolites, rats were
serially sacrificed over the course of 24 hours after drug
administration. Livers were freeze-clamped, homogenized in
perchloric acid, neutralized, and then analyzed for Compound B by
anion exchange HPLC.
[1739] For the determination of plasma metabolites, rats were
instrumented with carotid catheters prior to oral dosing. Blood
samples were withdrawn via the catheters at appropriate time points
over the course of 8 hours post drug administration. Plasma was
prepared from the blood samples by centrifugation, and plasma
protein precipitated by the addition of methanol to 60%. Compound A
metabolites were quantitated by reverse phase HPLC in the
deproteinated plasma samples. A C18 column (1.4 cm.times.250 mm)
was equilibrated with 10 mM sodium phosphate, pH 5.5 and eluted
with a gradient from this buffer to acetonitrile. Detection was at
254 nm.
[1740] The effect of Compound A on blood glucose and hepatic
fructose 1,6-bisphosphate levels was determined in 18-hour fasted
Sprague-Dawley rats (250-300 g). Animals were dosed as described
above. At appropriate time points post drug administration, rats
were anesthetized with halothane and a liver biopsy (approx. 1 g)
was taken, as well as a blood sample (2 ml) from the posterior vena
cava. A heparin flushed syringe and needle was used for blood
collection. The liver sample was immediately homogenized in
ice-cold 10% perchloric acid (3 ml), centrifuged, and the
supernatant neutralized with 1/3rd volume of 3 M KOH/3 M
KH.sub.2CO.sub.3. Following centrifugation and filtration, the
neutralized extract was analyzed for fructose 1,6-bisphosphate
content as described for isolated hepatocytes in Example C. Blood
glucose was measured by means of a Hemocue analyzer (Hemocue Inc,
Mission Viejo, Calif.).
[1741] Analysis of liver metabolites revealed that Compound A was
efficiently converted to Compound B, with intrahepatic levels of
the latter reaching 3 .mu.moles/g tissue within 1 hour. Although
levels declined slowly over time, Compound B was measurable out to
the final, 24 hour time point. In plasma
5-bromo-1-PD-ribofuranosyl-imidazole-carboxamide but not Compound A
was detectable, suggesting that Compound A was rapidly deacetylated
at all three positions.
[1742] The single 250 mg/kg dose of Compound A markedly lowered
blood glucose for approximately 8 hours, at which time levels in
the treated animals rebounded slowly to those of the
vehicle-treated controls. Drug treatment resulted in the elevation
of hepatic fructose 1,6-bisphosphate levels. The time course of
elevation of this gluconeogeneic intermediate correlated well with
the time course of glucose lowering. Peak elevation was observed at
near maximal glucose lowering, and as blood glucose levels
rebounded, fructose 1,6-bisphosphate levels slowly returned to
normal. The latter observations are consistent with the inhibition
of gluconeogenesis by Compound A at the level of fructose
1,6-bisphosphatase.
Example F
Analysis of Hepatic and Plasma Drug Levels After Administration
Compounds D and E Intraperitoneally to Normal Fasted Rats
[1743] Sprague-Dawley rats (250-300 g) were fasted for 18 hours and
then dosed intraperitoneally either with saline or FBPase
inhibitor. The vehicle used for drug administration was 10 mM
bicarbonate. One hour post injection, rats were anesthetized with
halothane, and liver and blood samples were taken and processed as
described in Example E. The neutralized liver extracts were
analyzed for FBPase inhibitor content by HPLC. A reverse phase YMC
ODS AQ column (250.times.4.6 cm) was used and eluted with a
gradient from 10 mM sodium phosphate pH 5.5 to 75% acetonitrile.
Absorbance was monitored at 310 nm. Glucose was measured in the
blood sample as described in Example C. Plasma was prepared by
centrifugation and extracted by addition of methanol to 60% (v/v).
The methanolic extract was clarified by centrifugation and
filtration and then analyzed by HPLC as described above.
[1744] Results for select compounds prepared in the examples are
shown in the table below. TABLE-US-00019 TABLE 4 Glucose Plasma
con. Liver conc. Compound Lowering, % (.mu.M) (nmoles/g) D 31 8.8
27.2 E 44.4 79.2 38.4 F 51 18 35 G 73 56.1
Example G
Oral Bioavailability Determination
[1745] The oral bioavailability of prodrugs and parent compounds
was determined by the urinary excretion method in the rat. 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 orally at
10-40 mg/kg or intravenously at .about.10 mg/kg. 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 as described in Example F. Analysis was
performed as described in Example F. For prodrugs, 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 the corresponding parent compound.
For parent compounds, the percentage oral bioavailability was
estimated by comparison of the recovery in urine of the parent
compound when administered orally to that recovered when
administered intravenously.
[1746] The estimated % oral bioavailability of select prodrugs and
parent compounds is shown below. TABLE-US-00020 Compound Oral
bioavailability, % G 18 H 4 I 5 J 21
Example H
PPAR .gamma. Binding
[1747] Human PPAR .gamma. g extracts, obtained from Sf9 insect
cells expressing the cloned human gene incorporated into a
baculovirus expression vector using procedures described in
Mangelsdorf et al. Cell 54: 199-207 (1991), are used for saturation
binding analysis. Extracts are incubated at 4 C for 3 h in buffer
containing 10 mM Tris (pH 8.0), 50 mM KCl, 10 mM dithiothreitol
with [.sup.3H]-BRL-49653 in the presence or absence of the insulin
sensitizer. Bound is separated from free radioactivity by elution
through 1-mL Sephadex G-25 desalting columns. Bound radioactivity
is eluted in the column void volume and is quantitated by liquid
scintillation counting. Insulin sensitizer treatment displaces
[3H]-BRL-49653 from the PPAR.gamma. receptor, and results in
reduced recovery of radioactivity in the bound fraction. The
tighter the affinity of the insulin sensitizer for the receptor,
the more radioactivity is displaced.
Example I
Adipocyte Binding
[1748] Adipocytes are prepared from adipose tissue obtained from
mammary gland by collagenase digestion (2 mg/ml collagenase; 4 ml/g
tissue) by the method of Rodbell. Krebs-Henseleit medium is used
(NaCl; 123 mM, NaHCO.sub.3; 26 mM, KCl; 5 mM, MgSO.sub.4; 1.2 mM,
KH.sub.2PO.sub.4; 1.25 mM, glucose 5.6 mM, pH 7.4) gassed with 95%
O.sub.2/5% CO.sub.2. The medium includes 4% BSA and is supplemented
with p-aminoclonidine (100 nM) and adenosine (200 .mu.M) to inhibit
lipolysis. Binding studies are performed by rinsing the adipocytes
in Dulbecco's modified Eagles medium/Hams F-12 nutrient mix medium
containing 15 mM HEPES, pH 7.4, supplemented with 200 nM adenosine.
After three washes to remove collagenase and BSA, 0.5 ml of cells
are added (in triplicate) tubes containing radiolabelled insulin
sensitizer. Final concentration of insulin sensitizer in all
incubations is 30 .mu.M. Tubes are incubated at 37 C for 1 h in a
shaking bath and cell-associated radioactivity is assessed by
separation of cells from medium by centrifugation (200 .mu.l of
incubation medium, in duplicate) through silicone oil (Dow Corning
200/200 cs) for 20 s at 10000 g in a Beckman microfuge. Cell
pellets are counted for .sup.125I content after cutting the
microfuge tube. Non-specific binding is estimated in the presence
of 3 .mu.M RBL 49653. Affinity of the insulin sensitizer for
adipocyte receptor is indicated by an increase in specific
.sup.125I content in the cell pellets.
Example J
Triglyceride Formation by Differentiated Adipocytes
[1749] The pre-adipocyte cell line, 3T3-L1 fibroblasts, are
obtained from ATCC. The cells are grown to confluence and
differentiated with insulin, dexamethasone and IBMX. Adipocyte
differentiation is observed by oil red O staining which stains the
lipid droplets within the cytoplasm red. The extent of adipocyte
differentiation is then monitored by microscope observation.
Mature, lipid-filled adipocytes are used 8-10 days
post-differentiation. Treatment of cells with insulin, a
thiazolidinedione, or RXR ligands induces triglyceride
accumulation.
Example K
Glucose Uptake
[1750] The pre-adipocyte cell line, 3T3-L1 fibroblasts are grown to
confluence and differentiated with insulin, dexamethasone and IBMX.
Mature, lipid-filled adipocytes are used 8-10 days
post-differentiation. Glucose transport is assessed after treatment
of differentiated cells with insulin sensitizers for 48 h.
Compounds are added freshly each day. 2-deoxyglucose transport is
determined by addition of 1 .mu.C of 25 .mu.M
2-deoxy-D-[2,6-.sup.3H] glucose. After 10 minutes, cells are freed
of tracer by extensive washing with ice-cold PBS and
cell-associated radioactivity determined by liquid scintillation
counting of alkali-solubilized extracts. Glucose uptake rates are
normalized for protein content. Insulin sensitizer treatment
increases the rate of glucose transport into the cells as indicated
by higher levels of cell-associated radioactivity.
Example L
Activation of PPAR.gamma./RXR Heterodimers
[1751] CV-1 cells are co-transfected with plasmids containing the
genes encoding PPAR.gamma., RXR, and a luciferase-based reporter
plasmid containing one or more PPRE's. Cells are treated with a
range of doses of ligand. A concentration-dependent increase in
luciferase induction is observed with ligands of RXR or of
PPAR.gamma..
Example M
Insulin Sensitivity Measured by Euglycemic-Hyperinsulinemic Clamp
Technique
[1752] ZDF Diabetic rats are treated with vehicle or an insulin
sensitizer for 7 or more days, and then instrumented with jugular
and carotid catheters. After a recovery period, animals are fasted
overnight, and a constant infusion of insulin is initiated. Blood
glucose levels are maintained at baseline with a variable rate
glucose infusion. Samples for plasma glucose are drawn every 10
minutes for the duration of the 4-hour protocol. Steady state
glucose infusion rates are higher in the insulin-sensitizer treated
group, indicating improved glucose disposal/insulin
sensitivity.
Example N
Combination Treatment with Troglitazone and an FBPase Inhibitor
(Compound G), and with Troglitazone and a Prodrug of an FBPase
Inhibitor (Compound J) in the ZDF Rat
Effects on Blood Glucose
[1753] The Zucker Diabetic Fatty (ZDF) rat is widely used as a
model for human type 2 diabetes as the progression of the disease
in these rodents is similar to that described for human patients
(Clark and Palmer 1982, Terrettaz and Jeanrenaud 1983). The mature
ZDF rat not only displays obesity, hyperglycemia, insulin
resistance and accelerated hepatic glucose production, but also
develops some of the common macro- and micro-vascular complications
associated with type 2 diabetes.
[1754] Clark J B, Palmer C J (1982) Diabetes 30: 126A Terrettaz J,
Jeanrenaud B (1983) Endocrinology 112: 1346-1351.
[1755] The purpose of this study was to determine whether
combination treatment with Troglitazone-Compound G or
Troglitazone-Compound J results in improved glycemic control in the
ZDF rat relative to either agent administered alone, and thus
establish whether combination therapy will be of clinical
benefit.
[1756] (a) Troglitazone-Compound G Protocol: Male ZDF rats were
purchased at 8 weeks of age from Genetics Models Inc.
(Indianapolis, Ind.). The rats were maintained under standard
vivarium conditions (25.degree. C., 12-hour light, 12-hour dark
cycle) and received powdered Purina 5008 chow and water ad libitum.
At 11 weeks of age, animals with blood glucose >500 mg/dl were
selected and divided into 4 treatment groups (n=8/group). The
treatments were control, Troglitazone, Compound G, and the
combination of Troglitazone and Compound G. Drugs were administered
as 0.2% food admixtures for 15 days. The dose of Troglitazone
selected (0.2%) is a maximal dose, which in pilot studies was found
to normalize blood glucose levels in 10-week old ZDF rats. It is
higher than the dose reported to prevent the onset of hyperglycemia
in prediabetic ZDF rats (Sreenan et al 1996). In animals with
established diabetes such as those selected for this study, the
effects of Troglitazone better approximate those in man, where
modest glucose lowering effects are generally observed (Inzucchi et
al 1998). The dose of Compound G selected (0.2%) is also a maximal
dose; a pilot study in the ZDF rat revealed that higher doses were
of no additional benefit (blood glucose lowering at 0.5% was
equivalent to that at 0.2%). Blood glucose levels were measured in
tail vein samples by means of a HemoCue glucose analyzer (HemoCue
Inc., Mission Viejo, Calif.). Values are expressed as the mean plus
or minus the standard error of the mean. Differences between groups
were evaluated by analysis of variance with the Tukey-Kramer post
hoc test. Results are considered significant with p<0.05.
[1757] (b) Troglitazone-Compound J Protocol: This study was carried
out exactly as described in the Troglitazone-Compound G section
above with two modifications: the treatment period was 21 days and
the dose of Compound J used was 0.4%. In a pilot study, Compound J
showed a trend (not significant) towards more pronounced blood
glucose lowering at 0.4% than at 0.2%. The 0.4% dose was therefore
chosen to ensure a maximal drug response.
[1758] Combination treatment with Troglitazone and Compound G
resulted in significantly greater reductions in blood glucose
levels than treatment with either agent alone (see table below). At
the end of the treatment period, blood glucose levels in the
combination group (.about.200 mg/dl) approximated those of normal
fed rats (.about.150 mg/dl). TABLE-US-00021 Blood Glucose, mg/dl
Treatment Day 0 Day 14 Control 655 .+-. 39 762 .+-. 31* Compound G
653 .+-. 55 530 .+-. 48 Troglitazone 655 .+-. 33 431 .+-. 73
Combination 661 .+-. 39 222 .+-. 39** *p < 0.05 versus all
groups **p < 0.05 versus all groups
[1759] Similar results were observed in the Troglitazone-Compound J
study: TABLE-US-00022 Blood Glucose, mg/dl Treatment Day 0 Day 21
Control 678 .+-. 19 815 .+-. 34* Compound J 674 .+-. 20 452 .+-. 40
Troglitazone 669 .+-. 23 514 .+-. 135 Combination 675 .+-. 31 232
.+-. 39** *p < 0.05 versus all groups **p < 0.05 versus all
groups
[1760] The data suggest that the combination of an insulin
sensitizer (Troglitazone) and an FBPase inhibitor (Compound G) or a
prodrug of an FBPase inhibitor (Compound J) may provide better
glycemic control than either agent alone in the treatment of type 2
diabetes.
Example O
Combination Treatment with Troglitazone and an FBPase Inhibitor
(Compound G), and with Troglitazone and a Prodrug of an FBPase
Inhibitor (Compound J) in the ZDF Rat
Effects on Plasma Triglycerides
[1761] Troglitazone treatment is known to reduce circulating
triglycerides both in animal models of diabetes and in man.
Triglyceride lowering is generally regarded as beneficial in Type 2
diabetics as these patients often suffer from hypertriglyceridemia
and are at risk of the associated cardiovascular complications. The
purpose of this study was to determine the effects of combination
treatment on plasma triglycerides.
[1762] On the final day of treatment in the study described in
Example N, blood samples were taken from the posterior vena cava of
each rat while under halothane anesthesia. Plasma was prepared by
centrifugation and triglyceride levels then measured by means of a
standard assay kit according to the instructions of the
manufacturer (Sigma Chemical Company). Differences between groups
were evaluated by analysis of variance with the Tukey-Kramer post
hoc test. Results are considered significant with p<0.05.
[1763] As illustrated in the tables below, troglitazone treatment
had the expected effect of significantly reducing plasma
triglyceride levels. In contrast, treatment with Compound G or
Compound J resulted in an approximate 2-fold elevation of plasma
triglycerides. Surprisingly, combination treatment resulted in the
same degree of triglyceride lowering as treatment with Troglitazone
alone.
[1764] (a) Troglitazone--Compound G TABLE-US-00023 Plasma
Triglycerides, mg/dl Treatment (Mean .+-. SEM) Control 352 .+-. 26
Compound G 795 .+-. 88** Troglitazone 131 .+-. 16* Combination 102
.+-. 14* *p < 0.05 vs Control **p < 0.05 vs all groups
[1765] (b) Troglitazone--Compound J TABLE-US-00024 Plasma
Triglycerides, mg/dl Treatment (Mean .+-. SEM) Control 421 .+-. 58
Compound J 759 .+-. 76** Troglitazone 249 .+-. 60* Combination 188
.+-. 45* *p < 0.05 vs Control **p < 0.05 vs all groups
[1766] This study indicates that the beneficial triglycride
lowering effects of Troglitazone are maintained in combination with
Compound G or Compound J. Remarkably, the increase in triglycerides
elicited by FBPase inhibitor monotherapy was suppressed in
combination with the insulin sensitizer.
Example P
Combination Treatment with Troglitazone and an FBPase Inhibitor
(Compound G), and with Troglitazone and a Prodrug of an FBPase
Inhibitor (Compound J) in the ZDF rat
Effects on Plasma Insulin
[1767] Severe type 2 diabetes in man is often associated with the
deterioration of pancreatic beta-cell function and eventually the
inability of the pancreas to secrete the amount of insulin
appropriate for the degree of hyperglycemia. This progression is
also evident in the ZDF rat. Animals initially go through a
hyperinsulinemic phase to compensate for elevated blood glucose
levels but eventually overstimulation of the pancreas results in
diminished insulin secretion and hypoinsulinemia can ensue
(Pickavance L et al 1998). The purpose of this study was to
determine whether the improved glycemic control afforded by
combination treatment with an insulin sensitizer and an FBPase
inhibitor can attenuate the deterioration of pancreatic beta-cell
function.
[1768] On the final day of treatment in the study described in
Example N, blood samples were taken from the posterior vena cava of
each rat while under halothane anesthesia. Plasma was prepared by
centrifugation and insulin levels then measured by means of an
enzyme-linked immunoassay kit according to the instructions of the
manufacturer (Amersham Life Sciences). Differences between groups
were evaluated by analysis of variance with the Tukey-Kramer post
hoc test. Results are considered significant with p<0.05.
[1769] There was no significant difference in plasma insulin levels
between control rats and those on either Troglitazone or Compound G
monotherapy (see tables below). Combination treatment, however,
resulted in a significant increase in plasma insulin levels
relative to all other groups, and in fact restored them to levels
similar to those observed in non diabetes prone, lean ZDF rats
(Pickavance et al 1998). TABLE-US-00025 Plasma Insulin, ng/ml
Treatment (Mean .+-. SEM) Control 1.88 .+-. 0.3 Compound G 1.94
.+-. 0.21 Troglitazone 3.61 .+-. 1.03 Combination 8.23 .+-. 2.67*
*p < 0.05 vs all groups
[1770] The data show that combination treatment synergistically
improves pancreatic endocrine function; insulin levels were
increased significantly over those in controls only in the
combination therapy group. This increase in plasma insulin could
potentially be due to a reversal of lipotoxicity (Unger, 1997) and
glucotoxicity (Leahy, 1990) in pancreatic islet cells. Attenuation
of lipotoxicity may result from the triglyceride lowering effects
of Troglitazone (Example O), while the attenuation of glucotoxicity
may result from the combined glucose lowering effects of
Trolitazone and Compound G (Example N).
Example Q
Combination Treatment with Troglitazone and an FBPase Inhibitor
(Compound G), and with Troglitazone and a Prodrug of an FBPase
Inhibitor (Compound J) in the ZDF rat
Effects on Blood Lactate
[1771] The aim of this study was to determine the effects of
combination treatment on blood lactate levels.
[1772] Blood samples were taken from the tail vein on days 0, 3, 7,
10 and 14 of the Troglitazone-Compound G combination study and on
days 0, 7, 14, and 21 of the Troglitazone-Compound J combination
study (study protocols are described in Example N). Following their
acidification with perchloric acid and clarification by
centrifugation, lactate was measured by means of a standard kit
according to the instructions of the manufacturer (Sigma Chemical
Company).
[1773] Baseline blood lactate levels for the Compound G and
Compound J monotherapy groups were 1.98.+-.0.17 mM and 2.24.+-.0.08
mM, respectively. The maximal blood lactate elevations over
baseline observed during the course of the studies were 2.5-fold
for Compound G monotherapy and 3-fold for Compound J monotherapy.
Blood lactate was typically elevated 2-fold over baseline in these
groups. Blood lactate was not elevated above baseline (.about.2 mM)
in the control or combination groups on any of the measurement
days.
[1774] Combination treatment with Troglitazone suppressed the blood
lactate elevations observed in the FBPase inhibitor or FBPase
inhibitor prodrug monotherapy groups. Combination treatment may
thus have the unexpected benefit of improving the safety profile of
FBPase inhibitors and their prodrugs.
Example R
Combination Treatment with Rosiglitazone and an FBPase Inhibitor
(Compound G), in the ZDF Rat
Effects on Blood Glucose
[1775] This study addressed whether combination treatment with
Rosiglitazone and Compound G results in improved glycemic control
in the Zucker Diabetic Fatty (ZDF) rat relative to either agent
administered alone.
[1776] The protocol for this study was identical to the one
described for the Troglitazone-Compound G combination in Example N
with the following changes: (a) rats with blood glucose levels
>600 mg/dl were included in the study, (b) the dose of
Rosiglitazone used was 0.0045% based on a literature report that
this dose prevented the onset of diabetes in the ZDF rat (Smith et
al 1997), and (c) the length of the study was 25 days.
[1777] Blood glucose levels were significantly reduced in all
treatment groups relative to the control group. Blood glucose
lowering in the combination group tended to be more pronounced but
was not significantly different than that in the Rosiglitazone or
Compound G monotherapy groups. As illustrated in the table below,
the response to Rosiglitazone was highly variable and was likely a
factor in the less than expected efficacy of combination treatment.
However, there was a clear benefit of adding Compound G treatment
on top of Rosiglitazone treatment; whereas only 6 out of 10 rats
responded to therapy in the Rosiglitazone monotherapy group, 10 out
of 10 rats responded in the combination group. TABLE-US-00026
Change in Blood glucose, Treatment mg/dl (day 25 vs day 0)
Responders.sup.a Control +113 .+-. 52 2/9 Compound G -120 .+-. 34*
8/9 Rosiglitazone -107 .+-. 78* 6/10 Combination -207 .+-. 44*
10/10 .sup.aRats whose blood glucose levels were lower on day 25
than on day 0 *p < 0.05 compared to control
[1778] The variable response to Rosiglitazone observed in the ZDF
rat in this study has also been encountered in the clinic where
reductions in fasting plasma glucose observed have ranged from less
than 45 mg/dl (60% of patients) to greater than 140 mg/dl (25% of
patients) (Patel et al 1999). Based on the trend towards improved
glycemic control as well as the higher response rate of rats in the
combination versus other treatment groups, this study suggests that
co-treatment with an FBPase inhibitor could benefit patients on
Rosiglitazone monotherapy.
Example S
Combination Treatment with Troglitazone and an FBPase Inhibitor
(Compound G), in the db/db Mouse
Effects on Blood Glucose
[1779] The db/db mouse, like the ZDF rat, is a standard model of
type 2 diabetes which displays many of the characteristics of human
diabetes, including obesity, increased hepatic glucose output,
insulin resistance, and hyperglycemia (Coleman and Hummel 1967).
The purpose of this study was to determine whether combination
treatment with an insulin sensitizer (Troglitazone) and an FBPase
inhibitor (Compound G) could provide better antihyperglycemic
activity than treatment with either agent alone.
[1780] Male db/db mice were purchased at 8 weeks of age from
Jackson Labs (Bar Harbor, Me.). The mice were maintained under
standard vivarium conditions (25.degree. C., 12-hour light, 12-hour
dark cycle) and received powdered Purina 5008 chow and water ad
libitum. At 10 weeks of age, animals with blood glucose >400
mg/dl and <900 mg/dl were selected and divided into 4 treatment
groups (n=5-6/group). The treatments were control, Troglitazone,
Compound G, and the combination of Troglitazone and Compound G.
Troglitazone was administered as an 0.1% food admixture and
Compound G as an 0.4% food admixture. Treatment was for 18 days.
The dose of Troglitazone selected (0.1%) is reported to exert the
maximal glucose lowering possible in this model (Fujiwara et al.,
1995). The dose of Compound G selected (0.4%) is also a maximal
dose; a 6-day pilot study revealed that a higher dose (0.6%) was of
no additional benefit. Blood glucose levels were measured in tail
vein samples by means of a HemoCue glucose analyzer (HemoCue Inc.,
Mission Viejo, Calif.). Values are expressed as the mean plus or
minus the standard error of the mean. Differences between groups
were evaluated by analysis of variance with the Tukey-Kramer post
hoc test. Results are considered significant with p<0.05.
[1781] As shown in the table below, on the last treatment day (day
18), blood glucose levels in the combination group were
significantly lower than those in the control, as well as the
Troglitazone and Compound G monotherapy groups. TABLE-US-00027
Blood Glucose, mg/dl Treatment Day 0 Day 18 Control 707 .+-. 65 870
.+-. 32* Compound G 708 .+-. 55 646 .+-. 37 Troglitazone 710 .+-.
44 509 .+-. 70 Combination 709 .+-. 42 263 .+-. 49** *p < 0.05
versus all groups **p < 0.05 versus all groups
[1782] Combination treatment with Troglitazone and Compound G
profoundly reduced hyperglycemia in the db/db mouse and was
significantly more efficacious than treatment with either agent
alone. The data suggest that combination treatment with an insulin
sensitizer and an FBPase inhibitor may be of clinical benefit in
the treatment of type 2 diabetes.
Example T
Combination Treatment with Troglitazone and an FBPase Inhibitor
(Compound A), in the db/db Mouse
Effects on Blood Glucose
[1783] Treatment of mature db/db mice with maximal doses of
Troglitazone results in a partial reduction of the hyperglycemia
characteristic of this animal model of type 2 diabetes (Fujiwara et
al, 1995). The aim of this study was to determine whether treatment
with the FBPase inhibitor Compound A could further improve the
glycemic control of db/db mice treated with a maximal dose of
Troglitazone.
[1784] Male C57BL/KsJ-db/db mice were obtained from Jackson
Laboratories (Bar Harbor, Me.) at 9 weeks of age. The mice were
maintained under standard vivarium conditions (25.degree. C.,
12-hour light, 12-hour dark cycle) and received Harlan-Teklad mouse
chow and water ad libitum. At approximately 11 weeks of age, mice
with levels between 340 and 450 mg/dl were selected and divided
into three statistically equivalent groups (n=6/group). Group 1
(controls) received powdered Purina 5008 chow alone. Troglitazone
was given as a powdered Purina 5008 admixture (0.1%) for 7 days to
Groups 2 and 3. This dose is reported to elicit the maximal
hypoglycemic effect of Troglitazone in this model (Fujiwara et al
1995). Compound A was administered orally in polyethlene glycol
(PEG 400) to Group 3 at a dose of 250 mg/kg on the 4th and 7th day
of the study. Blood glucose levels were measured in tail vein
samples by means of a HemoCue glucose analyzer (HemoCue Inc.,
Mission Viejo, Calif.). Values are expressed as the mean plus or
minus the standard error of the mean. Differences between groups
were evaluated by analysis of variance with the Tukey-Kramer post
hoc test. Results are considered significant with p<0.05.
[1785] On the fourth day of the study, the Troglitazone-treated
groups (2 and 3), as expected, showed significantly lower fed blood
glucose values than the untreated controls (Group 1):
TABLE-US-00028 Blood glucose, mg/dl Group Treatment (8 am day 4) 1
Control 336.5 .+-. 13.4 2 Troglitazone 240 .+-. 21.3* 3
Troglitazone 237.5 .+-. 18.5* *p < 0.05 vs Group 1
[1786] Following the above measurements, Group 3 was treated with
-a single oral dose of Compound A and Groups 1 and 2 with an
equivalent volume of vehicle. Nine hours post administration, blood
glucose levels were found to have increased in the control group
(Group 1), to have stayed essentially the same in Group 2, but to
have significantly decreased by 30% in the Compound A-treated group
(Group 3): TABLE-US-00029 Blood glucose, mg/dl Group Treatment (5
pm day 4) 1 Control 376.5 .+-. 8.4 2 Troglitazone 232.5 .+-. 17* 3
Troglitazone/Compound A 167 .+-. 10.3** *p < 0.05 vs Group 1 *p
< 0.05 vs Groups 1 and 2
[1787] On the 7th day of the study, a second dose of Compound A
(Group 3) or vehicle (Groups 1 and 2) was administered. Food was
withheld for 6 hours post drug/vehicle administration. As shown in
the table below, the mice in Group 3 (combination therapy) achieved
blood glucose levels which were on average 44% lower than those of
Group 2 (Troglitazone monotherapy) during the treatment period.
TABLE-US-00030 Blood glucose, mg/dl Group Treatment 8 am, day 7 2
pm, day 7 1 control) 392 13.3 279.5 .+-. 19. 2 Troglitazone 237
25.5 195 .+-. 12.1* 3 Troglitazone/Compound A 243 20.4 109.5 .+-.
10.7** *p < 0.05 vs Group 1 **p < 0.05 vs Groups 1 and 2
[1788] Combination treatment of Troglitazone and Compound A
resulted in significantly lower blood glucose levels both in the
fed and fasted state than when Troglitazone was administered alone.
This study suggests that the addition of an FBPase inhibitor to the
treatment regimen of patients on insulin sensitizer therapy could
provide significantly improved glycemic control.
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[1789] Coleman D L, Hummel K P (1967) Diabetologia 3: 238-248
[1790] Fujiwara T et al (1995) Metabolism 44: 486-490 [1791]
Inzucchi S E, Maggs D G, Spollett G R et al (1998) N. Engl. J. Med.
338: 867-872 [1792] Leahy J L (1990) Diabetes Care 13: 992-1010
[1793] Patel J, Anderson R J, Rappaport E B (1999) Diabetes,
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P S, King P, Ishii S, Tanaka H, Williams G (1998) Br. J. Pharmacol.
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Unger R H (1997) Trends Endocrinol. Metab. 8: 276-281
* * * * *