U.S. patent application number 11/742023 was filed with the patent office on 2007-10-04 for novel heteroaromatic inhibitors of fructose-1,6-bisphosphatase.
This patent application is currently assigned to Metabasis Therapeutics, Inc.. Invention is credited to Atul Agarwal, Qun Dang, Mark D. Erion, Srinivas Rao Kasibhatla, K. Raja Reddy, M. Rami Reddy.
Application Number | 20070232571 11/742023 |
Document ID | / |
Family ID | 26808618 |
Filed Date | 2007-10-04 |
United States Patent
Application |
20070232571 |
Kind Code |
A1 |
Dang; Qun ; et al. |
October 4, 2007 |
Novel Heteroaromatic Inhibitors of Fructose-1,6-Bisphosphatase
Abstract
Novel FBPase inhibitors of the formula I and X ##STR1## are
useful in the treatment of diabetes and other conditions associated
with elevated blood glucose.
Inventors: |
Dang; Qun; (San Diego,
CA) ; Kasibhatla; Srinivas Rao; (San Diego, CA)
; Reddy; K. Raja; (San Diego, CA) ; Erion; Mark
D.; (Del Mar, CA) ; Reddy; M. Rami; (San
Diego, CA) ; Agarwal; Atul; (Hamden, CT) |
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: |
26808618 |
Appl. No.: |
11/742023 |
Filed: |
April 30, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10636474 |
Aug 6, 2003 |
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11742023 |
Apr 30, 2007 |
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10231953 |
Aug 30, 2002 |
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10636474 |
Aug 6, 2003 |
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09389698 |
Sep 3, 1999 |
6489476 |
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10231953 |
Aug 30, 2002 |
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60135504 |
Sep 9, 1998 |
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60111077 |
Dec 7, 1998 |
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Current U.S.
Class: |
514/110 ;
544/180; 544/224; 544/243; 544/337; 546/1; 546/25; 548/100;
548/117; 548/125; 548/128; 548/136; 548/146; 548/206; 548/215;
548/240; 548/300.1; 548/356.1; 548/400; 568/12; 568/15 |
Current CPC
Class: |
A61P 9/00 20180101; C07F
9/65586 20130101; C07F 9/655345 20130101; C07F 9/6539 20130101;
C07F 9/657181 20130101; A61P 43/00 20180101; A61P 3/08 20180101;
C07F 9/5728 20130101; C07F 9/6578 20130101; C07F 9/65324 20130101;
C07F 9/6541 20130101; A61P 3/00 20180101; C07F 9/58 20130101; C07F
9/650952 20130101; C07F 9/6512 20130101; C07F 9/65517 20130101;
C07F 9/65395 20130101; C07F 9/65846 20130101; C07F 9/65583
20130101; A61P 3/10 20180101; A61P 9/10 20180101; A61P 5/48
20180101; A61P 3/06 20180101; C07F 9/4006 20130101; C07F 9/65515
20130101; C07F 9/653 20130101 |
Class at
Publication: |
514/110 ;
544/180; 544/224; 544/243; 544/337; 546/001; 546/025; 548/100;
548/117; 548/125; 548/128; 548/136; 548/146; 548/206; 548/215;
548/240; 548/300.1; 548/356.1; 548/400; 568/012; 568/015 |
International
Class: |
A61K 31/66 20060101
A61K031/66; C07F 9/02 20060101 C07F009/02 |
Claims
1. A compound of formula (I): ##STR200## wherein R.sup.5 is
selected from the group consisting of: ##STR201## 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 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 there is
no N in the linking group unless it is connected directly to a
carbonyl or in the ring of a heterocycle; and wherein X is not a 2
carbon atom -alkyl- or -alkenyl- group; with the proviso that X is
not substituted with --COOR.sup.2, --SO.sub.3R.sup.1, or
--PO.sub.3R.sup.1.sub.2; 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 ##STR202## 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 substitutent 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.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; 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.22, and --OR.sup.1; and with
the provisos 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 -alkyl-, an optionally substituted
-alkenyl-, 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)
R.sup.1 is not unsubstituted C1-C10 alkyl; 6) when X is not an
-aryl- group, then R.sup.5 is not substituted with two or more aryl
groups; and pharmaceutically acceptable prodrugs and salts
thereof.
2. The compound of claim 1, wherein said compound is of formula
(X): ##STR203## 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, alkoxyalkyl, --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; X.sup.2 is an
optionally substituted linking group that links R.sup.5 to the
phosphorus atom via 1-3 atoms, including 0-1 heteroatoms selected
from N, O, and S and the remaining atoms are carbon, 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.3R.sup.1, or --PO.sub.3R.sup.1.sub.2; 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.sup.3, 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 ##STR204## 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 substitutent 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, wherein 0-2 atoms are heteroatoms and the remaining atoms
are carbon, 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, --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,
alkyl, or together R.sup.4 and R.sup.4 form a cyclic alkyl; R.sup.6
is selected from the group consisting of --H, lower alkyl,
acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; 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
pharmaceutically acceptable prodrugs or salts thereof.
3. The compound of claim 1, wherein said compound is of formula XI:
##STR205## wherein: E.sup.2 is selected from the group consisting
of --NR.sup.4.sub.2 and lower alkyl; L.sup.2 is selected from the
group consisting of --CH.sub.3 and H; 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; or pharmaceutically
acceptable prodrugs or salts thereof.
4. The compound of claim 1, wherein said compound is of formula
XII: ##STR206## wherein: B' is a lower alkyl; X is furan-2,5-diyl;
or pharmaceutically acceptable prodrugs or salts thereof.
5. The compound of claim 1 wherein R.sup.5 is selected from the
group consisting of 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 substitutent.
6. The compound of claim 1 wherein 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, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 perhaloalkyl,
C.sub.1-C.sub.6 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; 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; E is
selected from the group consisting of --H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl,
C.sub.4-C.sub.6 alicyclic, alkoxyalkyl, --C(O)OR.sup.3,
--CONR.sup.4.sub.2, --CN, --NR.sup.9.sub.2, --OR.sup.3, --SR.sup.3,
C.sub.1-C.sub.6 perhaloalkyl, halo, and null, all except --H, --CN,
perhaloalkyl, and halo are optionally substituted; and each R.sup.4
is independently selected from the group consisting of --H, and
C.sub.1-C.sub.2 alkyl.
7. The compound of claim 1 wherein R.sup.5 is: ##STR207##
8. The compound of claim 1 wherein R.sup.5 is: ##STR208##
9. The compound of claim 1 wherein R.sup.5 is selected from the
group consisting of: ##STR209## wherein 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, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 perhaloalkyl,
C.sub.1-C.sub.6 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; 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; E'' is
selected from the group consisting of --H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.4-C.sub.6
alicyclic, alkoxyalkyl, --C(O)OR.sup.3, --CONR.sup.4.sub.2, --CN,
--NR.sup.9.sub.2, --OR.sup.3, --SR.sup.3, C.sub.1-C.sub.6
perhaloalkyl, and halo, all except H, --CN, perhaloalkyl, and halo
are optionally substituted; and each R.sup.4 is independently
selected from the group consisting of --H and C.sub.1-C.sub.2
alkyl.
10. The compound of claim 9 wherein R.sup.5 is selected from the
group consisting of: ##STR210##
11. The compound of claim 9, wherein R.sup.5 is selected from the
group consisting of: ##STR211##
12. The compound of claim 8 wherein R.sup.5 is selected from the
group consisting of: ##STR212##
13. The compound of claim 1 wherein 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.
14. The compound of claim 13 wherein X is selected from the group
consisting of -heteroaryl-, and -alkoxycarbonyl-.
15. The compound of claim 1 wherein said compound is a compound of
formulae II, III, or IV ##STR213##
16. A method of inhibiting an FBPase comprising contacting a FBPase
with a compound according to claim 1.
17. A method of treating diabetes comprising administering a
compound according to claim 1 to a mammal in an amount effective to
treat diabetes.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
10/636,474, filed Aug. 6, 2003, which is a continuation of
application Ser. No. 10/231,953, filed Aug. 30, 2002, now
abandoned, which is a continuation of application Ser. No.
09/389,698, filed Sep. 3, 1999, now U.S. Pat. No. 6,489,476, which
claims the benefit of U.S. Provisional Application Ser. No.
60/135,504, filed Sep. 9, 1998 and U.S. Provisional Application
Ser. No. 60/111,077, filed Dec. 7, 1998, the disclosures of which
are hereby incorporated by reference in their entireties, including
all figures and tables.
FIELD OF THE INVENTION
Background and Introduction to the Invention
[0002] The following description of the background of the invention
is provided to aid in understanding the invention, but is not
admitted to be, or to describe, prior art to the invention. All
cited publications are incorporated by reference in their
entirety.
[0003] Diabetes mellitus (or diabetes) is one of the most prevalent
diseases in the world today. Diabetic 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] Gluconeogenesis from pyruvate and other 3-carbon precursors
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.
[0008] Of the four enzymes specific to gluconeogenesis,
fructose-1,6-bisphosphatase (hereinafter "FBPase") is the most
suitable target for a gluconeogenesis inhibitor based on efficacy
and safety considerations. Studies indicate that nature uses the
FBPase/PFK cycle as a major control point (metabolic switch)
responsible for determining whether metabolic flux proceeds in the
direction of glycolysis or gluconeogenesis. Claus, et al.,
Mechanisms of Insulin Action, Belfrage, P. editor, pp. 305-321,
Elsevier Science 1992; Regen, et al. J. Theor. Biol. 111:635-658
(1984); Pilkis, et al. Annu. Rev. Biochem, 57:755-783 (1988).
FBPase is inhibited by fructose-2,6-bisphosphate in the cell.
Fructose-2,6-bisphosphate binds to the substrate site of the
enzyme. AMP binds to an allosteric site on the enzyme.
[0009] Synthetic inhibitors of FBPase have also 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.
[0010] 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.
[0011] Gruber et al. U.S. Pat. No. 5,658,889 described the use of
inhibitors of the A site of FBPase to treat diabetes. WO 98/39344,
WO/39343, and WO 98/39342 describe specific inhibitors of FBPase to
treat diabetes.
SUMMARY OF THE INVENTION
[0012] The present invention is directed towards novel
heteroaromatic compounds containing a phosphonate group and are
potent FBPase inhibitors. In another aspect, the present invention
is directed to the preparation of this type of compound and to the
in vitro and in vivo FBPase inhibitory activity of these compounds.
Another aspect of the present invention is directed to the clinical
use of these FBPase inhibitors as a method of treatment or
prevention of diseases responsive to inhibition of gluconeogenesis
and in diseases responsive to lowered blood glucose levels.
[0013] The compounds are also useful in treating or preventing
excess glycogen storage diseases and diseases such as
cardiovascular diseases including atherosclerosis, myocardial
ischemic injury, and diseases such as metabolic disorders such as
hypercholesterolemia, hyperlipidemia which are exacerbated by
hyperinsulinema and hyperglycemia.
[0014] The invention also comprises the novel compounds and methods
of using them as specified below in formulae I and X. Also included
in the scope of the present invention are prodrugs of the compounds
of formulae I and X. ##STR2##
[0015] Since these compounds may have asymmetric centers, the
present invention is directed not only to racemic mixtures of these
compounds, but also to individual stereoisomers. The present
invention also includes pharmaceutically acceptable and/or useful
salts of the compounds of formulae I and X, including acid addition
salts. The present inventions also encompass prodrugs of compounds
of formulae I and X.
Definitions
[0016] In accordance with the present invention and as used herein,
the following terms are defined with the following meanings, unless
explicitly stated otherwise.
[0017] X and X.sup.2 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
[0018] 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 substitutents of the
heteroaromatic ring are described in such a way that the term ends
with the group attached to the heteroaromatic ring. Generally,
substitutents are named such that the term ends with the group at
the point of attachment.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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 ##STR3##
[0023] 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.
[0024] 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.
[0025] The term "optionally substituted" or "substituted" includes
groups substituted by one to four substitutents, 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 substitutents.
Preferably these substitutents 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.
[0026] 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.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] The term "acyl" refers to --C(O)R where R is alkyl and
aryl.
[0031] The term "carboxy esters" refers to --C(O)OR where R is
alkyl, aryl, aralkyl, and alicyclic, all optionally
substituted.
[0032] The term "carboxyl" refers to --C(O)OH.
[0033] The term "oxo" refers to .dbd.O in an alkyl group.
[0034] 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.
[0035] The term "carbonylamino" and "-carbonylamino-" refers to
RCONR-- and --CONR--, respectively, where each R is independently
hydrogen or alkyl.
[0036] The term "halogen" or "halo" refers to --F, --Cl, --Br and
--I.
[0037] The term "-oxyalkylamino-" refers to --O-alk-NR--, where
"alk" is an alkylene group and R is H or alkyl.
[0038] 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.
[0039] 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.
[0040] The term "-oxyalkyl-" refers to the group --O-alk- where
"alk" is an alkylene group.
[0041] The term "-alkylcarboxyalkyl-" refers to the group
-alk-C(O)--O-alk- where each alk is independently an alkylene
group.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] The term "sulphonyl" or "sulfonyl" refers to --SO.sub.3R,
where R is H, alkyl, aryl, aralkyl, and alicyclic.
[0047] 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 substitutent attached
to the cyclic phosph(oramid)ate, it is attached at the first
carbon.
[0048] 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 substitutent attached
to the cyclic phosph(oramid)ate, it is attached at the first
carbon.
[0049] The term "alkylene" refers to a divalent straight chain,
branched chain or cyclic saturated aliphatic group.
[0050] 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.
[0051] The term "acyloxy" refers to the ester group --O--C(O)R,
where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or
alicyclic.
[0052] 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.
[0053] 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
.alpha. to the phosphorus atom.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] The term "alkyloxyaryl-" refers to an aryl group substituted
with an alkyloxy group.
[0058] In "lower alkyloxyaryl-", the alkyl group is lower
alkyl.
[0059] The term "aryloxyalkyl-" refers to an alkyl group
substituted with an aryloxy group.
[0060] 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.
[0061] 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--.
[0062] 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.
[0063] The terms "alkylthio-" and "-alkylthio-" refer to the groups
alkyl-S--, and -alk-S--, respectively, wherein "alk" is alkylene
group.
[0064] 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.
[0065] The term "alkoxycarbonyloxy-" refers to
alkyl-O--C(O)--O--.
[0066] The term "aryloxycarbonyloxy-" refers to
aryl-O--C(O)--O--.
[0067] The term "alkylthiocarbonyloxy-" refers to
alkyl-S--C(O)--O--.
[0068] 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.
[0069] 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.
[0070] 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--.
[0071] 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.
[0072] 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.
[0073] The term "-alkylaminocarbonyl-" refers to the group
-alk-NR--C(O)-- wherein "alk" is an alkylene group and R is H or
lower alkyl.
[0074] 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.
[0075] The term "thiocarbonate" refers to --O--C(S)--O-- either in
a chain or in a cyclic group.
[0076] The term "hydroxyalkyl" refers to an alkyl group substituted
with one --OH.
[0077] The term "haloalkyl" refers to an alkyl group substituted
with one halo, selected from the group I, Cl, Br, F.
[0078] The term "cyano" refers to --C.ident.N.
[0079] The term "nitro" refers to --NO.sub.2.
[0080] The term "acylalkyl" refers to an alkyl-C(O)-alk-, where
"alk" is alkylene.
[0081] The term "heteroarylalkyl" refers to an alkyl group
substituted with a heteroaryl group.
[0082] The term "-1,1-dihaloalkyl-" refers to an X group where the
1 position and therefore halogens are a to the phosphorus atom.
[0083] 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.
[0084] 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.
[0085] The term "amidino" refers to --C(NR)--NR.sub.2 where each R
group is independently selected from the group of --H, alkyl,
alkenyl, alkynyl, aryl, and alicyclic, all except --H are
optionally substituted.
[0086] The term "pharmaceutically acceptable salt" includes salts
of compounds of formula 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.
[0087] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the "drug"
substance (a biologically active compound) as a result of
spontaneous chemical reaction(s), enzyme catalyzed chemical
reaction(s), and/or metabolic chemical reaction(s). Standard
prodrugs are formed using groups attached to functionality, e.g.
HO--, HS--, HOOC--, R.sub.2N--, associated with the FBPase
inhibitor, that cleave in vivo. Standard prodrugs include but are
not limited to carboxylate esters where the group is alkyl aryl,
aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of
hydroxyl, thiol and amines where the group attached is an acyl
group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
Standard prodrugs of phosphonic acids are also included and may be
represented by R.sup.1 in formulae I and X. 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.
[0088] The term "prodrug ester" as employed herein includes, but is
not limited to, the following groups and combinations of these
groups:
[0089] [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 ##STR4## [0090] wherein R, R', and R''
are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO
90/08155; WO 90/10636).
[0091] [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)). ##STR5##
[0092] wherein R is --H, alkyl, aryl, alkylaryl, alkoxy, aryloxy,
alkylthio, arylthio, alkylamino, arylamino, cycloalkyl, or
alicyclic.
[0093] [3] Another class of these double esters known as
alkyloxycarbonyloxymethyl esters, as shown in formula A, where K 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 -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 AMP 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.
[0094] [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). ##STR6## [0095] wherein Y is H,
alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino,
alkoxycarbonyl, hydroxy, cyano, and alicyclic.
[0096] [5] Benzyl esters have also been reported to generate the
parent phosphonic acid. In some cases, using substitutents at the
para-position can accelerate the hydrolysis. Benzyl analogs with
4-acyloxy or 4-alkyloxy group [Formula D, X.dbd.H, OR or O(CO)K 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. I 2345 (1992); Brook, et al. WO 91/19721.
##STR7## [0097] wherein X and Y are independently H, alkyl, aryl,
alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl,
halo, or alkyloxycarbonyl; and [0098] R' and R'' are independently
H, alkyl, aryl, alkylaryl, halogen, and alicyclic.
[0099] [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. ##STR8##
[0100] wherein Z is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,
aryloxycarbonyl, or alkylthio.
[0101] 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:
##STR9##
[0102] wherein R is --H, alkyl, cycloalkyl, or alicyclic; and
[0103] wherein Y is --H, alkyl, aryl, alkylaryl, cyano, alkoxy,
acyloxy, halogen, amino, alicyclic, and alkoxycarbonyl.
[0104] The prodrugs of Formula E-3 are an example of "optionally
substituted alicyclic where the cyclic moiety contains a carbonate
or thiocarbonate."
[0105] [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. ##STR10## wherein
[0106] R is alkyl, aryl, heteroaryl; [0107] X is hydrogen,
alkylcarbonyloxy, alkyloxycarbonyloxy; and [0108] Y is alkyl, aryl,
heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen,
hydroxy, acyloxy, amino.
[0109] [8] Phosphoramidate derivatives have been explored as
phosphate prodrugs (e.g. McGuigan et al., J. Med. Chem., 1999, 42:
393 and references cited therein) as shown in Formula G.
##STR11##
[0110] Cyclic phosphoramidates have also been studied as
phosphonate prodrugs because og their speculated higher stability
compared to non-cyclic phosphoramidates (e.g. Starrett et al., J.
Med. Chem., 1994, 37: 1857.
[0111] 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 H. ##STR12##
[0112] 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). The Structure ##STR13## has a plane of symmetry running
through the phosphorus-oxygen double bond when R.sup.6.dbd.R.sup.6,
V.dbd.W, W'.dbd.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--.
[0113] 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: ##STR14##
[0114] 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: ##STR15##
[0115] 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.
[0116] 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: ##STR16##
[0117] 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 substitutent
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:
##STR17##
[0118] The structure above has an acyloxy substitutent that is
three carbon atoms from a Y, and an optional substitutent,
--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.
[0119] 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: ##STR18##
[0120] The structure above has V=aryl, and a spiro-fused
cyclopropyl group for W and W.
[0121] The term "cyclic phosph(oramid)ate" refers to ##STR19##
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.
[0122] The term "liver" refers to liver and to like tissues and
cells that contain the CYP3A4 isozyme or any other P450 isozyme
found to oxidize the phosph(oramid)ate esters of the invention.
Based on Example F, we have found that prodrugs of formula VI and
VIII are selectively oxidized by the cytochrome P450 isoenzyme
CYP3A4. According to DeWaziers et al (J. Pharm. Exp. Ther., 253,
387-394 (1990)), CYP3A4 is located in humans in the following
tissues (determined by immunoblotting and enzyme measurements):
TABLE-US-00001 Tissues % of liver activity Liver 100 Duodenum 50
jejunum 30 ileum 10 colon <5 (only P450 isoenzyme found) stomach
<5 esophagus <5 kidney not detectable
Thus, "liver" more preferably refers to the liver, duodenum,
jejunum, ileum, colon, stomach, and esophagus. Most preferably,
liver refers to the liver organ.
[0123] The term "enhancing" refers to increasing or improving a
specific properly.
[0124] The term "liver specificity" refers to the ratio: [ drug
.times. .times. or .times. .times. a .times. .times. drug .times.
.times. metabolite .times. .times. in .times. .times. liver .times.
.times. tissue ] [ drug .times. .times. or .times. .times. a
.times. .times. drug .times. .times. metabolite .times. .times. in
.times. .times. blood .times. .times. or .times. .times. another
.times. .times. tissue ] ##EQU1## as measured in animals treated
with the drug or a prodrug. The ratio can be determined by
measuring tissue levels at a specific time or may represent an AUC
based on values measured at three or more time points.
[0125] The term "increased or enhanced liver specificity" refers to
an increase in the liver specificity ratio in animals treated with
the prodrug relative to animals treated with the parent drug.
[0126] 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.
[0127] The term "parent drug" refers to any compound which delivers
the same biologically active compound. The parent drug form is
R.sup.5--X--P(O)(OH).sub.2 and standard prodrugs, such as
esters.
[0128] 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.
[0129] 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%.
[0130] 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.
[0131] 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.
[0132] The term "sustained delivery" refers to an increase in the
period in which there is adequate blood levels of the biologically
active drug to have a therapeutic effect.
[0133] The term "bypassing drug resistance" refers to the loss or
partial loss of therapeutic effectiveness of a drug (drug
resistance) due to changes in the biochemical pathways and cellular
activities important for producing and maintaining the biologically
active form of the drug at the desired site in the body and to the
ability of an agent to bypass this resistance through the use of
alternative pathways and cellular activities.
[0134] 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
R.sup.5--X--P(O)(OH).sub.2 are biologically active.
[0135] The term "therapeutically effective amount" refers to an
amount that has any beneficial effect in treating a disease or
condition.
Preferred Compounds of Formula I
[0136] 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.
[0137] In the method claims, preferred are the following compounds
of formula (I): ##STR20## wherein:
[0138] 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;
[0139] each G' is independently selected from the group consisting
of C and N and wherein no more than two G' groups are N;
[0140] 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;
[0141] 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;
[0142] E is selected from the group consisting of --H, alkyl,
alkenyl, alkynyl, aryl, alicyclic, alkoxyalkyl, --C(O)OR.sup.3,
--CONK.sup.4.sub.2, --CN, --NR.sup.9.sub.3, --NO.sub.2, --OR.sup.3,
--SR.sup.3, perhaloalkyl, halo, and null, all except --H, --CN,
perhaloalkyl, and halo are optionally substituted;
[0143] J is selected from the group consisting of --H and null;
[0144] 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 there is
no N in the linking group unless it is connected directly to a
carbonyl or in the ring of a heterocycle; and wherein X is not a 2
carbon atom -alkyl- or -alkenyl- group; with the proviso that X is
not substituted with --COOR.sup.2, --SO.sub.3R.sup.1, or
--PO.sub.3R.sup.1.sub.2;
[0145] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0146] 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,
[0147] 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;
[0148] 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 ##STR21## wherein
[0149] 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
[0150] 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
[0151] 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;
[0152] 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 substitutent 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;
[0153] 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;
[0154] 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;
[0155] 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.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.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2;
[0156] p is an integer 2 or 3;
[0157] q is an integer 1 or 2;
[0158] with the provisos that:
[0159] a) V, Z, W, W' are not all --H; and
[0160] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0161] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0162] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0163] 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;
[0164] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0165] 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;
[0166] R.sup.11 is selected from the group consisting of: alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and with the provisos that:
[0167] 1) when G' is N, then the respective A, B, D, or E is null;
[0168] 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; [0169] 3) when
R.sup.5 is a six-membered ring, then X is not any 2 atom linker, an
optionally substituted -alkyl-, an optionally substituted
-alkenyl-, an optionally substituted -alkyloxy-, or an optionally
substituted -alkylthio-; [0170] 4) when G is N, then the respective
A or B is not halogen or a group directly bonded to G via a
heteroatom; [0171] 5) R.sup.1 is not unsubstituted C1-C10 alkyl;
[0172] 6) when X is not an -aryl- group, then R.sup.5 is not
substituted with two or more aryl groups;
[0173] and pharmaceutically acceptable prodrugs and salts
thereof.
[0174] In the methods of using such compounds, 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,
1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl,
1,2,4-triazinyl, and 1,3-selenazolyl, all of which contain at least
one substitutent.
[0175] More preferred are compounds where R.sup.5 is: ##STR22##
wherein
[0176] 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;
[0177] 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;
[0178] 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, --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
[0179] C'' is selected from the group consisting of --H, alkyl,
alkylalkenyl, alkylalkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl,
and alkoxyalkyl, all optionally substituted;
[0180] R.sup.4 is selected from the group consisting of --H and
C1-C2 alkyl.
[0181] Particularly preferred are such compounds where R.sup.5 is:
##STR23## wherein
[0182] 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;
[0183] 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;
[0184] 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
[0185] each R.sup.4 is independently selected from the group
consisting of --H and C1-C2 alkyl
[0186] In the methods, preferred X groups include -alkyl(hydroxy)-,
-alkyl-, -alkynyl-, -aryl-, -carbonylalkyl-, -1,1-dihaloalkyl-,
-alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-,
-alkylaminocarbonyl-, -alkylcarbonylamino-, -alicyclic-, -aralkyl-,
-alkylaryl-, -alkoxycarbonyl-, -carbonyloxyalkyl-,
-alkoxycarbonylamino-, -alkylaminocarbonylamino-, -alkylamino-, and
-alkenyl-, all optionally substituted.
[0187] In the compound and method claims, preferred are novel
compounds of formula (I): ##STR24## wherein R.sup.1 is selected
from the group consisting of: ##STR25## wherein:
[0188] 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;
[0189] each G' is independently selected from the group consisting
of C and N and wherein no more than two G' groups are N;
[0190] A is selected from the group consisting of --H,
--NR.sup.4.sub.2, --CONR.sup.4.sub.2, --CO.sub.2R.sup.3, halo,
--S(O)R.sup.3, --SO.sub.2R.sup.3, alkyl, alkenyl, alkynyl,
perhaloalkyl, haloalkyl, aryl, --CH.sub.2OH,
--CH.sub.2NR.sup.4.sub.2, --CH.sub.2CN, --CN, --C(S)NH.sub.2,
--OR.sup.2, --SR.sup.3, --N.sub.3, --NHC(S)NR.sup.4.sub.2, --NHAc,
and null;
[0191] 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;
[0192] 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;
[0193] J is selected from the group consisting of --H and null;
[0194] 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 there is
no N in the linking group unless it is connected directly to a
carbonyl or in the ring of a heterocycle; and wherein X is not a 2
carbon atom -alkyl- or -alkenyl- group; with the proviso that X is
not substituted with --COOR.sup.2, --SO.sub.2R.sup.1, or
--PO.sub.3R.sup.1.sub.2;
[0195] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0196] 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,
[0197] 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;
[0198] 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 ##STR26## wherein
[0199] 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
[0200] 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
[0201] 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;
[0202] 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 substitutent 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;
[0203] 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;
[0204] 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;
[0205] 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,
--CH.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;
[0206] p is an integer 2 or 3;
[0207] q is an integer 1 or 2;
[0208] with the provisos that:
[0209] a) V, Z, W, W' are not all --H; and
[0210] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0211] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0212] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0213] 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;
[0214] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0215] 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;
[0216] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and with the provisos that:
[0217] 1) when G' is N, then the respective A, B, D, or E is null;
[0218] 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; [0219] 3) when
R.sup.5 is a six-membered ring, then X is not any 2 atom linker, an
optionally substituted -alkyl-, an optionally substituted
-alkenyl-, an optionally substituted -alkyloxy-, or an optionally
substituted -alkylthio-; [0220] 4) when G is N, then the respective
A or B is not halogen or a group directly bonded to G via a
heteroatom; [0221] 5) R.sup.1 is not unsubstituted C1-C10 alkyl;
[0222] 6) when X is not an -aryl- group, then R.sup.5 is not
substituted with two or more aryl groups;
[0223] and pharmaceutically acceptable prodrugs and salts
thereof.
[0224] 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 substitutent.
[0225] In one aspect, preferred are compounds of formula I
where:
[0226] 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;
[0227] each B and D are independently selected from the group
consisting of --H, alkyl, alkenyl, alkynyl, aryl, alicyclic,
aralkyl, alkoxyallyl, --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;
[0228] 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.9.sub.2,
--OR.sup.3, --SR.sup.3, C1-C6 perhaloalkyl, halo, and null, all
except --H, --CN, perhaloalkyl, and halo are optionally
substituted; and
[0229] each R.sup.4 is independently selected from the group
consisting of --H, and C1-C2 alkyl.
[0230] In another preferred aspect, R.sup.5 is: ##STR27##
[0231] In another preferred aspect, R.sup.5 is: ##STR28##
[0232] In another preferred aspect, R.sup.5 is selected from the
group consisting of: ##STR29## wherein
[0233] 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;
[0234] 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;
[0235] 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
[0236] each R.sup.4 is independently selected from the group
consisting of --H and C1-C2 alkyl.
[0237] More preferred are such where R.sup.5 is selected from the
group consisting of: ##STR30##
[0238] Also more preferred are such where R.sup.5 is selected from
the group consisting of: ##STR31##
[0239] Also more preferred are such where R.sup.5 is selected from
the group consisting of: ##STR32##
[0240] Preferred X groups include -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.
[0241] More preferred X groups include -heteroaryl-,
-alkylcarbonylamino-, -alkylaminocarbonyl-, -alkoxycarbonyl-, and
-alkoxyalkyl-.
[0242] Particularly preferred X groups include -heteroaryl-, and
-alkoxycarbonyl-. Especially preferred are furan-3,5-diyl,
-methylaminocarbonyl-, and methyloxycarbonyl-.
[0243] Also particularly preferred are compounds where X is as
shown in formulae II, III, or IV ##STR33##
[0244] Especially preferred are compounds where X is as shown in
formulae II and IV.
[0245] Preferred A groups include --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, null, and --NHAc. More 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.2, null, and --H.
Especially preferred A groups include --NH.sub.2, --Cl, --Br, null,
and --CH.sub.2.
[0246] Preferred A'' groups include --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.2N.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. More 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.
Especially preferred A'' groups include --NH.sub.2, --Cl, --Br, and
--CH.sub.3.
[0247] Preferred B groups include --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, and
null, all except --H, --CN, perhaloalkyl, null, and halo are
optionally substituted. More preferred B groups include --H,
--C(O)R.sup.11, --C(O)SR.sup.3, alkyl, aryl, alicyclic, halo,
--NR.sup.9.sub.2, --OR.sup.3, null and --SR.sup.3. Especially
preferred B groups include --H, --C(O)OR.sup.3, --C(O)SR.sup.3,
C1-C6 alkyl, alicyclic, halo, heteroaryl, null, and --SR.sup.3.
[0248] Preferred B'' groups include --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. More preferred B'' groups include --H, --C(O)R.sup.11,
--C(O)SR.sup.3, alkyl, aryl, alicyclic, halo, --NR.sup.9.sub.2,
--OR.sup.3, and --SR.sup.3. Especially preferred B'' groups include
--H, --C(O)OR.sup.3, --C(O)SR.sup.3, C1-C6 alkyl, alicyclic, halo,
heteroaryl, and --SR.sup.3.
[0249] Preferred D groups include --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, null, and halo are
optionally substituted. More preferred D groups include --H,
--C(O)R.sup.11, alkyl, --C(O)SR.sup.3, aryl, alicyclic, halo,
--NR.sup.9.sub.2, null and --SR.sup.3. Especially preferred D
groups include --H, --C(O)OR.sup.3, lower alkyl, alicyclic, null,
and halo.
[0250] Preferred D'' groups include --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, and halo,
all except --H, --CN, perhaloalkyl, and halo are optionally
substituted. More 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. Especially preferred D'' groups include --H,
--C(O)OR.sup.3, lower alkyl, alicyclic, and halo.
[0251] Preferred E groups include --H, C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl, --C(O)OR.sup.3,
--CONR.sup.4.sub.2, --CN, --NR.sup.9.sub.2, --OR.sup.3, --SR.sup.3,
C1-C6 perhaloalkyl, halo, and null, all except --H, --CN,
perhaloalkyl, null, and halo are optionally substituted. More
preferred E groups include --H, C1-C6 alkyl, lower alicyclic,
halogen, --CN, --C(O)OR.sup.3, --SR.sup.3, --CONR.sup.4.sub.2, and
null. Especially preferred E groups include --H, --Br, --Cl, and
null.
[0252] Preferred E'' groups include --H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, aryl, C4-C6 alicyclic, alkoxyalkyl,
--C(O)OR.sup.3, --CONR.sup.4.sub.2, --CN, --NR.sup.9.sub.2,
--OR.sup.3, --SR.sup.3, C1-C6 perhaloalkyl, and halo, all except
--H, --CN, perhaloalkyl, and halo are optionally substituted. More
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.
Especially preferred E'' groups include --H, --Br, and --Cl.
[0253] In one preferred aspect,
[0254] A'' is selected from the group consisting of --NH.sub.2,
--CONE.sub.2, halo, --CH.sub.3, --CF.sub.3, --CH.sub.2-halo, --CN,
--OCH.sub.3, --SCH.sub.3, and --H;
[0255] 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;
[0256] 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;
[0257] E'' is selected from the group consisting of --H, C1-C6
alkyl, lower alicyclic, halo, --CN, --C(O)OR.sup.3, and
--SR.sup.3.
[0258] 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;
[0259] 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
[0260] 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
[0261] when Y is --O-- or --NR.sup.6--, then together R.sup.1 and
R.sup.1 are ##STR34## wherein
[0262] 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
[0263] 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 substitutent 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;
[0264] 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;
[0265] 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;
[0266] 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--R.sup.3, --(CH.sub.2).sub.p--OR.sup.2, and
--(CH.sub.2).sub.p--SR.sup.2;
[0267] p is an integer 2 or 3;
[0268] with the provisos that:
[0269] a) V, Z, W, W' are not all --H;
[0270] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic; and
[0271] c) both Y groups are not --NR.sup.6--;
[0272] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0273] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0274] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0275] in one particularly preferred aspect, R.sup.5 is
##STR35##
[0276] 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;
[0277] 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
[0278] 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 ##STR36##
[0279] wherein
[0280] V is selected from the group consisting of optionally
substituted aryl, and optionaly substituted heteroaryl; and Z, W',
and W are H; and
[0281] R.sup.6 is selected from the group consisting of --H, and
lower alkyl
[0282] The following such compounds and their salts are most
preferred:
[0283] 1) A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is
--CH.sub.2--CH(CH.sub.3).sub.2;
[0284] 2) A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is
--COOEt;
[0285] 3) A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is
--SCH.sub.3;
[0286] 4) A'' is --NH.sub.2, X is furan-2,5-diyl, and B'' is
--SCH.sub.2CH.sub.2SCH.sub.3;
[0287] 5) A'' is --NH.sub.2, X is methyleneoxycarbonyl, and B'' is
--CH(CH.sub.3).sub.2.
[0288] In another particularly preferred aspect, R.sup.5 is
##STR37##
[0289] 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
[0290] 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;
[0291] 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;
[0292] or when Y is independently selected from --O-- and
--NR.sup.6--, then together R.sup.1 and R.sup.1 are ##STR38##
wherein
[0293] 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.
[0294] In another particularly preferred aspect, R.sup.5 is
##STR39##
[0295] 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,
[0296] 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;
[0297] 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 ##STR40## wherein
[0298] V is selected from the group consisting of optionally
substituted aryl and optionally substituted heteroaryl; and Z, W',
and W are H.
[0299] In another particularly preferred aspect, R.sup.5 is
##STR41##
[0300] 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;
[0301] 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
[0302] when at least one Y group is --O--, then together R.sup.1
and R.sup.1 are ##STR42## wherein
[0303] V is selected from the group consisting of optionally
substituted aryl and optionally substituted heteroaryl; and Z, W',
and W are H.
[0304] Preferred are compounds of formula (X): ##STR43##
wherein:
[0305] G'' is selected from the group consisting of --O-- and
--S--;
[0306] 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 alkenyl, 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;
[0307] X.sup.2 is an optionally substituted linking group that
links R.sup.5 to the phosphorus atom via 1-3 atoms, including 0-1
heteroatoms, selected from N, O, and S, and wherein in the atom
attached to the phosphorus is a carbon atom;
[0308] with the proviso that X.sup.2 is not substituted with
--COOR.sup.2, --SO.sub.3R.sup.1, or --PO.sub.3R.sup.1.sub.2;
[0309] Y is independently selected from the group consisting of
--O--, and --NR.sup.6--;
[0310] 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,
[0311] 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;
[0312] 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 ##STR44## wherein
[0313] 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
[0314] 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
[0315] 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;
[0316] 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 substitutent 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;
[0317] 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;
[0318] 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;
[0319] 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
[0320] p is an integer 2 or 3;
[0321] q is an integer 1 or 2;
[0322] with the provisos that:
[0323] a) V, Z, W, W' are not all --H; and
[0324] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic;
[0325] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0326] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0327] 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;
[0328] R.sup.6 is selected from the group consisting of --H, lower
alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
[0329] 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;
[0330] R.sup.11 is selected from the group consisting of alkyl,
aryl, --NR.sup.2.sub.2, and --OR.sup.2; and
[0331] pharmaceutically acceptable prodrugs and salts thereof.
[0332] The preferred G'' group is --S--.
[0333] Preferred A.sup.2, L.sup.2, E.sup.2, and J.sup.2 groups
include --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 preferred A.sup.2, E.sup.2, E.sup.2
and J.sup.2 groups include --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. Particularly preferred J.sup.2 groups are --H, and
lower alkyl. Particularly preferred A.sup.2 groups include
--NH.sub.2, --H, halo, and C1-C5 alkyl.
[0334] Particularly preferred compounds include those where L.sup.2
and E.sup.2 are 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.
[0335] Preferred X.sup.2 groups include -alkyl-, -alkenyl-,
-alkynyl-, -alkylene-NR.sup.4--, -alkylene-O--, alkylene-S--,
--C(O)-alkylene-, and -alkylene-C(O)--. More preferred X.sup.2
groups include -alkylene-O--, alkylene-S--, and -alkyl-, Especially
preferred X.sup.2 groups include -methyleneoxy-.
[0336] 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;
[0337] 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;
[0338] 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;
[0339] J.sup.2 is selected from the groups consisting of H,
halogen, and lower alkyl;
[0340] G'' is --S--;
[0341] X.sup.2 is --CH.sub.2O--; and
[0342] at least one Y group is --O--; and pharmaceutically
acceptable salts and prodrugs thereof. Also particularly preferred
are such compounds where A.sup.2 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 --N--, 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.
[0343] 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.
[0344] In compounds of formula I and 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--;
[0345] In another particularly preferred aspect, both Y groups are
--O--, and R.sup.1 and R.sup.1 together are ##STR45## 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.
[0346] In another particularly preferred aspect, one Y is --O-- and
its corresponding R.sup.1 is phenyl, or phenyl substituted with 1-2
substitutents 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.
[0347] In general, preferred substitutents, V, Z, W, and W' of
formulae I and X are chosen such that they exhibit one or more of
the following properties:
[0348] (1) enhance the oxidation reaction since this reaction is
likely to be the rate determining step and therefore must compete
with drug elimination processes.
[0349] (2) enhance stability in aqueous solution and in the
presence of other non-p450 enzymes;
[0350] (3) enhance cell penetration, e.g. substitutents are not
charged or of high molecular weight since both properties can limit
oral bioavailability as well as cell penetration;
[0351] (4) promote the .beta.-elimination reaction following the
initial oxidation by producing ring-opened products that have one
or more of the following properties [0352] a) fail to recyclize;
[0353] b) undergo limited covalent hydration; [0354] c) promote
.beta.-elimination by assisting in the proton abstraction; [0355]
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 [0356] e) limit
metabolism of reaction intermediates (e.g. ring-opened ketone);
[0357] (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 substitutents that limit Michael additions,
reactions, e.g. [0358] a) electron donating Z groups that decrease
double bond polarization; [0359] b) W groups that sterically block
nucleophilic addition to .beta.-carbon; [0360] c) Z groups that
eliminate the double bond after the elimination reaction either
through retautomerization (enol->keto) or hydrolysis (e.g.
enamine); [0361] d) V groups that contain groups that add to the
.alpha.,.beta.-unsaturated ketone to form a ring; [0362] e) Z
groups that form a stable ring via Michael addition to double bond;
and [0363] f) groups that enhance detoxification of the by-product
by one or more of the following characteristics: [0364] (i) confine
to liver; and [0365] (ii) make susceptible to detoxification
reactions (e.g. ketone reduction); and
[0366] (6) capable of generating a pharmacologically active
product.
[0367] 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;
[0368] 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.2).sub.2].sub.q--C(O)SR.sup.3,
--C(R.sup.4).sub.2COOR.sup.3, and -cycloalkylene-COOR.sup.3;
[0369] or when either Y is independently selected from --O-- and
--NR.sup.6--, then together R.sup.1 and R.sup.1 are ##STR46##
wherein
[0370] 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
[0371] 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 substitutent 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;
[0372] 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;
[0373] 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;
[0374] 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.2CO.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;
[0375] p is an integer 2 or 3;
[0376] q is an integer 1 or 2;
[0377] with the provisos that:
[0378] a) V, Z, W, W' are not all --H;
[0379] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic; and
[0380] c) both Y groups are not --NR.sup.6--;
[0381] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0382] R.sup.3 is selected from the group consisting of alkyd aryl,
alicyclic, and aralkyl;
[0383] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0384] 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
[0385] 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.
[0386] 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.
[0387] 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.
[0388] 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.
[0389] 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.
[0390] In another preferred aspect, when one Y is --O--, then its
corresponding R.sup.1 is 2-CH.sub.2-phenyl, and the other Y is
--NH, and its corresponding, R1 is --CH.sub.2CO.sub.2Et.
[0391] 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.
[0392] Also preferred are compounds wherein both Y groups are C--,
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.
[0393] 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.
[0394] In one aspect, particularly preferred are compounds wherein
both Y groups are --O--, and R.sup.1 is H.
[0395] In another aspect, particularly preferred are compounds
where both Y groups are --O--, and R.dbd. is
--CH.sub.2OC(O)OEt.
[0396] More preferred are compounds wherein at least one Y is
--O--, and together R.sup.1 and R.sup.1 are ##STR47## wherein
[0397] 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
[0398] 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 substitutent 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;
[0399] 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;
[0400] 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;
[0401] 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,
--CR.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;
[0402] p is an integer 2 or 3;
[0403] with the provisos that:
[0404] a) V, Z, W, W'are not all --H;
[0405] b) when Z is --R.sup.2, then at least one of V, W, and W' is
not --H, alkyl, aralkyl, or alicyclic; and
[0406] c) both Y groups are not --NR.sup.6--;
[0407] R.sup.2 is selected from the group consisting of R.sup.3 and
--H;
[0408] R.sup.3 is selected from the group consisting of alkyl,
aryl, alicyclic, and aralkyl;
[0409] R.sup.6 is selected from the group consisting of --H, and
lower alkyl.
[0410] 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.
[0411] 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 substitutents 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 substitutents 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.
[0412] More preferred V groups of formula VI 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.
[0413] 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.
[0414] 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.
[0415] 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 substitutent selected from the group
consisting of hydroxy, acyloxy, alkosycarbonyloxy,
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--.
[0416] Another preferred V group is 1-alkene. Oxidation by p450
enzymes is known to occur at benzylic and allylic carbons.
[0417] 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.
[0418] 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.
[0419] 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.
[0420] In one aspect, prodrugs of formula VI are preferred:
##STR48## wherein
[0421] 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.
[0422] In one aspect, the compounds of formula VI preferably have a
group Z which is H, alkyl, alicyclic, hydroxy, alkoxy, ##STR49## 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 .beta.-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: ##STR50##
[0423] In another aspect, prodrugs of formula VII are preferred:
##STR51## wherein
[0424] 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.2C(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.2C(O)R.sup.3, and
--CHR.sup.2OCO.sub.2R.sup.3.
[0425] In another aspect, prodrugs of formula VIII are preferred:
##STR52## wherein
[0426] Z' is selected from the group consisting of --OH,
--OC(O)R.sup.3, --OCO.sub.2R.sup.3, and --OC(O)SR.sup.3;
[0427] 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--.
[0428] 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: ##STR53## has
a plane of symmetry. Preferably Y is --O--.
[0429] 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.
[0430] Preferably, oral bioavailability is at least 5%. More
preferably, oral bioavailability is at least 10%.
[0431] 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.
[0432] The preferred compounds of formula VIII 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--O(O)(NHR.sup.6).sub.2,
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.
[0433] In the following examples of preferred compounds, the
following prodrugs are preferred: [0434] Acyloxyalkyl esters;
[0435] Alkoxycarbonyloxyalkyl esters; [0436] Aryl esters; [0437]
Benzyl and substituted benzyl esters; [0438] Disulfide containing
esters; [0439] Substituted (1,3-dioxolen-2-one)methyl esters;
[0440] Substituted 3-phthalidyl esters; [0441]
Cyclic-[5-hydroxycyclohexan-1,3-diyl)diesters and hydroxy protected
forms; [0442] Cyclic-[2-hydroxymethylpropan-1,3-diyl]diesters and
hydroxy protected forms; [0443] Cyclic-(1-arylpropan-1,3-diyl);
[0444] Monoaryl ester N-substituted mono phosphoramidates; [0445]
Bis Omega substituted lactone esters; and all mixed esters resulted
from possible combinations of above esters;
[0446] More preferred are the following: [0447]
Bis-pivaloyloxymethyl esters; [0448] Bis-isobutyryloxymethyl
esters; [0449] Cyclic-[1-(3-chlorophenyl)propan-1,3-diyl]diesters;
[0450] Cyclic-[1-(3,5-dichlorophenyl)propan-1,3-diyl]diester;
[0451] Cyclic-[1-(3-bromo-4-fluorophenyl)propan-1,3-diyl]diester;
[0452] Cyclic-[2-hydroxymethylpropan-1,3-diyl]diester; [0453]
Cyclic-[2-acetoxymethylpropan-1,3-diyl]diester; [0454]
Cyclic-[2-methyloxycarbonyloxymethylpropan-1,3-diyl]diester; [0455]
Cyclic-[1-phenylpropan-1,3-diyl]diesters; [0456]
Cyclic-[1-(2-pyridyl)propan-1,3-diyl)]diesters; [0457]
Cyclic-[1-(3-pyridyl)propan-1,3-diyl]diesters; [0458]
Cyclic-[1-(4-pyridyl)propan-1,3-diyl]diesters; [0459]
Cyclic-[5-hydroxycyclohexan-1,3-diyl]diesters and hydroxy protected
forms; [0460] Bis-benzoylthiomethyl esters; [0461]
Bis-benzoylthioethyl esters; [0462] Bis-benzoyloxymethyl esters;
[0463] Bis-p-fluorobenzoyloxymethyl esters; [0464]
Bis-6-chloronicotinoyloxymethyl esters; [0465]
Bis-5-bromonicotinoyloxymethyl esters; [0466]
Bis-thiophenecarbonyloxymethyl esters; [0467] Bis-2-furoyloxymethyl
esters; [0468] Bis-3-furoyloxymethyl esters; [0469] Diphenyl
esters; [0470] Bis-(4-methoxyphenyl)esters; [0471]
Bis-(2-methoxyphenyl)esters; [0472] Bis-(2-ethoxyphenyl)esters;
[0473] Mono-(2-ethoxyphenyl)esters;
[0474] Bis-(4-acetamidophenyl)esters; [0475]
Bis-(4-acetoxyphenyl)esters; [0476] Bis-(4-hydroxyphenyl)esters;
[0477] Bis-(2-acetoxyphenyl)esters; [0478]
Bis-(3-acetoxyphenyl)esters; [0479] Bis-(4-morpholinophenyl)esters;
[0480] Bis-[4-(1-triazolophenyl)esters; [0481]
Bis-(3-N,N-dimethylaminophenyl)esters; [0482]
Bis-(1,2,3,4-tetrahydronapthalen-2-yl)esters; [0483]
Bis-(3-chloro-4-methoxy)benzyl esters; [0484]
Bis-(3-bromo-4-methoxy)benzyl esters; [0485]
Bis-(3-cyano-4-methoxy)benzyl esters; [0486]
Bis-(3-chloro-4-acetoxy)benzyl esters; [0487]
Bis-(3-bromo-4-acetoxy)benzyl esters; [0488]
Bis-(3-cyano-4-acetoxy)benzyl esters; [0489] Bis-(4-chloro)benzyl
esters; [0490] Bis-(4-acetoxy)benzyl esters; [0491]
Bis-(3,5-dimethoxy-4-acetoxy)benzyl esters; [0492]
Bis-(3-methyl-4-acetoxy)benzyl esters; [0493] Bis-(benzyl)esters;
[0494] Bis-(3-methoxy-4-acetoxy)benzyl esters; [0495]
Bis-(6'-hydroxy-3',4'-dithia)hexyl esters; [0496]
Bis-(6'-acetoxy-3',4'-dithia)hexyl esters;
(3,4-dithiahexan-1,6-diyl)esters; [0497]
Bis-(5-methyl-1,3-dioxolen-2-one-4-yl)methyl esters; [0498]
Bis-(5-ethyl-1,3-dioxolen-2-one-4-yl)methyl esters; [0499]
Bis-(5-tert-butyl-1,3-dioxolen-2-one-4-yl)methyl esters;
[0500] Bis-3-(5,6,7-trimethoxy)phthalidyl esters; [0501]
Bis-(cyclohexyloxycarbonyloxymethyl) esters; [0502]
Bis-(isopropyloxycarbonyloxymethyl)esters; [0503]
Bis-(ethyloxycarbonyloxymethyl)esters; [0504]
Bis-(methyloxycarbonyloxymethyl)esters; [0505]
Bis-(isopropylthiocarbonyloxymethyl)esters; [0506]
Bis-(phenyloxycarbonyloxymethyl)esters; [0507]
Bis-(benzyloxycarbonyloxymethyl)esters; [0508]
Bis-(phenylthiocarbonyloxymethyl)esters; [0509]
Bis-(p-methoxyphenoxycarbonyloxymethyl)esters; [0510]
Bis-(m-methoxyphenoxycarbonyloxymethyl)esters; [0511]
Bis-(o-methoxyphenoxycarbonyloxymethyl)esters; [0512]
Bis-(o-methylphenoxycarbonyloxymethyl)esters; [0513]
Bis-(p-chlorophenoxycarbonyloxymethyl)esters; [0514]
Bis-(1,4-biphenoxycarbonyloxymethyl)esters; [0515]
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters; [0516]
Bis-(N-phenyl-N-methylcarbamoyloxymethyl)esters; [0517]
Bis-(2,2,2-trichloroethyl)esters; [0518] Bis-(2-bromoethyl)esters;
[0519] Bis-(2-iodoethyl)esters; [0520] Bis-(2-azidoethyl)esters;
[0521] Bis-(2-acetoxyethyl)esters; [0522] Bis-(2-aminoethyl)esters;
[0523] Bis-(2-N,N-dimethylaminoethyl)esters; [0524]
Bis-(2-aminoethyl)esters; [0525] Bis-(methoxycarbonylmethyl)esters;
[0526] Bis-(2-aminoethyl)esters;
[0527] Bis-[N,N-di(2-hydroxyethyl)]carbamoylmethylesters; [0528]
Bis-(2-aminoethyl)esters; [0529]
Bis-(2-methyl-5-thiazolomethyl)esters; [0530]
Bis-(bis-2-hydroxyethylcarbamoylmethyl)esters. [0531]
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(N(H)--CH(Me)CO.sub.2Et) [0532]
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(N(H)--CH(Me)CO.sub.2Me) [0533]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-3-Cl)(NH--CH(Me)CO.sub.2Et) [0534]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--CH(Me)CO.sub.2Et) [0535]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4-Cl)(NH--CH(Me)CO.sub.2Et) [0536]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4-NHAc)(NH--CH(Me)CO.sub.2Et) [0537]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--CH(Me)CO.sub.2Et) [0538]
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Et) [0539]
O-phenyl-[N-(1-methoxycarbony-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Me) [0540]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-3-Cl)(--C(Me).sub.2CO.sub.2Et) [0541]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--C(Me).sub.2CO.sub.2Et) [0542]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-4-Cl)(NH--C(Me).sub.2CO.sub.2Et) [0543]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidate-
s (--P(O)(OPh-4--NHAc)(NH--C(Me).sub.2CO.sub.2Et) [0544]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoram-
idates (--P(O)(OPh-2-CO.sub.2Et)(NE-C(Me).sub.2CO.sub.2Et) [0545]
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Et) [0546]
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Me) [0547]
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-3-Cl)(NH--CH.sub.2CO.sub.2Et) [0548]
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--CH.sub.2CO.sub.2Et) [0549]
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4-Cl)(NH--CH.sub.2CO.sub.2Et) [0550]
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4-NHAc)NH--CH.sub.2CO.sub.2Et) [0551]
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NE-CH.sub.2CO.sub.2Et)
[0552] Most preferred are the following: [0553]
Bis-pivaloyloxymethyl esters; [0554] Bis-isobutyryloxymethyl
esters; [0555] Cyclic-[1-(3-chlorophenyl)propan-1,3-diyl]diesters;
[0556] Cyclic-[1,3,5-dichlorophenyl)propan-1,3-diyl]diester; [0557]
Cyclic-[1-(3-bromo-4-fluorophenyl)propan-1,3-diyl]diester; [0558]
Cyclic-(2-hydroxymethylpropan-1,3-diyl)ester; [0559]
Cyclic-(2-acetoxymethylpropan-1,3-diyl)ester; [0560]
Cyclic-(2-methyloxycarbonyloxymethylpropan-1,3-diyl)ester; [0561]
Cyclic-(2-cyclohexylcarbonyloxymethylpropan-1,3-diyl)ester; [0562]
Cyclic-[phenylpropan-1,3-diyl]diesters; [0563]
Cyclic-[1-(2-pyridyl)propan-1,3-diyl)]diesters; [0564]
Cyclic-[1-(3-pyridyl)propan-1,3-diyl]diesters; [0565]
Cyclic-[1-(4-pyridyl)propan-1,3-diyl]diesters; [0566]
Cyclic-[5-hydroxycyclohexan-1,3-diyl]diesters and hydroxy protected
forms; [0567] Bis-benzoylthiomethyl esters; [0568]
Bis-benzoylthioethylesters; [0569] Bis-benzoyloxymethyl esters;
[0570] Bis-p-fluorobenzoyloxymethyl esters; [0571]
Bis-6-chloronicotinoyloxymethyl esters; [0572]
Bis-5-bromonicotinoyloxymethyl esters; [0573]
Bis-thiophenecarbonyloxymethyl esters; [0574] Bis-2-furoyloxymethyl
esters; [0575] Bis-3-furoyloxymethyl esters; [0576] Diphenyl
esters; [0577] Bis-(2-methylphenyl)esters; [0578]
Bis-(2-methoxyphenyl)esters; [0579] Bis-(2-ethoxyphenyl)esters;
[0580] Bis-(4-methoxyphenyl)esters; [0581]
Bis-(3-bromo-4-methoxybenzyl)esters; [0582]
Bis-(4-acetoxybenzyl)esters; [0583]
Bis-(3,5-dimethoxy-4-acetoxybenzyl)esters; [0584]
Bis-(3-methyl-4-acetoxybenzyl) esters; [0585]
Bis-(3-methoxy-4-acetoxybenzyl)esters; [0586]
Bis-(3-chloro-4-acetoxybenzyl)esters; [0587]
Bis-(cyclohexyloxycarbonyloxymethyl)esters; [0588]
Bis-(isopropyloxycarbonyloxymethyl)esters; [0589]
Bis-(ethyloxycarbonyloxymethyl)esters; [0590]
Bis-(methyloxycarbonyloxymethyl)esters; [0591]
Bis-(isopropylthiocarbonyloxymethyl)esters; [0592]
Bis-(phenyloxycarbonyloxymethyl)esters; [0593]
Bis-(benzyloxycarbonyloxymethyl)esters; [0594]
Bis-(phenylthiocarbonyloxymethyl)esters; [0595]
Bis-(p-methoxyphenoxycarbonyloxymethyl)esters; [0596]
Bis-(m-methoxyphenoxycarbonyloxymethy)esters;
[0597] Bis-(o-methoxyphenoxycarbonyloxymethyl)esters; [0598]
Bis-(o-methylphenoxycarbonyloxymethyl)esters; [0599]
Bis-(p-chlorophenoxycarbonyloxymethyl)esters; [0600]
Bis-(1,4-biphenoxycarbonyloxymethyl)esters; [0601]
Bis-[(2-phthalimidoethyl)oxycarbonyloxymethyl]esters; [0602]
Bis-(6-hydroxy-3,4-dithia)hexyl esters; [0603]
Cyclic-(3,4-dithiahexan-1,6-diyl)esters; [0604]
Bis-(2-bromoethyl)esters; [0605] Bis-(2-aminoethyl)esters; [0606]
Bis-(2-N,N-diaminoethyl)esters; [0607]
O-phenyl-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--*CH(Me)CO.sub.2Et) [0608]
O-phenyl-[N-(1-methoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--*CH(Me)CO.sub.2Me) [0609]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-3-Cl)(NH--*CH(Me)CO.sub.2Et) [0610]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--*CH(Me)CO.sub.2Et) [0611]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4-Cl)(NH--*CH(Me)CO.sub.2Et) [0612]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-4-NHAc)(NH--*CH(Me)CO.sub.2Et) [0613]
O-(2-ethoxycarbonylphenyl)-[N-(1-ethoxycarbonyl)ethyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--*CH(Me)CO.sub.2Et) [0614]
O-phenyl-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Et) [0615]
O-phenyl-[N-(1-methoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh)(NH--C(Me).sub.2CO.sub.2Me) [0616]
O-(3-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-3-Cl)(NH--C(Me).sub.2CO.sub.2Et) [0617]
O-(2-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--C(Me).sub.2CO.sub.2Et) [0618]
O-(4-chlorophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidates
(--P(O)(OPh-4-Cl)(NH--C(Me).sub.2CO.sub.2Et) [0619]
O-(4-acetamidophenyl)-[N-(1-ethoxycarbonyl-1-methyl)ethyl]phosphoramidate-
s (--P(O)(OPh-4-NHAc)(NH--C(Me).sub.2CO.sub.2Et) [0620]
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)
[0621] In the above prodrugs an asterisk (*) on a carbon refers to
the L-configuration. [0622]
O-phenyl-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Et) [0623]
O-phenyl-[N-(methoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh)(NH--CH.sub.2CO.sub.2Me) [0624]
O-(3-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-3-Cl)(NH--CH.sub.2CO.sub.2Et) [0625]
O-(2-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-Cl)(NH--CH.sub.2CO.sub.2Et) [0626]
O-(4-chlorophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4-Cl)(NH--CH.sub.2CO.sub.2Et) [0627]
O-(4-acetamidophenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-4-NHAc)(NH--CH.sub.2CO.sub.2Et) [0628]
O-(2-ethoxycarbonylphenyl)-[N-(ethoxycarbonyl)methyl]phosphoramidates
(--P(O)(OPh-2-CO.sub.2Et)(NH--CH.sub.2CO.sub.2Et)
[0629] The following compounds of formula I wherein R.sup.5 is a
thiazolyl, or an oxazolyl, or a selenazolyl, or a pyrazolyl, or an
imidazolyl or an isoxazolyl or a 1,2,4-triazolyl, or a
1,2,4-thiadiazolyl, or a 1,2,4-oxadiazolyl, and pharmaceutically
acceptable salts and prodrugs thereof are preferred. These
preferred compounds are shown in structures (i)-(iv), below:
##STR54##
[0630] The preferred compounds are listed in Table 1 by designated
numbers assigned to A, B, X and Y' moieties in the above formulae
i-iv according to the following convention: A.B.X.Y'. For each
moiety, structures are assigned to a number shown in the following
tables for A, B, X, and Y'. The following terms are used: Pr-c is
cyclopropyl, Pr-n is n-propyl, Pr-i is isopropyl, Bu-n is n-butyl,
Bu-I is isobutyl, Bu-c is cyclobutyl, Bu-s is sec-butyl, Bu-t is
tert-butyl and hexyl-c is cyclohexyl.
[0631] Variable A is selected from seven different
substitutents.
[0632] The A groups are assigned the following numbers:
TABLE-US-00002 TABLE A 1 2 3 4 5 6 7 A = H NH.sub.2 Br Cl F Me
CF.sub.3
[0633] Variable B is divided into four Groups, each listing, nine
different substitutents.
[0634] The Group 1 substitutents for variable B are assigned the
following numbers: TABLE-US-00003 1 2 3 4 5 6 7 8 9 B = H Me Et
Pr-n Pr-i Pr-c Br Cl I
[0635] The Group 2 substitutents for variable B are assigned the
following numbers: TABLE-US-00004 1 2 3 4 5 6 7 8 9 B = F CN
CH.sub.2Pr-c CH.sub.2OMe neopentyl C(O)OMe OEt SMe C(O)SMe
[0636] The Group 3 substitutents for variable B are assigned the
following numbers: TABLE-US-00005 1 2 3 4 5 6 7 8 9 B = SEt
4-pyridyl Bu-c C(O)OEt NMe.sub.2 SPr-n CF.sub.3 Bu-n Bu-i
[0637] The Group 4 substitutents for variable B are assigned the
following numbers: TABLE-US-00006 1 2 3 4 5 6 7 8 9 B = SPr-c OPr-i
OPr-c SPr-i 2-furanyl 2-thienyl OMe CH.sub.2SMe Bn
[0638] Variable X is selected from nine different
substitutents.
[0639] The X groups are assigned the following numbers:
TABLE-US-00007 TABLE X 1 2 3 4 5 6 7 8 9 X = Furan- Pyridin-
Oxazol- C(O)--OCH.sub.2 C(O)--NHCH.sub.2 C(O)--SCH.sub.2
C(O)--N(Me)CH.sub.2 NHC(O)--CH.sub.2 CH.sub.2O CH.sub.2 2,5-diyl
2,6-diyl 2,5-diyl
The direction of X groups is defined as going from the heterocycle
to the phosphorus atom as shown in formula (i), (ii), (iii) and
(iv).
[0640] Variable Y' is selected from six different
substitutents.
[0641] The Y' groups are assigned the following numbers:
TABLE-US-00008 TABLE Y 1 2 3 4 5 6 Y' = S O Se NH NMe NEt
[0642] TABLE-US-00009 TABLE 1 1.1.1.1 1.1.1.2 1.1.1.3 1.1.1.4
1.1.1.5 1.1.1.6 1.1.2.1 1.1.2.2 1.1.2.3 1.1.2.4 1.1.2.5 1.1.2.6
1.1.3.1 1.1.3.2 1.1.3.3 1.1.3.4 1.1.3.5 1.1.3.6 1.1.4.1 1.1.4.2
1.1.4.3 1.1.4.4 1.1.4.5 1.1.4.6 1.1.5.1 1.1.5.2 1.1.5.3 1.1.5.4
1.1.5.5 1.1.5.6 1.1.6.1 1.1.6.2 1.1.6.3 1.1.6.4 1.1.6.5 1.1.6.6
1.1.7.1 1.1.7.2 1.1.7.3 1.1.7.4 1.1.7.5 1.1.7.6 1.1.8.1 1.1.8.2
1.1.8.3 1.1.8.4 1.1.8.5 1.1.8.6 1.1.9.1 1.1.9.2 1.1.9.3 1.1.9.4
1.1.9.5 1.1.9.6 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.5 1.2.1.6
1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.2.6 1.2.3.1 1.2.3.2
1.2.3.3 1.2.2.4 1.2.3.5 1.2.3.6 1.2.4.1 1.2.4.2 1.2.4.3 1.2.4.4
1.2.4.5 1.2.4.6 1.2.5.1 1.2.5.2 1.2.5.3 1.2.5.4 1.2.5.5 1.2.5.6
1.2.6.1 1.2.6.2 1.2.6.3 1.2.6.4 1.2.6.5 1.2.6.6 1.2.7.1 1.2.7.2
1.2.7.3 1.2.7.4 1.2.7.5 1.2.7.6 1.2.8.1 1.2.8.2 1.2.9.3 1.2.8.4
1.2.8.5 1.2.8.6 1.2.9.1 1.2.9.2 1.2.9.3 1.2.9.4 1.2.9.5 1.2.9.6
1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.1.6 1.3.2.1 1.3.2.2
1.3.2.3 1.3.2.4 1.3.2.5 1.3.2.6 1.3.3.1 1.3.3.2 1.3.3.3 1.3.3.4
1.3.3.5 1.3.3.6 1.3.4.1 1.3.4.2 1.3.4.3 1.3.4.4 1.3.4.5 1.3.4.6
1.3.5.1 1.3.5.2 1.3.5.3 1.3.5.4 1.3.5.5 1.3.5.6 1.3.6.1 1.3.6.2
1.3.6.3 1.3.6.4 1.3.6.5 1.3.6.6 1.3.7.1 1.3.7.2 1.3.7.3 1.3.7.4
1.3.7.5 1.3.7.6 1.3.8.1 1.3.8.2 1.3.8.3 1.3.8.4 1.3.8.5 1.3.8.6
1.3.9.1 1.3.9.2 1.3.9.3 1.3.9.4 1.3.9.5 1.3.9.6 1.4.1.1 1.4.1.2
1.4.1.3 1.4.1.4 1.4.1.5 1.4.1.6 1.4.2.1 1.4.2.2 1.4.2.3 1.4.2.4
1.4.2.5 1.4.2.6 1.4.3.1 1.4.3.2 1.4.3.3 1.4.3.4 1.4.3.5 1.4.3.6
1.4.4.1 1.4.4.2 1.4.4.3 1.4.4.4 1.4.4.5 1.4.4.6 1.4.5.1 1.4.5.2
1.4.5.3 1.4.5.4 1.4.5.5 1.4.5.6 1.4.6.1 1.4.6.2 1.4.6.3 1.4.6.4
1.4.6.5 1.4.6.6 1.4.7.1 1.4.7.2 1.4.7.3 1.4.7.4 1.4.7.5 1.4.7.6
1.4.8.1 1.4.8.2 1.4.8.3 1.4.8.4 1.4.8.5 1.4.8.6 1.4.9.1 1.4.9.2
1.4.9.3 1.4.9.4 1.4.9.5 1.4.9.6 1.5.1.1 1.5.1.2 1.5.1.3 1.5.1.4
1.5.1.5 1.5.1.6 1.5.2.1 1.5.2.2 1.5.2.3 1.5.2.4 1.5.2.5 1.5.2.6
1.5.3.1 1.5.3.2 1.5.3.3 1.5.3.4 1.5.3.5 1.5.3.6 1.5.4.1 1.5.4.2
1.5.4.3 1.5.4.4 1.5.4.5 1.5.4.6 1.5.5.1 1.5.5.2 1.5.5.3 1.5.5.4
1.5.5.5 1.5.5.6 1.5.6.1 1.5.6.2 1.5.6.3 1.5.6.4 1.5.6.5 1.5.6.6
1.5.7.1 1.5.7.2 1.5.7.3 1.5.7.4 1.5.7.5 1.5.7.6 1.5.8.1 1.5.8.2
1.5.8.3 1.5.8.4 1.5.8.5 1.5.3.6 1.5.9.1 1.5.9.2 1.5.9.3 1.5.9.4
1.5.9.5 1.5.9.6 1.6.1.1 1.6.1.2 1.6.1.3 1.6.1.4 1.6.1.5 1.6.1.6
1.6.2.1 1.6.2.2 1.6.2.3 1.6.2.4 1.6.2.5 1.6.2.6 1.6.3.1 1.6.3.2
1.6.3.3 1.6.3.4 1.6.3.5 1.6.3.6 1.6.4.1 1.6.4.2 1.6.4.3 1.6.4.4
1.6.4.5 1.6.4.6 1.6.5.1 1.6.5.2 1.6.5.3 1.6.5.4 1.6.5.5 1.6.5.6
1.6.6.1 1.6.6.2 1.6.6.3 1.6.6.4 1.6.6.5 1.6.6.6 1.6.7.1 1.6.7.2
1.6.7.3 1.6.7.4 1.6.7.5 1.6.7.6 1.6.8.1 1.6.8.2 1.6.8.3 1.6.8.4
1.6.8.5 1.6.8.6 1.6.9.1 1.6.9.2 1.6.9.3 1.6.9.4 1.6.9.5 1.6.9.6
1.7.1.1 1.7.1.2 1.7.1.3 1.7.1.4 1.7.1.5 1.7.1.6 1.7.2.1 1.7.2.2
1.7.2.3 1.7.2.4 1.7.2.5 1.7.2.6 1.7.3.1 1.7.3.2 1.7.3.3 1.7.3.4
1.7.3.5 1.7.3.6 1.7.4.1 1.7.4.2 1.7.4.3 1.7.4.4 1.7.4.5 1.7.4.6
1.7.5.1 1.7.5.2 1.7.5.3 1.7.5.4 1.7.5.5 1.7.5.6 1.7.6.1 1.7.6.2
1.7.6.3 1.7.6.4 1.7.6.5 1.7.6.6 1.7.7.1 1.7.7.2 1.7.7.3 1.7.7.4
1.7.7.5 1.7.7.6 1.7.8.1 1.7.8.2 1.7.8.3 1.7.8.4 1.7.8.5 1.7.8.6
1.7.9.1 1.7.9.2 1.7.9.3 1.7.9.4 1.7.9.5 1.7.9.6 1.8.1.1 1.8.1.2
1.8.1.3 1.8.1.4 1.8.1.5 1.8.1.6 1.8.2.1 1.8.2.2 1.8.2.3 1.8.2.4
1.8.2.5 1.8.2.6 1.8.3.1 1.8.3.2 1.8.3.3 1.8.3.4 1.8.3.5 1.8.3.6
1.8.4.1 1.8.4.2 1.8.4.3 1.8.4.4 1.8.4.5 1.8.4.6 1.8.5.1 1.8.5.2
1.8.5.3 1.8.5.4 1.8.5.5 1.8.5.6 1.8.6.1 1.8.6.2 1.8.6.3 1.8.6.4
1.8.6.5 1.8.6.6 1.8.7.1 1.8.7.2 1.8.7.3 1.8.7.4 1.8.7.5 1.8.7.6
1.8.8.1 1.8.8.2 1.8.8.3 1.8.8.4 1.8.8.5 1.8.8.6 1.8.9.1 1.8.9.2
1.8.9.3 1.8.9.4 1.8.9.5 1.8.9.6 1.9.1.1 1.9.1.2 1.9.1.3 1.9.1.4
1.9.1.5 1.9.1.6 1.9.2.1 1.9.2.2 1.9.2.3 1.9.2.4 1.9.2.5 1.9.2.6
1.9.3.1 1.9.3.2 1.9.3.3 1.9.3.4 1.9.3.5 1.9.3.6 1.9.4.1 1.9.4.2
1.9.4.3 1.9.4.4 1.9.4.5 1.9.4.6 1.9.5.1 1.9.5.2 1.9.5.3 1.9.5.4
1.9.5.5 1.9.5.6 1.9.6.1 1.9.6.2 1.9.6.3 1.9.6.4 1.9.6.5 1.9.6.6
1.9.7.1 1.9.7.2 1.9.7.3 1.9.7.4 1.9.7.5 1.9.7.6 1.9.8.1 1.9.8.2
1.9.8.3 1.9.8.4 1.9.8.5 1.9.8.6 1.9.9.1 1.9.9.2 1.9.9.3 1.9.9.4
1.9.9.5 1.9.9.6 2.1.1.1 2.1.1.2 2.1.1.3 2.1.1.4 2.1.1.5 2.1.1.6
2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4 2.1.2.5 2.1.2.6 2.1.3.1 2.1.3.2
2.1.3.3 2.1.3.4 2.1.3.5 2.1.3.6 2.1.4.1 2.1.4.2 2.1.4.3 2.1.4.4
2.1.4.5 2.1.4.6 2.1.5.1 2.1.5.2 2.1.5.3 2.1.5.4 2.1.5.5 2.1.5.6
2.1.6.1 2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.5 2.1.6.6 2.1.7.1 2.1.7.2
2.1.7.3 2.1.7.4 2.1.7.5 2.1.7.6 2.1.8.1 2.1.8.2 2.1.8.3 2.1.8.4
2.1.8.5 2.1.8.6 2.1.9.1 2.1.9.2 2.1.9.3 2.1.9.4 2.1.9.5 2.1.9.6
2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.2.1 2.2.2.2
2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.3.1 2.2.3.2 2.2.3.3 2.2.3.4
2.2.3.5 2.2.3.6 2.2.4.1 2.2.4.2 2.2.4.3 2.2.4.4 2.2.4.5 2.2.4.6
2.2.5.1 2.2.5.2 2.2.5.3 2.2.5.4 2.2.5.5 2.2.5.6 2.2.6.1 2.2.6.2
2.2.6.3 2.2.6.4 2.2.6.5 2.2.6.6 2.2.7.1 2.2.7.2 2.2.7.3 2.2.7.4
2.2.7.5 2.2.7.6 2.2.8.1 2.2.8.2 2.2.8.3 2.2.8.4 2.2.8.5 2.2.8.6
2.2.9.1 2.2.9.2 2.2.9.3 2.2.9.4 2.2.9.5 2.2.9.6 2.3.1.1 2.3.1.2
2.3.1.3 2.3.1.4 2.3.1.5 2.3.1.6 2.3.2.1 2.3.2.2 2.3.2.3 2.3.2.4
2.3.2.5 2.3.2.6 2.3.3.1 2.3.3.2 2.3.3.3 2.3.3.4 2.3.3.5 2.3.3.6
2.3.4.1 2.3.4.2 2.3.4.3 2.3.4.4 2.3.4.5 2.3.4.6 2.3.5.1 2.3.5.2
2.3.5.3 2.3.5.4 2.3.5.5 2.3.5.6 2.3.6.1 2.3.6.2 2.3.6.3 2.3.6.4
2.3.6.5 2.3.6.6 2.3.7.1 2.3.7.2 2.3.7.3 2.3.7.4 2.3.7.5 2.3.7.6
2.3.8.1 2.3.8.2 2.3.8.3 2.3.8.4 2.3.8.5 2.3.8.6 2.3.9.1 2.3.9.2
2.3.9.3 2.3.9.4 2.3.9.5 2.3.9.6 2.4.1.1 2.4.1.2 2.4.1.3 2.4.1.4
2.4.1.5 2.4.1.6 2.4.2.1 2.4.2.2 2.4.2.3 2.4.2.4 2.4.2.5 2.4.2.6
2.4.3.1 2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.5 2.4.3.6 2.4.4.1 2.4.4.2
2.4.4.3 2.4.4.4 2.4.4.5 2.4.4.6 2.4.5.1 2.4.5.2 2.4.5.3 2.4.5.4
2.4.5.5 2.4.5.6 2.4.6.1 2.4.6.2 2.4.6.3 2.4.6.4 2.4.6.5 2.4.6.6
2.4.7.1 2.4.7.2 2.4.7.3 2.4.7.4 2.4.7.5 2.4.7.6 2.4.8.1 2.4.8.2
2.4.8.3 2.4.8.4 2.4.8.5 2.4.8.6 2.4.9.1 2.4.9.2 2.4.9.3 2.4.9.4
2.4.9.5 2.4.9.6 2.5.1.1 2.5.1.2 2.5.1.3 2.5.1.4 2.5.1.5 2.5.1.6
2.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2.5.2.5 2.5.2.6 2.5.3.1 2.5.3.2
2.5.3.3 2.5.3.4 2.5.3.5 2.5.3.6 2.5.4.1 2.5.4.2 2.5.4.3 2.5.4.4
2.5.4.5 2.5.4.6 2.5.5.1 2.5.5.2 2.5.5.3 2.5.5.4 2.5.5.5 2.5.5.6
2.5.6.1 2.5.6.2 2.5.6.3 2.5.6.4 2.5.6.5 2.5.6.6 2.5.7.1 2.5.7.2
2.5.7.3 2.5.7.4 2.5.7.5 2.5.7.6 2.5.8.1 2.5.8.2 2.5.8.3 2.5.8.4
2.5.8.5 2.5.8.6 2.5.9.1 2.5.9.2 2.5.9.3 2.5.9.4 2.5.9.5 2.5.9.6
2.6.1.1 2.6.1.2 2.6.1.3 2.6.1.4 2.6.1.5 2.6.1.6 2.6.2.1 2.6.2.2
2.6.2.3 2.6.2.4 2.6.2.5 2.6.2.6 2.6.3.1 2.6.3.2 2.6.3.3 2.6.3.4
2.6.3.5 2.6.3.6 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6
2.6.5.1 2.6.5.2 2.6.5.3 2.6.5.4 2.6.5.5 2.6.5.6 2.6.6.1 2.6.6.2
2.6.6.3 2.6.6.4 2.6.6.5 2.6.6.6 2.6.7.1 2.6.7.2 2.6.7.3 2.6.7.4
2.6.7.5 2.6.7.6 2.6.8.1 2.6.8.2 2.6.8.3 2.6.8.4 2.6.8.5 2.6.8.6
2.6.9.1 2.6.9.2 2.6.9.3 2.6.9.4 2.6.9.5 2.6.9.6 2.7.1.1 2.7.1.2
2.7.1.3 2.7.1.4 2.7.1.5 2.7.1.6 2.7.2.1 2.7.2.2 2.7.2.3 2.7.2.4
2.7.2.5 2.7.2.6 2.7.3.1 2.7.3.2 2.7.3.3 2.7.3.4 2.7.3.5 2.7.3.6
2.7.4.1 2.7.4.2 2.7.4.3 2.7.4.4 2.7.4.5 2.7.4.6 2.7.5.1 2.7.5.2
2.7.5.3 2.7.5.4 2.7.5.5 2.7.5.6 2.7.6.1 2.7.6.2 2.7.6.3 2.7.6.4
2.7.6.5 2.7.6.6 2.7.7.1 2.7.7.2 2.7.7.3 2.7.7.4 2.7.7.5 2.7.7.6
2.7.8.1 2.7.8.2 2.7.8.3 2.7.8.4 2.7.8.5 2.7.8.6 2.7.9.1 2.7.9.2
2.7.9.3 2.7.9.4 2.7.9.5 2.7.9.6 2.8.1.1 2.8.1.2 2.8.1.3 2.8.1.4
2.8.1.5 2.8.1.6 2.8.2.1 2.8.2.2 2.8.2.3 2.8.2.4 2.8.2.5 2.8.2.6
2.8.3.1 2.8.3.2 2.8.3.3 2.8.3.4 2.8.3.5 2.8.3.6 2.8.4.1 2.3.4.2
2.8.4.3 2.8.4.4 2.8.4.5 2.8.4.6 2.8.5.1 2.8.5.2 2.8.5.3 2.8.5.4
2.8.5.5 2.8.5.6 2.8.6.1 2.8.6.2 2.8.6.3 2.8.6.4 2.8.6.5 2.8.6.6
2.8.7.1 2.8.7.2 2.8.7.3 2.8.7.4 2.8.7.5 2.8.7.6 2.8.8.1 2.8.8.2
2.8.8.3 2.8.8.4 2.8.8.5 2.8.8.6 2.8.9.1 2.8.9.2 2.8.9.3 2.8.9.4
2.8.9.5 2.8.9.6 2.9.1.1 2.9.1.2 2.9.1.3 2.9.1.4 2.9.1.5 2.9.1.6
2.9.2.1 2.9.2.2 2.9.2.3 2.9.2.4 2.9.2.5 2.9.2.6 2.9.3.1 2.9.3.2
2.9.3.3 2.9.3.4 2.9.3.5 2.9.3.6 2.9.4.1 2.9.4.2 2.9.4.3 2.9.4.4
2.9.4.5 2.9.4.6 2.9.5.1 2.9.5.2 2.9.5.3 2.9.5.4 2.9.5.5 2.9.5.6
2.9.6.1 2.9.6.2 2.9.6.3 2.9.6.4 2.9.6.5 2.9.6.6 2.9.7.1 2.9.7.2
2.9.7.3 2.9.7.4 2.9.7.5 2.9.7.6 2.9.8.1 2.9.8.2 2.9.8.3 2.9.8.4
2.9.8.5 2.9.8.6 2.9.9.1 2.9.9.2 2.9.9.3 2.9.9.4 2.9.9.5 2.9.9.6
3.1.1.1 3.1.1.2 3.1.1.3 3.1.1.4 3.1.1.5 3.1.1.6 3.1.2.1 3.1.2.2
3.1.2.3 3.1.2.4 3.1.2.5 3.1.2.6 3.1.3.1 3.1.3.2 3.1.3.3 3.1.3.4
3.1.3.5 3.1.3.6 3.1.4.1 3.1.4.2 3.1.4.3 3.1.4.4 3.1.4.5 3.1.4.6
3.1.5.1 3.1.5.2 3.1.5.3 3.1.5.4 3.1.5.5 3.1.5.6 3.1.6.1 3.1.6.2
3.1.6.3 3.1.6.4 3.1.6.5 3.1.6.6 3.1.7.1 3.1.7.2 3.1.7.3 3.1.7.4
3.1.7.5 3.1.7.6 3.1.8.1 3.1.8.2 3.1.8.3 3.1.8.4 3.1.8.5 3.1.8.6
3.1.9.1 3.1.9.2 3.1.9.3 3.1.9.4 3.1.9.5 3.1.9.6 3.2.1.1 3.2.1.2
3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.2.2.1 3.2.2.2 3.2.2.3 3.2.2.4
3.2.2.5 3.2.2.6 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.4 3.2.3.5 3.2.3.6
3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4 3.2.4.5 3.2.4.6 3.2.5.1 3.2.5.2
3.2.5.3 3.2.5.4 3.2.5.5 3.2.5.6 3.2.6.1 3.2.6.2 3.2.6.3 3.2.6.4
3.2.6.5 3.2.6.6 3.2.7.1 3.2.7.2 3.2.7.3 3.2.7.4 3.2.7.5 3.2.7.6
3.2.8.1 3.2.8.2 3.2.8.3 3.2.8.4 3.2.8.5 3.2.8.6 3.2.9.1 3.2.9.2
3.2.9.3 3.2.9.4 3.2.9.5 3.2.9.6 3.3.1.1 3.3.1.2 3.3.1.3 3.3.1.4
3.3.1.5 3.3.1.6 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.6
3.3.3.1 3.3.3.2 3.3.3.3 3.3.3.4 3.3.3.5 3.3.3.6 3.3.4.1 3.3.4.2
3.3.4.3 3.3.4.4 3.3.4.5 3.3.4.6 3.3.5.1 3.3.5.2 3.3.5.3 3.3.5.4
3.3.5.5 3.3.5.6 3.3.6.1 3.3.6.2 3.3.6.3 3.3.6.4 3.3.6.5 3.3.6.6
3.3.7.1 3.3.7.2 3.3.7.3 3.3.7.4 3.3.7.5 3.3.7.6 3.3.8.1 3.3.8.2
3.3.8.3 3.3.8.4 3.3.8.5 3.3.8.6 3.3.9.1 3.3.9.2 3.3.9.3 3.3.9.4
3.3.9.5 3.3.9.6 3.4.1.1 3.4.1.2 3.4.1.3 3.4.1.4 3.4.1.5 3.4.1.6
3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 3.4.2.5 3.4.2.6 3.4.3.1 3.4.3.2
3.4.3.3 3.4.3.4 3.4.3.5 3.4.3.6 3.4.4.1 3.4.4.2 3.4.4.3 3.4.4.4
3.4.4.5 3.4.4.6 3.4.5.1 3.4.5.2 3.4.5.3 3.4.5.4 3.4.5.5 3.4.5.6
3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.4 3.4.6.5 3.4.6.6 3.4.7.1 3.4.7.2
3.4.7.3 3.4.7.4 3.4.7.5 3.4.7.6 3.4.8.1 3.4.8.2 3.4.8.3 3.4.8.4
3.4.8.5 3.4.8.6 3.4.9.1 3.4.9.2 3.4.9.3 3.4.9.4 3.4.9.5 3.4.9.6
3.5.1.1 3.5.1.2 3.5.1.3 3.5.1.4 3.5.1.5 3.5.1.6 3.5.2.1 3.5.2.2
3.5.2.3 3.5.2.4 3.5.2.5 3.5.2.6 3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4
3.5.3.5 3.5.3.6 3.5.4.1 3.5.4.2 3.5.4.3 3.5.4.4 3.5.4.5 3.5.4.6
3.5.5.1 3.5.5.2 3.5.5.3 3.5.5.4 3.5.5.5 3.5.5.6 3.5.6.1 3.5.6.2
3.5.6.3 3.5.6.4 3.5.6.5 3.5.6.6 3.5.7.1 3.5.7.2 3.5.7.3 3.5.7.4
3.5.7.5 3.5.7.6 3.5.8.1 3.5.8.2 3.5.8.3 3.5.8.4 3.5.8.5 3.5.8.6
3.5.9.1 3.5.9.2 3.5.9.3
3.5.9.4 3.5.9.5 3.5.9.6 3.6.1.1 3.6.1.2 3.6.1.3 3.6.1.4 3.6.1.5
3.6.1.6 3.6.2.1 3.6.2.2 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.3.1
3.6.3.2 3.6.3.3 3.6.3.4 3.6.3.5 3.6.3.6 3.6.4.1 3.6.4.2 3.6.4.3
3.6.4.4 3.6.4.5 3.6.4.6 3.6.5.1 3.6.5.2 3.6.5.3 3.6.5.4 3.6.5.5
3.6.5.6 3.6.6.1 3.6.6.2 3.6.6.3 3.6.6.4 3.6.6.5 3.6.6.6 3.6.7.1
3.6.7.2 3.6.7.3 3.6.7.4 3.6.7.5 3.6.7.6 3.6.8.1 3.6.8.2 3.6.8.3
3.6.8.4 3.6.8.5 3.6.8.6 3.6.9.1 3.6.9.2 3.6.9.3 3.6.9.4 3.6.9.5
3.6.9.6 3.7.1.1 3.7.1.2 3.7.1.3 3.7.1.4 3.7.1.5 3.7.1.6 3.7.2.1
3.7.2.2 3.7.2.3 3.7.2.4 3.7.2.5 3.7.2.6 3.7.3.1 3.7.3.2 3.7.3.3
3.7.3.4 3.7.3.5 3.7.3.6 3.7.4.1 3.7.4.2 3.7.4.3 3.7.4.4 3.7.4.5
3.7.4.6 3.7.5.1 3.7.5.2 3.7.5.3 3.7.5.4 3.7.5.5 3.7.5.6 3.7.6.1
3.7.6.2 3.7.6.3 3.7.6.4 3.7.6.5 3.7.6.6 3.7.7.1 3.7.7.2 3.7.7.3
3.7.7.4 3.7.7.5 3.7.7.6 3.7.8.1 3.7.8.2 3.7.8.3 3.7.8.4 3.7.8.5
3.7.8.6 3.7.9.1 3.7.9.2 3.7.9.3 3.7.9.4 3.7.9.5 3.7.9.6 3.8.1.1
3.8.1.2 3.8.1.3 3.8.1.4 3.8.1.5 3.8.1.6 3.8.2.1 3.8.2.2 3.8.2.3
3.8.2.4 3.8.2.5 3.8.2.6 3.8.3.1 3.8.3.2 3.8.3.3 3.8.3.4 3.8.3.5
3.8.3.6 3.8.4.1 3.8.4.2 3.8.4.3 3.8.4.4 3.8.4.5 3.8.4.6 3.8.5.1
3.8.5.2 3.8.5.3 3.8.5.4 3.8.5.5 3.8.5.6 3.8.6.1 3.8.6.2 3.8.6.3
3.8.6.4 3.3.6.5 3.8.6.6 3.8.7.1 3.8.7.2 3.8.7.3 3.8.7.4 3.8.7.5
3.8.7.6 3.8.8.1 3.8.8.2 3.8.8.3 3.8.8.4 3.8.8.5 3.8.8.6 3.8.9.1
3.8.9.2 3.8.9.3 3.8.9.4 3.8.9.5 3.8.9.6 3.9.1.1 3.9.1.2 3.9.1.3
3.9.1.4 3.9.1.5 3.9.1.6 3.9.2.1 3.9.2.2 3.9.2.3 3.9.2.4 3.9.2.5
3.9.2.6 3.9.3.1 3.9.3.2 3.9.3.3 3.9.3.4 3.9.3.5 3.9.3.6 3.9.4.1
3.9.4.2 3.9.4.3 3.9.4.4 3.9.4.5 3.9.4.6 3.9.5.1 3.9.5.2 3.9.5.3
3.9.5.4 3.9.5.5 3.9.5.6 3.9.6.1 3.9.6.2 3.9.6.3 3.9.6.4 3.9.6.5
3.9.6.6 3.9.7.1 3.9.7.2 3.9.7.3 3.9.7.4 3.9.7.5 3.9.7.6 3.9.8.1
3.9.8.2 3.9.8.3 3.9.8.4 3.9.8.5 3.9.8.6 3.9.9.1 3.9.9.2 3.9.9.3
3.9.9.4 3.9.9.5 3.9.9.6 4.1.1.1 4.1.1.2 4.1.1.3 4.1.1.4 4.1.1.5
4.1.1.6 4.1.2.1 4.1.2.2 4.1.2.3 4.1.2.4 4.1.2.5 4.1.2.6 4.1.3.1
4.1.3.2 4.1.3.3 4.1.3.4 4.1.3.5 4.1.3.6 4.1.4.1 4.1.4.2 4.1.4.3
4.1.4.4 4.1.4.5 4.1.4.6 4.1.5.1 4.1.5.2 4.1.5.3 4.1.5.4 4.1.5.5
4.1.5.6 4.1.6.1 4.1.6.2 4.1.6.3 4.1.6.4 4.1.6.5 4.1.6.6 4.1.7.1
4.1.7.2 4.1.7.3 4.1.7.4 4.1.7.5 4.1.7.6 4.1.8.1 4.1.8.2 4.1.8.3
4.1.8.4 4.1.8.5 4.1.8.6 4.1.9.1 4.1.9.2 4.1.9.3 4.1.9.4 4.1.9.5
4.1.9.6 4.2.1.1 4.2.1.2 4.2.1.3 4.2.1.4 4.2.1.5 4.2.1.6 4.2.2.1
4.2.2.2 4.2.2.3 4.2.2.4 4.2.2.5 4.2.2.6 4.2.3.1 4.2.3.2 4.2.3.3
4.2.3.4 4.2.3.5 4.2.3.6 4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.4 4.2.4.5
4.2.4.6 4.2.5.1 4.2.5.2 4.2.5.3 4.2.5.4 4.2.5.5 4.2.5.6 4.2.6.1
4.2.6.2 4.2.6.3 4.2.6.4 4.2.6.5 4.2.6.6 4.2.7.1 4.2.7.2 4.2.7.3
4.2.7.4 4.2.7.5 4.2.7.6 4.2.8.1 4.2.8.2 4.2.8.3 4.2.8.4 4.2.8.5
4.2.8.6 4.2.9.1 4.2.9.2 4.2.9.3 4.2.9.4 4.2.9.5 4.2.9.6 4.3.1.1
4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.6 4.3.2.1 4.3.2.2 4.3.2.3
4.3.2.4 4.3.2.5 4.3.2.6 4.3.3.1 4.3.3.2 4.3.3.3 4.3.3.4 4.3.3.5
4.3.3.6 4.3.4.1 4.3.4.2 4.3.4.3 4.3.4.4 4.3.4.5 4.3.4.6 4.3.5.1
4.3.5.2 4.3.5.3 4.3.5.4 4.3.5.5 4.3.5.6 4.3.6.1 4.3.6.2 4.3.6.3
4.3.6.4 4.3.6.5 4.3.6.6 4.3.7.1 4.3.7.2 4.3.7.3 4.3.7.4 4.3.7.5
4.3.7.6 4.3.8.1 4.3.8.2 4.3.8.3 4.3.8.4 4.3.8.5 4.3.8.6 4.3.9.1
4.3.9.2 4.3.9.3 4.3.9.4 4.3.9.5 4.3.9.6 4.4.1.1 4.4.1.2 4.4.1.3
4.4.1.4 4.4.1.5 4.4.1.6 4.4.2.1 4.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5
4.4.2.6 4.4.3.1 4.4.3.2 4.4.3.3 4.4.3.4 4.4.3.5 4.4.3.6 4.4.4.1
4.4.4.2 4.4.4.3 4.4.4.4 4.4.4.5 4.4.4.6 4.4.5.1 4.4.5.2 4.4.5.3
4.4.5.4 4.4.5.5 4.4.5.6 4.4.6.1 4.4.6.2 4.4.6.3 4.4.6.4 4.4.6.5
4.4.6.6 4.4.7.1 4.4.7.2 4.4.7.3 4.4.7.4 4.4.7.5 4.4.7.6 4.4.8.1
4.4.8.2 4.4.8.3 4.4.8.4 4.4.8.5 4.4.8.6 4.4.9.1 4.4.9.2 4.4.9.3
4.4.9.4 4.4.9.5 4.4.9.6 4.5.1.1 4.5.1.2 4.5.1.3 4.5.1.4 4.5.1.5
4.5.1.6 4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.2.6 4.5.3.1
4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.5.3.6 4.5.4.1 4.5.4.2 4.5.4.3
4.5.4.4 4.5.4.5 4.5.4.6 4.5.5.1 4.5.5.2 4.5.5.3 4.5.5.4 4.5.5.5
4.5.5.6 4.5.6.1 4.5.6.2 4.5.6.3 4.5.6.4 4.5.6.5 4.5.6.6 4.5.7.1
4.5.7.2 4.5.7.3 4.5.7.4 4.5.7.5 4.5.7.6 4.5.8.1 4.5.8.2 4.5.8.3
4.5.8.4 4.5.8.5 4.5.8.6 4.5.9.1 4.5.9.2 4.5.9.3 4.5.9.4 4.5.9.5
4.5.9.6 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.1.5 4.6.1.6 4.6.2.1
4.6.2.2 4.6.2.3 4.6.2.4 4.6.2.5 4.6.2.6 4.6.3.1 4.6.3.2 4.6.3.3
4.6.3.4 4.6.3.5 4.6.3.6 4.6.4.1 4.6.4.2 4.6.4.3 4.6.4.4 4.6.4.5
4.6.4.6 4.6.5.1 4.6.5.2 4.6.5.3 4.6.5.4 4.6.5.5 4.6.5.6 4.6.6.1
4.6.6.2 4.6.6.3 4.6.6.4 4.6.6.5 4.6.6.6 4.6.7.1 4.6.7.2 4.6.7.3
4.6.7.4 4.6.7.5 4.6.7.6 4.6.8.1 4.6.8.2 4.6.8.3 4.6.8.4 4.6.8.5
4.6.8.6 4.6.9.1 4.6.9.2 4.6.9.3 4.6.9.4 4.6.9.5 4.6.9.6 4.7.1.1
4.7.1.2 4.7.1.3 4.7.1.4 4.7.1.5 4.7.1.6 4.7.2.1 4.7.2.2 4.7.2.3
4.7.2.4 4.7.2.5 4.7.2.6 4.7.3.1 4.7.3.2 4.7.3.3 4.7.3.4 4.7.3.5
4.7.3.6 4.7.4.1 4.7.4.2 4.7.4.3 4.7.4.4 4.7.4.5 4.7.4.6 4.7.5.1
4.7.5.2 4.7.5.3 4.7.5.4 4.7.5.5 4.7.5.6 4.7.6.1 4.7.6.2 4.7.6.3
4.7.6.4 4.7.6.5 4.7.6.6 4.7.7.1 4.7.7.2 4.7.7.3 4.7.7.4 4.7.7.5
4.7.7.6 4.7.8.1 4.7.3.2 4.7.8.3 4.7.8.4 4.7.8.5 4.7.8.6 4.7.9.1
4.7.9.2 4.7.9.3 4.7.9.4 4.7.9.5 4.7.9.6 4.8.1.1 4.8.1.2 4.8.1.3
4.8.1.4 4.8.1.5 4.8.1.6 4.8.2.1 4.8.2.2 4.8.2.3 4.8.2.4 4.8.2.5
4.8.2.6 4.8.3.1 4.8.3.2 4.8.3.3 4.8.3.4 4.8.3.5 4.8.3.6 4.8.4.1
4.8.4.2 4.8.4.3 4.8.4.4 4.8.4.5 4.8.4.6 4.8.5.1 4.8.5.2 4.8.5.3
4.8.5.4 4.8.5.5 4.8.5.6 4.8.6.1 4.8.6.2 4.8.6.3 4.8.6.4 4.8.6.5
4.8.6.6 4.8.7.1 4.8.7.2 4.8.7.3 4.8.7.4 4.8.7.5 4.8.7.6 4.8.8.1
4.8.8.2 4.8.8.3 4.8.8.4 4.8.8.5 4.8.8.6 4.8.9.1 4.8.9.2 4.8.9.3
4.8.9.4 4.8.9.5 4.8.9.6 4.9.1.1 4.9.1.2 4.9.1.3 4.9.1.4 4.9.1.5
4.9.1.6 4.9.2.1 4.9.2.2 4.9.2.3 4.9.2.4 4.9.2.5 4.9.2.6 4.9.3.1
4.9.3.2 4.9.3.3 4.9.3.4 4.9.3.5 4.9.3.6 4.9.4.1 4.9.4.2 4.9.4.3
4.9.4.4 4.9.4.5 4.9.4.6 4.9.5.1 4.9.5.2 4.9.5.3 4.9.5.4 4.9.5.5
4.9.5.6 4.9.6.1 4.9.6.2 4.9.6.3 4.9.6.4 4.9.6.5 4.9.6.6 4.9.7.1
4.9.7.2 4.9.7.3 4.9.7.4 4.9.7.5 4.9.7.6 4.9.8.1 4.9.8.2 4.9.8.3
4.9.8.4 4.9.8.5 4.9.8.6 4.9.9.1 4.9.9.2 4.9.9.3 4.9.9.4 4.9.9.5
4.9.9.6 5.1.1.1 5.1.1.2 5.1.1.3 5.1.1.4 5.1-1.5 5.1.1.6 5.1.2.1
5.1.2.2 5.1.2.3 5.1.2.4 5.1.2.5 5.1.2.6 5.1.3.1 5.1.3.2 5.1.3.3
5.1.3.4 5.1.3.5 5.1.3.6 5.1.4.1 5.1.4.2 5.1.4.3 5.1.4.4 5.1.4.5
5.1.4.6 5.1.5.1 5.1.5.2 5.1.5.3 5.1.5.4 5.1.5.5 5.1.5.6 5.1.6.1
5.1.6.2 5.1.6.3 5.1.6.4 5.1.6.5 5.1.6.6 5.1.7.1 5.1.7.2 5.1.7.3
5.1.7.4 5.1.7.5 5.1.7.6 5.1.8.1 5.1.8.2 5.1.8.3 5.1.8.4 5.1.8.5
5.1.8.6 5.1.9.1 5.1.9.2 5.1.9.3 5.1.9.4 5.1.9.5 5.1.9.6 5.2.1.1
5.2.1.2 5.2.1.3 5.2.1.4 5.2.1.5 5.2.1.6 5.2.2.1 5.2.2.2 5.2.2.3
5.2.2.4 5.2.2.5 5.2.2.6 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4 5.2.3.5
5.2.3.6 5.2.4.1 5.2.4.2 5.2.4.3 5.2.4.4 5.2.4.5 5.2.4.6 5.2.5.1
5.2.5.2 5.2.5.3 5.2.5.4 5.2.5.5 5.2.5.6 5.2.6.1 5.2.6.2 5.2.6.3
5.2.6.4 5.2.6.5 5.2.6.6 5.2.7.1 5.2.7.2 5.2.7.3 5.2.7.4 5.2.7.5
5.2.7.6 5.2.8.1 5.2.8.2 5.2.8.3 5.2.3.4 5.2.8.5 5.2.8.6 5.2.9.1
5.2.9.2 5.2.9.3 5.2.9.4 5.2.9.5 5.2.9.6 5.3.1.1 5.3.1.2 5.3.1.3
5.3.1.4 5.3.1.5 5.3.1.6 5.3.2.1 5.3.2.2 5.3.2.3 5.3.2.4 5.3.2.5
5.3.2.6 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.3.5 5.3.3.6 5.3.4.1
5.3.4.2 5.3.4.3 5.3.4.4 5.3.4.5 5.3.4.6 5.3.5.1 5.3.5.2 5.3.5.3
5.3.5.4 5.3.5.5 5.3.5.6 5.3.6.1 5.3.6.2 5.3.6.3 5.3.6.4 5.3.6.5
5.3.6.6 5.3.7.1 5.3.7.2 5.3.7.3 5.3.7.4 5.3.7.5 5.3.7.6 5.3.8.1
5.3.8.2 5.3.8.3 5.3.8.4 5.3.8.5 5.3.8.6 5.3.9.1 5.3.9.2 5.3.9.3
5.3.9.4 5.3.9.5 5.3.9.6 5.4.1.1 5.4.1.2 5.4.1.3 5.4.1.4 5.4.1.5
5.4.1.6 5.4.2.1 5.4.2.2 5.4.2.3 5.4.2.4 5.4.2.5 5.4.2.6 5.4.3.1
5.4.3.2 5.4.3.3 5.4.3.4 5.4.3.5 5.4.3.6 5.4.4.1 5.4.4.2 5.4.4.3
5.4.4.4 5.4.4.5 5.4.4.6 5.4.5.1 5.4.5.2 5.4.5.3 5.4.5.4 5.4.5.5
5.4.5.6 5.4.6.1 5.4.6.2 5.4.6.3 5.4.6.4 5.4.6.5 5.4.6.6 5.4.7.1
5.4.7.2 5.4.7.3 5.4.7.4 5.4.7.5 5.4.7.6 5.4.8.1 5.4.8.2 5.4.8.3
5.4.8.4 5.4.8.5 5.4.8.6 5.4.9.1 5.4.9.2 5.4.9.3 5.4.9.4 5.4.9.5
5.4.9.6 5.5.1.1 5.5.1.2 5.5.1.3 5.5.1.4 5.5.1.5 5.5-1.6 5.5.2.1
5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.3.1 5.5.3.2 5.5.3.3
5.5.3.4 5.5.3.5 5.5.3.6 5.5.4.1 5.5.4.2 5.5.4.3 5.5.4.4 5.5.4.5
5.5.4.6 5.5.5.1 5.5.5.2 5.5.5.3 5.5.5.4 5.5.5.5 5.5.5.6 5.5.6.1
5.5.6.2 5.5.6.3 5.5.6.4 5.5.6.5 5.5.6.6 5.5.7.1 5.5.7.2 5.5.7.3
5.5.7.4 5.5.7.5 5.5.7.6 5.5.8.1 5.5.8.2 5.5.8.3 5.5.8.4 5.5.8.5
5.5.8.6 5.5.9.1 5.5.9.2 5.5.9.3 5.5.9.4 5.5.9.5 5.5.9.6 5.6.1.1
5.6.1.2 5.6.1.3 5.6.1.4 5.6.1.5 5.6.1.6 5.6.2.1 5.6.2.2 5.6.2.3
5.6.2.4 5.6.2.5 5.6.2.6 5.6.3.1 5.6.3.2 5.6.3.3 5.6.3.4 5.6.3.5
5.6.3.6 5.6.4.1 5.6.4.2 5.6.4.3 5.6.4.4 5.6.4.5 5.6.4.6 5.6.5.1
5.6.5.2 5.6.5.3 5.6.5.4 5.6.5.5 5.6.5.6 5.6.6.1 5.6.6.2 5.6.6.3
5.6.6.4 5.6.6.5 5.6.6.6 5.6.7.1 5.6.7.2 5.6.7.3 5.6.7.4 5.6.7.5
5.6.7.6 5.6.8.1 5.6.8.2 5.6.8.3 5.6.8.4 5.6.8.5 5.6.8.6 5.6.9.1
5.6.9.2 5.6.9.3 5.6.9.4 5.6.9.5 5.6.9.6 5.7.1.1 5.7.1.2 5.7.1.3
5.7.1.4 5.7.1.5 5.7.1.6 5.7.2.1 5.7.2.2 5.7.2.3 5.7.2.4 5.7.2.5
5.7.2.6 5.7.3.1 5.7.3.2 5.7.3.3 5.7.3.4 5.7.3.5 5.7.3.6 5.7.4.1
5.7.4.2 5.7.4.3 5.7.4.4 5.7.4.5 5.7.4.6 5.7.5.1 5.7.5.2 5.7.5.3
5.7.5.4 5.7.5.5 5.7.5.6 5.7.6.1 5.7.6.2 5.7.6.3 5.7.6.4 5.7.6.5
5.7.6.6 5.7.7.1 5.7.7.2 5.7.7.3 5.7.7.4 5.7.7.5 5.7.7.6 5.7.8.1
5.7.8.2 5.7.8.3 5.7.8.4 5.7.8.5 5.7.8.6 5.7.9.1 5.7.9.2 5.7.9.3
5.7.9.4 5.7.9.5 5.7.9.6 5.8.1.1 5.8.1.2 5.8.1.3 5.8.1.4 5.8.1.5
5.8.1.6 5.8.2.1 5.8.2.2 5.8.2.3 5.8.2.4 5.8.2.5 5.8.2.6 5.8.3.1
5.8.3.2 5.8.3.3 5.8.3.4 5.8.3.5 5.8.3.6 5.8.4.1 5.8.4.2 5.8.4.3
5.8.4.4 5.8.4.5 5.8.4.6 5.8.5.1 5.8.5.2 5.8.5.3 5.8.5.4 5.8.5.5
5.8.5.6 5.8.6.1 5.8.6.2 5.8.6.3 5.8.6.4 5.8.6.5 5.8.6.6 5.8.7.1
5.8.7.2 5.8.7.3 5.8.7.4 5.8.7.5 5.8.7.6 5.8.8.1 5.8.8.2 5.8.8.3
5.8.8.4 5.8.8.5 5.8.8.6 5.8.9.1 5.8.9.2 5.8.9.3 5.8.9.4 5.8.9.5
5.8.9.6 5.9.1.1 5.9.1.2 5.9.1.3 5.9.1.4 5.9.1.5 5.9.1.6 5.9.2.1
5.9.2.2 5.9.2.3 5.9.2.4 5.9.2.5 5.9.2.6 5.9.3.1 5.9.3.2 5.9.3.3
5.9.3.4 5.9.3.5 5.9.3.6 5.9.4.1 5.9.4.2 5.9.4.3 5.9.4.4 5.9.4.5
5.9.4.6 5.9.5.1 5.9.5.2 5.9.5.3 5.9.5.4 5.9.5.5 5.9.5.6 5.9.6.1
5.9.6.2 5.9.6.3 5.9.6.4 5.9.6.5 5.9.6.6 5.9.7.1 5.9.7.2 5.9.7.3
5.9.7.4 5.9.7.5 5.9.7.6 5.9.8.1 5.9.8.2 5.9.8.3 5.9.8.4 5.9.8.5
5.9.8.6 5.9.9.1 5.9.9.2 5.9.9.3 5.9.9.4 5.9.9.5 5.9.9.6 6.1.1.1
6.1.1.2 6.1.1.3 6.1.1.4 6.1.1.5 6.1.1.6 6.1.2.1 6.1.2.2 6.1.2.3
6.1.2.4 6.1.2.5 6.1.2.6 6.1.3.1 6.1.3.2 6.1.3.3 6.1.3.4 6.1.3.5
6.1.3.6 6.1.4.1 6.1.4.2 6.1.4.3 6.1.4.4 6.1.4.5 6.1.4.6 6.1.5.1
6.1.5.2 6.1.5.3 6.1.5.4 6.1.5.5 6.1.5.6 6.1.6.1 6.1.6.2 6.1.6.3
6.1.6.4 6.1.6.5 6.1.6.6 6.1.7.1 6.1.7.2 6.1.7.3 6.1.7.4 6.1.7.5
6.1.7.6 6.1.8.1 6.1.8.2 6.1.8.3 6.1-8.4 6.1.8.5 6.1.8.6 6.1.9.1
6.1.9.2 6.1.9.3 6.1.9.4 6.1.9.5 6.1.9.6 6.2.1.1 6.2.1.2 6.2.1.3
6.2.1.4 6.2.1.5 6.2.1.6
6.2.2.1 6.2.2.2 6.2.2.3 6.2.2.4 6.2.2.5 6.2.2.6 6.2.3.1 6.2.3.2
6.2.3.3 6.2.3.4 6.2.3.5 6.2.3.6 6.2.4.1 6.2.4.2 6.2.4.3 6.2.4.4
6.2.4.5 6.2.4.6 6.2.5.1 6.2.5.2 6.2.5.3 6.2.5.4 6.2.5.5 6.2.5.6
6.2.6.1 6.2.6.2 6.2.6.3 6.2.6.4 6.2.6.5 6.2.6.6 6.2.7.1 6.2.7.2
6.2.7.3 6.2.7.4 6.2.7.5 6.2.7.6 6.2.8.1 6.2.8.2 6.2.8.3 6.2.8.4
6.2.8.5 6.2.8.6 6.2.9.1 6.2.9.2 6.2.9.3 6.2.9.4 6.2.9.5 6.2.9.6
6.3.1.1 6.3.1.2 6.3.1.3 6.3.1.4 6.3.1.5 6.3.1.6 6.3.2.1 6.3.2.2
6.3.2.3 6.3.2.4 6.3.2.5 6.3.2.6 6.3.3.1 6.3.3.2 6.3.3.3 6.3.3.4
6.3.3.5 6.3.3.6 6.3.4.1 6.3.4.2 6.3.4.3 6.3.4.4 6.3.4.5 6.3.4.6
6.3.5.1 6.3.5.2 6.3.5.3 6.3.5.4 6.3.5.5 6.3.5.6 6.3.6.1 6.3.6.2
6.3.6.3 6.3.6.4 6.3.6.5 6.3.6.6 6.3.7.1 6.3.7.2 6.3.7.3 6.3.7.4
6.3.7.5 6.3.7.6 6.3.8.1 6.3.8.2 6.3.8.3 6.3.8.4 6.3.8.5 6.3.8.6
6.3.9.1 6.3.9.2 6.3.9.3 6.3.9.4 6.3.9.5 6.3.9.6 6.4.1.1 6.4.1.2
6.4.1.3 6.4.1.4 6.4.1.5 6.4.1.6 6.4.2.1 6.4.2.2 6.4.2.3 6.4.2.4
6.4.2.5 6.4.2.6 6.4.3.1 6.4.3.2 6.4.3.3 6.4.3.4 6.4.3.5 6.4.3.6
6.4.4.1 6.4.4.2 6.4.4.3 6.4.4.4 6.4.4.5 6.4.4.6 6.4.5.1 6.4.5.2
6.4.5.3 6.4.5.4 6.4.5.5 6.4.5.6 6.4.6.1 6.4.6.2 6.4.6.3 6.4.6.4
6.4.6.5 6.4.6.6 6.4.7.1 6.4.7.2 6.4.7.3 6.4.7.4 6.4.7.5 6.4.7.6
6.4.8.1 6.4.8.2 6.4.8.3 6.4.8.4 6.4.8.5 6.4.8.6 6.4.9.1 6.4.9.2
6.4.9.3 6.4.9.4 6.4.9.5 6.4.9.6 6.5.1.1 6.5.1.2 6.5.1.3 6.5.1.4
6.5.1.5 6.5.1.6 6.5.2.1 6.5.2.2 6.5.2.3 6.5.2.4 6.5.2.5 6.5.2.6
6.5.3.1 6.5.3.2 6.5.3.3 6.5.3.4 6.5.3.5 6.5.3.6 6.5.4.1 6.5.4.2
6.5.4.3 6.5.4.4 6.5.4.5 6.5.4.6 6.5.5.1 6.5.5.2 6.5.5.3 6.5.5.4
6.5.5.5 6.5.5.6 6.5.6.1 6.5.6.2 6.5.6.3 6.5.6.4 6.5.6.5 6.5.6.6
6.5.7.1 6.5.7.2 6.5.7.3 6.5.7.4 6.5.7.5 6.5.7.6 6.5.8.1 6.5.8.2
6.5.8.3 6.5.8.4 6.5.8.5 6.5.8.6 6.5.9.1 6.5.9.2 6.5.9.3 6.5.9.4
6.5.9.5 6.5.9.6 6.6.1.1 6.6.1.2 6.6.1.3 6.6.1.4 6.6.1.5 6.6.1.6
6.6.2.1 6.6.2.2 6.6.2.3 6.6.2.4 6.6.2.5 6.6.2.6 6.6.3.1 6.6.3.2
6.6.3.3 6.6.3.4 6.6.3.5 6.6.3.6 6.6.4.1 6.6.4.2 6.6.4.3 6.6.4.4
6.6.4.5 6.6.4.6 6.6.5.1 6.6.5.2 6.6.5.3 6.6.5.4 6.6.5.5 6.6.5.6
6.6.6.1 6.6.6.2 6.6.6.3 6.6.6.4 6.6.6.5 6.6.6.6 6.6.7.1 6.6.7.2
6.6.7.3 6.6.7.4 6.6.7.5 6.6.7.6 6.6.8.1 6.6.8.2 6.6.8.3 6.6.8.4
6.6.8.5 6.6.8.6 6.6.9.1 6.6.9.2 6.6.9.3 6.6.9.4 6.6.9.5 6.6.9.6
6.7.1.1 6.7.1.2 6.7.1.3 6.7.1.4 6.7.1.5 6.7.1.6 6.7.2.1 6.7.2.2
6.7.2.3 6.7.2.4 6.7.2.5 6.7.2.6 6.7.3.1 6.7.3.2 6.7.3.3 6.7.3.4
6.7.3.5 6.7.3.6 6.7.4.1 6.7.4.2 6.7.4.3 6.7.4.4 6.7.4.5 6.7.4.6
6.7.5.1 6.7.5.2 6.7.5.3 6.7.5.4 6.7.5.5 6.7.5.6 6.7.6.1 6.7.6.2
6.7.6.3 6.7.6.4 6.7.6.5 6.7.6.6 6.7.7.1 6.7.7.2 6.7.7.3 6.7.7.4
6.7.7.5 6.7.7.6 6.7.8.1 6.7.8.2 6.7.8.3 6.7.8.4 6.7.8.5 6.7.8.6
6.7.9.1 6.7.9.2 6.7.9.3 6.7.9.4 6.7.9.5 6.7.9.6 6.8.1.1 6.8.1.2
6.8.1.3 6.8.1.4 6.8.1.5 6.8.1.6 6.8.2.1 6.8.2.2 6.8.2.3 6.8.2.4
6.8.2.5 6.8.2.6 6.8.3.1 6.8.3.2 6.8.3.3 6.8.3.4 6.8.3.5 6.8.3.6
6.8.4.1 6.8.4.2 6.8.4.3 6.8.4.4 6.8.4.5 6.8.4.6 6.8.5.1 6.8.5.2
6.8.5.3 6.8.5.4 6.8.5.5 6.8.5.6 6.8.6.1 6.8.6.2 6.8.6.3 6.8.6.4
6.8.6.5 6.8.6.6 6.8.7.1 6.8.7.2 6.8.7.3 6.8.7.4 6.8.7.5 6.8.7.6
6.8.8.1 6.8.8.2 6.8.8.3 6.8.8.4 6.8.8.5 6.8.8.6 6.8.9.1 6.8.9.2
6.8.9.3 6.8.9.4 6.8.9.5 6.8.9.6 6.9.1.1 6.9.1.2 6.9.1.3 6.9.1.4
6.9.1.5 6.9.1.6 6.9.2.1 6.9.2.2 6.9.2.3 6.9.2.4 6.9.2.5 6.9.2.6
6.9.3.1 6.9.3.2 6.9.3.3 6.9.3.4 6.9.3.5 6.9.3.6 6.9.4.1 6.9.4.2
6.9.4.3 6.9.4.4 6.9.4.5 6.9.4.6 6.9.5.1 6.9.5.2 6.9.5.3 6.9.5.4
6.9.5.5 6.9.5.6 6.9.6.1 6.9.6.2 6.9.6.3 6.9.6.4 6.9.6.5 6.9.6.6
6.9.7.1 6.9.7.2 6.9.7.3 6.9.7.4 6.9.7.5 6.9.7.6 6.9.8.1 6.9.8.2
6.9.8.3 6.9.8.4 6.9.8.5 6.9.8.6 6.9.9.1 6.9.9.2 6.9.9.3 6.9.9.4
6.9.9.5 6.9.9.6 7.1.1.1 7.1.1.2 7.1-1.3 7.1.1.4 7.1.1.5 7.1.1.6
7.1.2.1 7.1.2.2 7.1.2.3 7.1.2.4 7.1.2.5 7.1.2.6 7.1.3.1 7.1.3.2
7.1.3.3 7.1.3.4 7.1.3.5 7.1.3.6 7.1.4.1 7.1.4.2 7.1.4.3 7.1.4.4
7.1.4.5 7.1.4.6 7.1.5.1 7.1.5.2 7.1.5.3 7.1.5.4 7.1.5.5 7.1.5.6
7.1.6.1 7.1.6.2 7.1.6.3 7.1.6.4 7.1.6.5 7.1.6.6 7.1.7.1 7.1.7.2
7.1.7.3 7.1.7.4 7.1.7.5 7.1.7.6 7.1.8.1 7.1.8.2 7.1.8.3 7.1.8.4
7.1.8.5 7.1.8.6 7.1.9.1 7.1.9.2 7.1.9.3 7.1.9.4 7.1.9.5 7.1.9.6
7.2.1.1 7.2.1.2 7.2.1.3 7.2.1.4 7.2.1.5 7.2.1.6 7.2.2.1 7.2.2.2
7.2.2.3 7.2.2.4 7.2.2.5 7.2.2.6 7.2.3.1 7.2.3.2 7.2.3.3 7.2.3.4
7.2.3.5 7.2.3.6 7.2.4.1 7.2.4.2 7.2.4.3 7.2.4.4 7.2.4.5 7.2.4.6
7.2.5.1 7.2.5.2 7.2.5.3 7.2.5.4 7.2.5.5 7.2.5.6 7.2.6.1 7.2.6.2
7.2.6.3 7.2.6.4 7.2.6.5 7.2.6.6 7.2.7.1 7.2.7.2 7.2.7.3 7.2.7.4
7.2.7.5 7.2.7.6 7.2.8.1 7.2.8.2 7.2.8.3 7.2.8.4 7.2.8.5 7.2.8.6
7.2.9.1 7.2.9.2 7.2.9.3 7.2.9.4 7.2.9.5 7.2.9.6 7.3.1.1 7.3.1.2
7.3.1.3 7.3.1.4 7.3.1.5 7.3.1.6 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4
7.3.2.5 7.3.2.6 7.3.3.1 7.3.3.2 7.3.3.3 7.3.3.4 7.3.3.5 7.3.3.6
7.3.4.1 7.3.4.2 7.3.4.3 7.3.4.4 7.3.4.5 7.3.4.6 7.3.5.1 7.3.5.2
7.3.5.3 7.3.5.4 7.3.5.5 7.3.5.6 7.3.6.1 7.3.6.2 7.3.6.3 7.3.6.4
7.3.6.5 7.3.6.6 7.3.7.1 7.3.7.2 7.3.7.3 7.3.7.4 7.3.7.5 7.3.7.6
7.3.8.1 7.3.8.2 7.3.8.3 7.3.8.4 7.3.8.5 7.3.8.6 7.3.9.1 7.3.9.2
7.3.9.3 7.3.9.4 7.3.9.5 7.3-9.6 7.4.1.1 7.4.1.2 7.4.1.3 7.4.1.4
7.4.1.5 7.4.1.6 7.4.2.1 7.4.2.2 7.4.2.3 7.4.2.4 7.4.2.5 7.4.2.6
7.4.3.1 7.4.3.2 7.4.3.3 7.4.3.4 7.4.3.5 7.4.3.6 7.4.4.1 7.4.4.2
7.4.4.3 7.4.4.4 7.4.4.5 7.4.4.6 7.4.5.1 7.4.5.2 7.4.5.3 7.4.5.4
7.4.5.5 7.4.5.6 7.4.6.1 7.4.6.2 7.4.6.3 7.4.6.4 7.4.6.5 7.4.6.6
7.4.7.1 7.4.7.2 7.4.7.3 7.4.7.4 7.4.7.5 7.4.7.6 7.4.8.1 7.4.8.2
7.4.8.3 7.4.8.4 7.4.8.5 7.4.8.6 7.4.9.1 7.4.9.2 7.4.9.3 7.4.9.4
7.4.9.5 7.4.9.6 7.5.1.1 7.5.1.2 7.5.1.3 7.5.1.4 7.5.1.5 7.5.1.6
7.5.2.1 7.5.2.2 7.5.2.3 7.5.2.4 7.5.2.5 7.5.2.6 7.5.3.1 7.5.3.2
7.5.3.3 7.5.3.4 7.5.3.5 7.5.3.6 7.5.4.1 7.5.4.2 7.5.4.3 7.5.4.4
7.5.4.5 7.5.4.6 7.5.5.1 7.5.5.2 7.5.5.3 7.5.5.4 7.5.5.5 7.5.5.6
7.5.6.1 7.5.6.2 7.5.6.3 7.5.6.4 7.5.6.5 7.5.6.6 7.5.7.1 7.5.7.2
7.5.7.3 7.5.7.4 7.5.7.5 7.5.7.6 7.5.8.1 7.5.8.2 7.5.8.3 7.5.8.4
7.5.8.5 7.5.8.6 7.5.9.1 7.5.9.2 7.5.9.3 7.5.9.4 7.5.9.5 7.5.9.6
7.6.1.1 7.6.1.2 7.6.1.3 7.6.1.4 7.6.1.5 7.6.1.6 7.6.2.1 7.6.2.2
7.6.2.3 7.6.2.4 7.6.2.5 7.6.2.6 7.6.3.1 7.6.3.2 7.6.3.3 7.6.3.4
7.6.3.5 7.6.3.6 7.6.4.1 7.6.4.2 7.6.4.3 7.6.4.4 7.6.4.5 7.6.4.6
7.6.5.1 7.6.5.2 7.6.5.3 7.6.5.4 7.6.5.5 7.6.5.6 7.6.6.1 7.6.6.2
7.6.6.3 7.6.6.4 7.6.6.5 7.6.6.6 7.6.7.1 7.6.7.2 7.6.7.3 7.6.7.4
7.6.7.5 7.6.7.6 7.6.8.1 7.6.8.2 7.6.8.3 7.6.8.4 7.6.8.5 7.6.8.6
7.6.9.1 7.6.9.2 7.6.9.3 7.6.9.4 7.6.9.5 7.6.9.6 7.7.1.1 7.7.1.2
7.7.1.3 7.7.1.4 7.7.1.5 7.7.1.6 7.7.2.1 7.7.2.2 7.7.2.3 7.7.2.4
7.7.2.5 7.7.2.6 7.7.3.1 7.7.3.2 7.7.3.3 7.7.3.4 7.7.3.5 7.7.3.6
7.7.4.1 7.7.4.2 7.7.4.3 7.7.4.4 7.7.4.5 7.7.4.6 7.7.5.1 7.7.5.2
7.7.5.3 7.7.5.4 7.7.5.5 7.7.5.6 7.7.6.1 7.7.6.2 7.7.6.3 7.7.6.4
7.7.6.5 7.7.6.6 7.7.7.1 7.7.7.2 7.7.7.3 7.7.7.4 7.7.7.5 7.7.7.6
7.7.8.1 7.7.8.2 7.7.8.3 7.7.8.4 7.7.8.5 7.7.8.6 7.7.9.1 7.7.9.2
7.7.9.3 7.7.9.4 7.7.9.5 7.7.9.6 7.8.1.1 7.8.1.2 7.8.1.3 7.8.1.4
7.8.1.5 7.8.1.6 7.8.2.1 7.8.2.2 7.8.2.3 7.8.2.4 7.8.2.5 7.8.2.6
7.8.3.1 7.8.3.2 7.8.3.3 7.8.3.4 7.8.3.5 7.8.3.6 7.8.4.1 7.8.4.2
7.8.4.3 7.8.4.4 7.8.4.5 7.8.4.6 7.8.5.1 7.3.5.2 7.8.5.3 7.8.5.4
7.8.5.5 7.8.5.6 7.8.6.1 7.8.6.2 7.8.6.3 7.8.6.4 7.8.6.5 7.8.6.6
7.8.7.1 7.8.7.2 7.8.7.3 7.8.7.4 7.8.7.5 7.8.7.6 7.8.8.1 7.8.8.2
7.8.8.3 7.8.8.4 7.8.8.5 7.8.8.6 7.8.9.1 7.8.9.2 7.8.9.3 7.8.9.4
7.8.9.5 7.8.9.6 7.9.1.1 7.9.1.2 7.9.1.3 7.9.1.4 7.9.1.5 7.9.1.6
7.9.2.1 7.9.2.2 7.9.2.3 7.9.2.4 7.9.2.5 7.9.2.6 7.9.3.1 7.9.3.2
7.9.3.3 7.9.3.4 7.9.3.5 7.9.3.6 7.9.4.1 7.9.4.2 7.9.4.3 7.9.4.4
7.9.4.5 7.9.4.6 7.9.5.1 7.9.5.2 7.9.5.3 7.9.5.4 7.9.5.5 7.9.5.6
7.9.6.1 7.9.6.2 7.9.6.3 7.9.6.4 7.9.6.5 7.9.6.6 7.9.7.1 7.9.7.2
7.9.7.3 7.9.7.4 7.9.7.5 7.9.7.6 7.9.8.1 7.9.8.2 7.9.8.3 7.9.8.4
7.9.8.5 7.9.8.6 7.9.9.1 7.9.9.2 7.9.9.3 7.9.9.4 7.9.9.5 7.9.9.6
[0643] Therefore, compounds named in Table 1 of formula (i) having
--S-- as Y' are compounds with a thiazolyl as R.sup.5 in formula I.
For example, using Group 1 for variable B, the compound named
2.6.1.1 specifies --NH.sub.2 as A, -Pr-c as B, furan-2,5-diyl as X
and --S-- as Y', and this compound is
2-amino-5-cyclopropyl-4-[2-(5-phosphono)furanyl]thiazole prepared
in Example 3 as compound 3.27. Analogously, compounds named in
Table 1 of formula (i) having --O-- as Y' are compounds with an
oxazolyl as R.sup.5 in formula I. For example, using group 1 for
variable B, the compound named 2.4.1.2 in Table 1 of formula (i)
has the structure of
2-amino-5-propyl-4-[2-(phosphono))furanyl]oxazole prepared in
Example 10 as compound 10.2. Similarly, compounds named in Table 1
of formula (i) having --Se-- as Y' are compounds with a selenazolyl
as R.sup.5 in formula I. Thus, using Group 1 for variable B, the
compound named 2.3.1.3 in Table 1 of formula (i) has the structure
of 2-amino-5-ethyl-4-[2-(5-phosphono)furanyl]selenazole prepared in
Example 3 as compound 3.72.
[0644] Likewise, using Group 2 for variable B, the compound named
in Table 1 of formula (i) as 2.8.1.1 is
2-amino-5-methylthio-4-[2-(5-phosphono)furanyl]thiazole prepared in
Example 3 as compound 3.26. Using Group 3 for variable B, the
compound named in Table 1 of formula (i) as 2.9.1.1 is
2-amino-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole prepared in
Example 3 as compound 3.1.
[0645] Using Group 4 for variable B, the compound named in Table 1
of formula (i) as 2.6.1.1 is
2-amino-5-(2-thienyl)-4-[2-(5-phosphono)furanyl]thiazole prepared
in Example 6 as compound 6.3.
[0646] Some of the exemplary embodiments of the compounds named in
Table 1 using Groups 1-4 for variable B in the compounds of
formulae (i), (ii), (iii) and (iv) are listed in Table 2.
TABLE-US-00010 TABLE 2 compound Compound Synthetic groups number as
Example where B is A.B.X.Y No. formula A selected B X* Y 2.1.1.1
3.13 (i) NH2 1 H furan-2,5-diyl S 2.2.1.1 3.16 (i) NH2 1 Me
furan-2,5-diyl S 2.3.1.1 3.21 (i) NH2 1 Et furan-2,5-diyl S 2.4.1.1
3.24 (i) NH2 1 Pr-n furan-2,5-diyl S 2.5.1.1 3.2 (i) NH2 1 Pr-i
furan-2,5-diyl S 2.6.1.1 3.27 (i) NH2 1 Pr-c furan-2,5-diyl S
2.9.1.1 3.1 (i) NH2 3 Bu-i furan-2,5-diyl S 2.5.1.1 6.2 (i) NH2 4
2-furanyl furan-2,5-diyl S 2.3.1.1 3.30 (i) NH2 3 Bu-c
furan-2,5-diyl S 2.6.1.1 6.3 (i) NH2 4 2-thienyl furan-2,5-diyl S
2.8.1.1 4.2 (i) NH2 1 Cl furan-2,5-diyl S 2.7.1.1 4.1 (i) NH2 1 Br
furan-2,5-diyl S 2.9.1.1 4.3 (i) NH2 1 I furan-2,5-diyl S 2.8.1.1
3.26 (i) NH2 2 SMe furan-2,5-diyl S 2.1.1.1 3.59 (i) NH2 3 SEt
furan-2,5-diyl S 2.6.1.1 3.58 (i) NH2 3 SPr-n furan-2,5-diyl S
2.4.1.1 3.55 (i) NH2 4 SPr-i furan-2,5-diyl S 2.9.1.1 3.36 (i) NH2
4 Bn furan-2,5-diyl S 2.6.1.1 3.33 (i) NH2 2 C(O)OMe furan-2,5-diyl
S 2.4.1.1 3.25 (i) NH2 3 C(O)OEt furan-2,5-diyl S 1.1.1.1 3.3 (i) H
1 H furan-2,5-diyl S 1.9.1.1 3.7 (i) H 3 Bu-i furan-2,5-diyl S
6.8.1.1 3.50 (i) Me 2 SMe furan-2,5-diyl S 4.9.1.1 5.2 (i) Cl 3
Bu-i furan-2,5-diyl S 3.7.1.1 4.4 (i) Br 1 Br furan-2,5-diyl S
3.9.1.1 5.1 (i) Br 3 Bu-i furan-2,5-diyl S 6.6.1.1 3.42 (i) Me 1
Pr-c furan-2,5-diyl S 6.1.1.1 3.4 (i) Me 1 H furan-2,5-diyl S
6.2.1.1 3.17 (i) Me 1 Me furan-2,5-diyl S 6.7.1.1 4.5 (i) Me 1 Br
furan-2,5-diyl S 6.9.1.1 3.2 (i) Me 3 Bu-i furan-2,5-diyl S 6.3.1.1
3.41 (i) Me 1 Et furan-2,5-diyl S 6.4.1.1 3.43 (i) Me 3 C(O)OEt
furan-2,5-diyl S 1.4.1.1 3.65 (i) H 3 C(O)OEt furan-2,5-diyl S
6.1.9.1 8.1 (i) Me 1 H CH2OCH2 S 6.7.9.1 8.2 (i) Me 1 Br CH2OCH2 S
2.9.4.1 18.16 (i) NH2 4 Bn C(O)OCH2 S 2.1.9.1 8.3 (i) NH2 1 H
CH2OCH2 S 2.2.4.1 18.27 (i) NH2 1 Me C(O)OCH2 S 2.1.4.1 18.37 (i)
NH2 1 H C(O)OCH2 S 2.3.4.1 18.3 (i) NH2 1 Et C(O)OCH2 S 2.5.4.1
18.20 (i) NH2 1 Pr-i C(O)OCH2 S 2.5.5.1 18.19 (i) NH2 1 Pr-i
C(O)NHCH2 S 2.3.5.1 18.18 (i) NH2 1 Et C(O)NHCH2 S 2.2.5.1 18.24
(i) NH2 1 Me C(O)NHCH2 S 2.1.5.1 18.6 (i) NH2 1 H C(O)NHCH2 S
2.1.4.1 18.1 (i) NH2 1 H C(O)OCH2 S 2.7.5.1 18.11 (i) NH2 1 Br
C(O)NHCH2 S 2.7.4.1 18.2 (i) NH2 1 Br C(O)OCH2 S 2.6.4.1 18.15 (i)
NH2 4 2-thienyl C(O)OCH2 S 2.6.5.1 18.12 (i) NH2 4 2-thienyl
C(O)NHCH2 S 2.1.2.1 3.67 (i) NH2 1 H pyridin-2,6-diyl S 6.2.8.1
18.7 (iii) Me 1 Me NHC(O)CH2 S 2.1.1.2 10.5 (i) NH2 1 H
furan-2,5-diyl O 2.2.1.2 10.4 (i) NH2 1 Me furan-2,5-diyl O 2.3.1.2
10.3 (i) NH2 1 Et furan-2,5-diyl O 2.4.1.2 10.2 (i) NH2 1 Pr-n
furan-2,5-diyl O 2.8.1.2 10.12 (i) NH2 3 Bu-n furan-2,5-diyl O
2.9.1.2 10.1 (i) NH2 3 Bu-i furan-2,5-diyl O 2.6.1.2 10.37 (i) NH2
2 C(O)OMe furan-2,5-diyl O 2.1.4.2 18.22 (i) NH2 1 H C(O)OCH2 O
2.5.4.2 18.30 (i) NH2 1 Pr-i C(O)OCH2 O 2.2.4.2 18.33 (i) NH2 1 Me
C(O)OCH2 O 2.8.4.2 18.38 (i) NH2 3 Bu-n C(O)OCH2 O 2.4.4.2 18.40
(i) NH2 1 Pr-n C(O)OCH2 O 2.9.1.2 10.8 (i) NH2 4 Bn furan-2,5-diyl
O 2.8.1.2 10.34 (i) NH2 2 SMe furan-2,5-diyl O 2.1.1.2 10.42 (i)
NH2 3 SEt furan-2,5-diyl O 2.6.1.2 10.43 (i) NH2 3 SPr-n
furan-2,5-diyl O 2.4.1.2 10.40 (i) NH2 4 SPr-i furan-2,5-diyl O
2.4.1.2 10.27 (i) NH2 3 C(O)OEt furan-2,5-diyl O 1.9.1.2 10.11 (i)
H 3 Bu-i furan-2,5-diyl O 6.9.1.2 10.19 (i) Me 2 Bu-i
furan-2,5-diyl O 7.1.1.4 10.22 (i) CF3 1 H furan-2,5-diyl NH
6.9.1.4 10.21 (i) Me 3 Bu-i furan-2,5-diyl NH 6.9.1.5 11.2 (i) Me 3
Bu-i furan-2,5-diyl NMe 6.4.1.4 10.2 (i) Me 1 Pr-n furan-2,5-diyl
NH 6.9.1.5 11.2 (i) Me 3 Bu-i furan-2,5-diyl NMe 6.2.1.4 10.34
(iii) Me 1 Me furan-2,5-diyl NH 2.4.1.2 26.4 (ii) NH2 3 C(O)OEt
furan-2,5-diyl O 1.9.1.5 25.2 (ii) H 3 Bu-i furan-2,5-diyl NMe
1.9.1.4 25.1 (ii) H 3 Bu-i furan-2,5-diyl H 1.7.8.1 (iii) H 1 Br
NHC(O)CH2 S 1.1.8.1 (iii) H 1 H NHC(O)CH2 S *The direction of X
groups is defined as going from R5 to the phosphorus atom.
[0647] The following compounds of formula I wherein R.sup.5 is a
pyridinyl, or a pyrimidinyl, or a pyrazinyl or a pyridazinyl, and
pharmaceutically acceptable salts and prodrugs thereof are
preferred. These preferred compounds are shown in structures
(v)-(ix), below: ##STR55##
[0648] The preferred compounds of formula (v)-(ix) are listed in
Table 3 by designated numbers assigned to A, B, X, D and E in the
above formulae (v)-(ix) according to the following convention:
A.B.X.D.E. For compounds of formula (vi) D is null and designated
with number 0, for compounds of formula (vii) E is null and
designated with number 0, and for compounds of formula (viii) B is
null and designated with number 0. For example, all compounds named
in Table 3 of formula (vi) are assigned as A.B.X.0.E, all compounds
named in Table 3 of formula (vii) are assigned as A.B.X.D.0, all
compounds named in Table 3 of formula (viii) are assigned as
A.0.X.D.E, and all compounds named in Table 3 of formula (ix) are
assigned as 0.B.X.D.E. For each moiety, structures are assigned to
a number shown in the following tables for A, B, X, D, and E.
[0649] Variable A is selected from eight different
substitutents.
[0650] The A groups are assigned the following numbers:
TABLE-US-00011 TABLE A 1 2 3 4 5 6 7 8 A = H NH.sub.2 Br Cl F Me
CF.sub.3 C(O)NH.sub.2
[0651] Variable 3 is divided into four Groups, each listing eight
different substitutents.
[0652] The Group 1 substitutents for variable B are assigned the
following numbers: TABLE-US-00012 TABLE B 1 2 3 4 5 6 7 8 B = H Me
Et Pr-n Pr-i Pr-c Br Cl
[0653] The Group 2 substitutents for variable B are assigned the
following numbers: TABLE-US-00013 1 2 3 4 5 6 7 8 B = F CN
CH.sub.2Pr-c Bu-i C(O)SMe C(O)OMe OEt SMe
[0654] The Group 3 substitutents for variable B are assigned the
following numbers: TABLE-US-00014 1 2 3 4 5 6 7 8 B = SEt 4- Bu-c
C(O)OEt NMe.sub.2 SPr-n CF.sub.3 OPr- pyridyl n
[0655] The Group 4 substitutents for variable B are assigned the
following numbers: TABLE-US-00015 1 2 3 4 5 6 7 8 B = SPr-c OPr-i
OPr-c SPr-i 2-furanyl 2-thienyl OMe Bn
[0656] Variable X is divided into two Groups, each listing four
different substitutents.
[0657] The Group 1 substitutents for variable X are assigned with
the following numbers: TABLE-US-00016 TABLE X 1 2 3 4 X =
Furan-2,5-diyl Pyridin-2,6-diyl C(O)NHCH.sub.2 C(O)OCH.sub.2
The direction of X groups is defined as going from the heterocycle
to the phosphorus atom as shown in formula (v), (vi), (vii), (viii)
and (ix).
[0658] The Group 2 substitutents for variable X are assigned the
following numbers: TABLE-US-00017 1 2 3 4 X = NHC(O)CH.sub.2
C(O)N(Me)CH.sub.2 Ethyn-1,2-diyl CH.sub.2OCH.sub.2
[0659] Variable D is divided into two groups, each listing eight
different substitutents.
[0660] The D groups are assigned the following numbers:
TABLE-US-00018 TABLE D 1 2 3 4 5 6 7 8 D = H Me Et C(O)OEt SMe Pr-c
Br Cl
[0661] The Group 2 substitutents for variable D are assigned the
following numbers: TABLE-US-00019 1 2 3 4 5 6 7 8 D = F I CN
CH.sub.2Pr-c CH.sub.2OMe C(O)NH.sub.2 OMe CF.sub.$$
[0662] Variable E is divided into three Groups, each listing four
different substituents.
[0663] The Group 1 substitutents for variable E are assigned the
following numbers: TABLE-US-00020 TABLE E 1 2 3 4 E = H Me Et
Pr-n
[0664] The Group 2 substitutents for variable E are assigned the
following numbers: TABLE-US-00021 1 2 3 4 E = Br Cl F CN
[0665] The Group 3 substitutents for variable E are assigned the
following numbers: TABLE-US-00022 1 2 3 4 E = C(O)OMe Pr-c SMe
OMe
[0666] TABLE-US-00023 TABLE 3 1.1.1.1.1 1.1.1.1.2 1.1.1.1.3
1.1.1.1.4 1.1.1.2.1 1.1.1.2.2 1.1.1.2.3 1.1.1.2.4 1.1.1.3.1
1.1.1.3.2 1.1.1.3.3 1.1.1.3.4 1.1.1.4.1 1.1.1.4.2 1.1.1.4.3
1.1.1.4.4 1.1.1.5.1 1.1.1.5.2 1.1.1.5.3 1.1.1.5.4 1.1.1.6.1
1.1.1.6.2 1.1.1.6.3 1.1.1.6.4 1.1.1.7.1 1.1.1.7.2 1.1.1.7.3
1.1.1.7.4 1.1.1.8.1 1.1.1.8.2 1.1.1.8.3 1.1.1.8.4 1.1.2.1.1
1.1.2.1.2 1.1.2.1.3 1.1.2.1.4 1.1.2.2.1 1.1.2.2.2 1.1.2.2.3
1.1.2.2.4 1.1.2.3.1 1.1.2.3.2 1.1.2.3.3 1.1.2.3.4 1.1.2.4.1
1.1.2.4.2 1.1.2.4.3 1.1.2.4.4 1.1.2.5.1 1.1.2.5.2 1.1.2.5.3
1.1.2.5.4 1.1.2.6.1 1.1.2.6.2 1.1.2.6.3 1.1.2.6.4 1.1.2.7.1
1.1.2.7.2 1.1.2.7.3 1.1.2.7.4 1.1.2.8.1 1.1.2.8.2 1.1.2.8.3
1.1.2.8.4 1.1.3.1.1 1.1.3.1.2 1.1.3.1.3 1.1.3.1.4 1.1.3.2.1
1.1.3.2.2 1.1.3.2.3 1.1.3.2.4 1.1.3.3.1 1.1.3.3.2 1.1.3.3.3
1.1.3.3.4 1.1.3.4.1 1.1.3.4.2 1.1.3.4.3 1.1.3.4.4 1.1.3.5.1
1.1.3.5.2 1.1.3.5.3 1.1.3.5.4 1.1.3.6.1 1.1.3.6.2 1.1.3.6.3
1.1.3.6.4 1.1.3.7.1 1.1.3.7.2 1.1.3.7.3 1.1.3.7.4 1.1.3.8.1
1.1.3.8.2 1.1.3.8.3 1.1.3.8.4 1.1.4.1.1 1.1.4.1.2 1.1.4.1.3
1.1.4.1.4 1.1.4.2.1 1.1.4.2.2 1.1.4.2.3 1.1.4.2.4 1.1.4.3.1
1.1.4.3.2 1.1.4.3.3 1.1.4.3.4 1.1.4.4.1 1.1.4.4.2 1.1.4.4.3
1.1.4.4.4 1.1.4.5.1 1.1.4.5.2 1.1.4.5.3 1.1.4.5.4 1.1.4.6.1
1.1.4.6.2 1.1.4.6.3 1.1.4.6.4 1.1.4.7.1 1.1.4.7.2 1.1.4.7.3
1.1.4.7.4 1.1.4.8.1 1.1.4.8.2 1.1.4.8.3 1.1.4.8.4 1.2.1.1.1
1.2.1.1.2 1.2.1.1.3 1.2.1.1.4 1.2.1.2.1 1.2.1.2.2 1.2.1.2.3
1.2.1.2.4 1.2.1.3.1 1.2.1.3.2 1.2.1.3.3 1.2.1.3.4 1.2.1.4.1
1.2.1.4.2 1.2.1.4.3 1.2.1.4.4 1.2.1.5.1 1.2.1.5.2 1.2.1.5.3
1.2.1.5.4 1.2.1.6.1 1.2.1.6.2 1.2.1.6.3 1.2.1.6.4 1.2.1.7.1
1.2.1.7.2 1.2.1.7.3 1.2.1.7.4 1.2.1.8.1 1.2.1.8.2 1.2.1.8.3
1.2.1.8.4 1.2.2.1.1 1.2.2.1.2 1.2.2.1.3 1.2.2.1.4 1.2.2.2.1
1.2.2.2.2 1.2.2.2.3 1.2.2.2.4 1.2.2.3.1 1.2.2.3.2 1.2.2.3.3
1.2.2.3.4 1.2.2.4.1 1.2.2.4.2 1.2.2.4.3 1.2.2.4.4 1.2.2.5.1
1.2.2.5.2 1.2.2.5.3 1.2.2.5.4 1.2.2.6.1 1.2.2.6.2 1.2.2.6.3
1.2.2.6.4 1.2.2.7.1 1.2.2.7.2 1.2.2.7.3 1.2.2.7.4 1.2.2.8.1
1.2.2.8.2 1.2.2.8.3 1.2.2.8.4 1.2.3.1.1 1.2.3.1.2 1.2.3.1.3
1.2.3.1.4 1.2.3.2.1 1.2.3.2.2 1.2.3.2.3 1.2.3.2.4 1.2.3.3.1
1.2.3.3.2 1.2.3.3.3 1.2.3.3.4 1.2.3.4.1 1.2.3.4.2 1.2.3.4.3
1.2.3.4.4 1.2.3.5.1 1.2.3.5.2 1.2.3.5.3 1.2.3.5.4 1.2.3.6.1
1.2.3.6.2 1.2.3.6.3 1.2.3.6.4 1.2.3.7.1 1.2.3.7.2 1.2.3.7.3
1.2.3.7.4 1.2.3.8.1 1.2.3.8.2 1.2.3.8.3 1.2.3.8.4 1.2.4.1.1
1.2.4.1.2 1.2.4.1.3 1.2.4.1.4 1.2.4.2.1 1.2.4.2.2 1.2.4.2.3
1.2.4.2.4 1.2.4.3.1 1.2.4.3.2 1.2.4.3.3 1.2.4.3.4 1.2.4.4.1
1.2.4.4.2 1.2.4.4.3 1.2.4.4.4 1.2.4.5.1 1.2.4.5.2 1.2.4.5.3
1.2.4.5.4 1.2.4.6.1 1.2.4.6.2 1.2.4.6.3 1.2.4.6.4 1.2.4.7.1
1.2.4.7.2 1.2.4.7.3 1.2.4.7.4 1.2.4.8.1 1.2.4.8.2 1.2.4.8.3
1.2.4.8.4 1.3.1.1.1 1.3.1.1.2 1.3.1.1.3 1.3.1.1.4 1.3.1.2.1
1.3.1.2.2 1.3.1.2.3 1.3.1.2.4 1.3.1.3.1 1.3.1.3.2 1.3.1.3.3
1.3.1.3.4 1.3.1.4.1 1.3.1.4.2 1.3.1.4.3 1.3.1.4.4 1.3.1.5.1
1.3.1.5.2 1.3.1.5.3 1.3.1.5.4 1.3.1.6.1 1.3.1.6.2 1.3.1.6.3
1.3.1.6.4 1.3.1.7.1 1.3.1.7.2 1.3.1.7.3 1.3.1.7.4 1.3.1.8.1
1.3.1.8.2 1.3.1.8.3 1.3.1.8.4 1.3.2.1.1 1.3.2.1.2 1.3.2.1.3
1.3.2.1.4 1.3.2.2.1 1.3.2.2.2 1.3.2.2.3 1.3.2.2.4 1.3.2.3.1
1.3.2.3.2 1.3.2.3.3 1.3.2.3.4 1.3.2.4.1 1.3.2.4.2 1.3.2.4.3
1.3.2.4.4 1.3.2.5.1 1.3.2.5.2 1.3.2.5.3 1.3.2.5.4 1.3.2.6.1
1.3.2.6.2 1.3.2.6.3 1.3.2.6.4 1.3.2.7.1 1.3.2.7.2 1.3.2.7.3
1.3.2.7.4 1.3.2.8.1 1.3.2.8.2 1.3.2.8.3 1.3.2.8.4 1.3.3.1.1
1.3.3.1.2 1.3.3.1.3 1.3.3.1.4 1.3.3.2.1 1.3.3.2.2 1.3.3.2.3
1.3.3.2.4 1.3.3.3.1 1.3.3.3.2 1.3.3.3.3 1.3.3.3.4 1.3.3.4.1
1.3.3.4.2 1.3.3.4.3 1.3.3.4.4 1.3.3.5.1 1.3.3.5.2 1.3.3.5.3
1.3.3.5.4 1.3.3.6.1 1.3.3.6.2 1.3.3.6.3 1.3.3.6.4 1.3.3.7.1
1.3.3.7.2 1.3.3.7.3 1.3.3.7.4 1.3.3.8.1 1.3.3.8.2 1.3.3.8.3
1.3.3.8.4 1.3.4.1.1 1.3.4.1.2 1.3.4.1.3 1.3.4.1.4 1.3.4.2.1
1.3.4.2.2 1.3.4.2.3 1.3.4.2.4 1.3.4.3.1 1.3.4.3.2 1.3.4.3.3
1.3.4.3.4 1.3.4.4.1 1.3.4.4.2 1.3.4.4.3 1.3.4.4.4 1.3.4.5.1
1.3.4.5.2 1.3.4.5.3 1.3.4.5.4 1.3.4.6.1 1.3.4.6.2 1.3.4.6.3
1.3.4.6.4 1.3.4.7.1 1.3.4.7.2 1.3.4.7.3 1.3.4.7.4 1.3.4.8.1
1.3.4.8.2 1.3.4.8.3 1.3.4.8.4 1.4.1.1.1 1.4.1.1.2 1.4.1.1.3
1.4.1.1.4 1.4.1.2.1 1.4.1.2.2 1.4.1.2.3 1.4.1.2.4 1.4.1.3.1
1.4.1.3.2 1.4.1.3.3 1.4.1.3.4 1.4.1.4.1 1.4.1.4.2 1.4.1.4.3
1.4.1.4.4 1.4.1.5.1 1.4.1.5.2 1.4.1.5.3 1.4.1.5.4 1.4.1.6.1
1.4.1.6.2 1.4.1.6.3 1.4.1.6.4 1.4.1.7.1 1.4.1.7.2 1.4.1.7.3
1.4.1.7.4 1.4.1.8.1 1.4.1.8.2 1.4.1.8.3 1.4.1.8.4 1.4.2.1.1
1.4.2.1.2 1.4.2.1.3 1.4.2.1.4 1.4.2.2.1 1.4.2.2.2 1.4.2.2.3
1.4.2.2.4 1.4.2.3.1 1.4.2.3.2 1.4.2.3.3 1.4.2.3.4 1.4.2.4.1
1.4.2.4.2 1.4.2.4.3 1.4.2.4.4 1.4.2.5.1 1.4.2.5.2 1.4.2.5.3
1.4.2.5.4 1.4.2.6.1 1.4.2.6.2 1.4.2.6.3 1.4.2.6.4 1.4.2.7.1
1.4.2.7.2 1.4.2.7.3 1.4.2.7.4 1.4.2.8.1 1.4.2.8.2 1.4.2.8.3
1.4.2.8.4 1.4.3.1.1 1.4.3.1.2 1.4.3.1.3 1.4.3.1.4 1.4.3.2.1
1.4.3.2.2 1.4.3.2.3 1.4.3.2.4 1.4.3.3.1 1.4.3.3.2 1.4.3.3.3
1.4.3.3.4 1.4.3.4.1 1.4.3.4.2 1.4.3.4.3 1.4.3.4.4 1.4.3.5.1
1.4.3.5.2 1.4.3.5.3 1.4.3.5.4 1.4.3.6.1 1.4.3.6.2 1.4.3.6.3
1.4.3.6.4 1.4.3.7.1 1.4.3.7.2 1.4.3.7.3 1.4.3.7.4 1.4.3.8.1
1.4.3.8.2 1.4.3.8.3 1.4.3.8.4 1.4.4.1.1 1.4.4.1.2 1.4.4.1.3
1.4.4.1.4 1.4.4.2.1 1.4.4.2.2 1.4.4.2.3 1.4.4.2.4 1.4.4.3.1
1.4.4.3.2 1.4.4.3.3 1.4.4.3.4 1.4.4.4.1 1.4.4.4.2 1.4.4.4.3
1.4.4.4.4 1.4.4.5.1 1.4.4.5.2 1.4.4.5.3 1.4.4.5.4 1.4.4.6.1
1.4.4.6.2 1.4.4.6.3 1.4.4.6.4 1.4.4.7.1 1.4.4.7.2 1.4.4.7.3
1.4.4.7.4 1.4.4.8.1 1.4.4.8.2 1.4.4.8.3 1.4.4.8.4 1.5.1.1.1
1.5.1.1.2 1.5.1.1.3 1.5.1.1.4 1.5.1.2.1 1.5.1.2.2 1.5.1.2.3
1.5.1.2.4 1.5.1.3.1 1.5.1.3.2 1.5.1.3.3 1.5.1.3.4 1.5.1.4.1
1.5.1.4.2 1.5.1.4.3 1.5.1.4.4 1.5.1.5.1 1.5.1.5.2 1.5.1.5.3
1.5.1.5.4 1.5.1.6.1 1.5.1.6.2 1.5.1.6.3 1.5.1.6.4 1.5.1.7.1
1.5.1.7.2 1.5.1.7.3 1.5.1.7.4 1.5.1.8.1 1.5.1.8.2 1.5.1.8.3
1.5.1.8.4 1.5.2.1.1 1.5.2.1.2 1.5.2.1.3 1.5.2.1.4 1.5.2.2.1
1.5.2.2.2 1.5.2.2.3 1.5.2.2.4 1.5.2.3.1 1.5.2.3.2 1.5.2.3.3
1.5.2.3.4 1.5.2.4.1 1.5.2.4.2 1.5.2.4.3 1.5.2.4.4 1.5.2.5.1
1.5.2.5.2 1.5.2.5.3 1.5.2.5.4 1.5.2.6.1 1.5.2.6.2 1.5.2.6.3
1.5.2.6.4 1.5.2.7.1 1.5.2.7.2 1.5.2.7.3 1.5.2.7.4 1.5.2.8.1
1.5.2.8.2 1.5.2.8.3 1.5.2.8.4 1.5.3.1.1 1.5.3.1.2 1.5.3.1.3
1.5.3.1.4 1.5.3.2.1 1.5.3.2.2 1.5.3.2.3 1.5.3.2.4 1.5.3.3.1
1.5.3.3.2 1.5.3.3.3 1.5.3.3.4 1.5.3.4.1 1.5.3.4.2 1.5.3.4.3
1.5.3.4.4 1.5.3.5.1 1.5.3.5.2 1.5.3.5.3 1.5.3.5.4 1.5.3.6.1
1.5.3.6.2 1.5.3.6.3 1.5.3.6.4 1.5.3.7.1 1.5.3.7.2 1.5.3.7.3
1.5.3.7.4 1.5.3.8.1 1.5.3.8.2 1.5.3.8.3 1.5.3.8.4 1.5.4.1.1
1.5.4.1.2 1.5.4.1.3 1.5.4.1.4 1.5.4.2.1 1.5.4.2.2 1.5.4.2.3
1.5.4.2.4 1.5.4.3.1 1.5.4.3.2 1.5.4.3.3 1.5.4.3.4 1.5.4.4.1
1.5.4.4.2 1.5.4.4.3 1.5.4.4.4 1.5.4.5.1 1.5.4.5.2 1.5.4.5.3
1.5.4.5.4 1.5.4.6.1 1.5.4.6.2 1.5.4.6.3 1.5.4.6.4 1.5.4.7.1
1.5.4.7.2 1.5.4.7.3 1.5.4.7.4 1.5.4.8.1 1.5.4.8.2 1.5.4.8.3
1.5.4.8.4 1.6.1.1.1 1.6.1.1.2 1.6.1.1.3 1.6.1.1.4 1.6.1.2.1
1.6.1.2.2 1.6.1.2.3 1.6.1.2.4 1.6.1.3.1 1.6.1.3.2 1.6.1.3.3
1.6.1.3.4 1.6.1.4.1 1.6.1.4.2 1.6.1.4.3 1.6.1.4.4 1.6.1.5.1
1.6.1.5.2 1.6.1.5.3 1.6.1.5.4 1.6.1.6.1 1.6.1.6.2 1.6.1.6.3
1.6.1.6.4 1.6.1.7.1 1.6.1.7.2 1.6.1.7.3 1.6.1.7.4 1.6.1.8.1
1.6.1.8.2 1.6.1.8.3 1.6.1.8.4 1.6.2.1.1 1.6.2.1.2 1.6.2.1.3
1.6.2.1.4 1.6.2.2.1 1.6.2.2.2 1.6.2.2.3 1.6.2.2.4 1.6.2.3.1
1.6.2.3.2 1.6.2.3.3 1.6.2.3.4 1.6.2.4.1 1.6.2.4.2 1.6.2.4.3
1.6.2.4.4 1.6.2.5.1 1.6.2.5.2 1.6.2.5.3 1.6.2.5.4 1.6.2.6.1
1.6.2.6.2 1.6.2.6.3 1.6.2.6.4 1.6.2.7.1 1.6.2.7.2 1.6.2.7.3
1.6.2.7.4 1.6.2.8.1 1.6.2.8.2 1.6.2.8.3 1.6.2.8.4 1.6.3.1.1
1.6.3.1.2 1.6.3.1.3 1.6.3.1.4 1.6.3.2.1 1.6.3.2.2 1.6.3.2.3
1.6.3.2.4 1.6.3.3.1 1.6.3.3.2 1.6.3.3.3 1.6.3.3.4 1.6.3.4.1
1.6.3.4.2 1.6.3.4.3 1.6.3.4.4 1.6.3.5.1 1.6.3.5.2 1.6.3.5.3
1.6.3.5.4 1.6.3.6.1 1.6.3.6.2 1.6.3.6.3 1.6.3.6.4 1.6.3.7.1
1.6.3.7.2 1.6.3.7.3 1.6.3.7.4 1.6.3.8.1 1.6.3.8.2 1.6.3.8.3
1.6.3.8.4 1.6.4.1.1 1.6.4.1.2 1.6.4.1.3 1.6.4.1.4 1.6.4.2.1
1.6.4.2.2 1.6.4.2.3 1.6.4.2.4 1.6.4.3.1 1.6.4.3.2 1.6.4.3.3
1.6.4.3.4 1.6.4.4.1 1.6.4.4.2 1.6.4.4.3 1.6.4.4.4 1.6.4.5.1
1.6.4.5.2 1.6.4.5.3 1.6.4.5.4 1.6.4.6.1 1.6.4.6.2 1.6.4.6.3
1.6.4.6.4 1.6.4.7.1 1.6.4.7.2 1.6.4.7.3 1.6.4.7.4 1.6.4.8.1
1.6.4.8.2 1.6.4.8.3 1.6.4.8.4 1.7.1.1.1 1.7.1.1.2 1.7.1.1.3
1.7.1.1.4 1.7.1.2.1 1.7.1.2.2 1.7.1.2.3 1.7.1.2.4 1.7.1.3.1
1.7.1.3.2 1.7.1.3.3 1.7.1.3.4 1.7.1.4.1 1.7.1.4.2 1.7.1.4.3
1.7.1.4.4 1.7.1.5.1 1.7.1.5.2 1.7.1.5.3 1.7.1.5.4 1.7.1.6.1
1.7.1.6.2 1.7.1.6.3 1.7.1.6.4 1.7.1.7.1 1.7.1.7.2 1.7.1.7.3
1.7.1.7.4 1.7.1.8.1 1.7.1.8.2 1.7.1.8.3 1.7.1.8.4 1.7.2.1.1
1.7.2.1.2 1.7.2.1.3 1.7.2.1.4 1.7.2.2.1 1.7.2.2.2 1.7.2.2.3
1.7.2.2.4 1.7.2.3.1 1.7.2.3.2 1.7.2.3.3 1.7.2.3.4 1.7.2.4.1
1.7.2.4.2 1.7.2.4.3 1.7.2.4.4 1.7.2.5.1 1.7.2.5.2 1.7.2.5.3
1.7.2.5.4 1.7.2.6.1 1.7.2.6.2 1.7.2.6.3 1.7.2.6.4 1.7.2.7.1
1.7.2.7.2 1.7.2.7.3 1.7.2.7.4 1.7.2.8.1 1.7.2.8.2 1.7.2.8.3
1.7.2.8.4 1.7.3.1.1 1.7.3.1.2 1.7.3.1.3 1.7.3.1.4 1.7.3.2.1
1.7.3.2.2 1.7.3.2.3 1.7.3.2.4 1.7.3.3.1 1.7.3.3.2 1.7.3.3.3
1.7.3.3.4 1.7.3.4.1 1.7.3.4.2 1.7.3.4.3 1.7.3.4.4 1.7.3.5.1
1.7.3.5.2 1.7.3.5.3 1.7.3.5.4 1.7.3.6.1 1.7.3.6.2 1.7.3.6.3
1.7.3.6.4 1.7.3.7.1 1.7.3.7.2 1.7.3.7.3 1.7.3.7.4 1.7.3.8.1
1.7.3.8.2 1.7.3.8.3 1.7.3.8.4 1.7.4.1.1 1.7.4.1.2 1.7.4.1.3
1.7.4.1.4 1.7.4.2.1 1.7.4.2.2 1.7.4.2.3 1.7.4.2.4 1.7.4.3.1
1.7.4.3.2 1.7.4.3.3 1.7.4.3.4 1.7.4.4.1 1.7.4.4.2 1.7.4.4.3
1.7.4.4.4 1.7.4.5.1 1.7.4.5.2 1.7.4.5.3 1.7.4.5.4 1.7.4.6.1
1.7.4.6.2 1.7.4.6.3 1.7.4.6.4 1.7.4.7.1 1.7.4.7.2 1.7.4.7.3
1.7.4.7.4 1.7.4.8.1 1.7.4.8.2 1.7.4.8.3 1.7.4.8.4 1.8.1.1.1
1.8.1.1.2 1.8.1.1.3 1.8.1.1.4 1.8.1.2.1 1.8.1.2.2 1.8.1.2.3
1.8.1.2.4 1.8.1.3.1 1.8.1.3.2 1.8.1.3.3 1.8.1.3.4 1.8.1.4.1
1.8.1.4.2 1.8.1.4.3 1.8.1.4.4 1.8.1.5.1 1.8.1.5.2 1.8.1.5.3
1.8.1.5.4 1.8.1.6.1 1.8.1.6.2 1.8.1.6.3 1.8.1.6.4 1.8.1.7.1
1.8.1.7.2 1.8.1.7.3 1.8.1.7.4 1.8.1.8.1 1.8.1.8.2 1.8.1.8.3
1.8.1.8.4 1.8.2.1.1 1.8.2.1.2 1.8.2.1.3 1.8.2.1.4 1.8.2.2.1
1.8.2.2.2 1.8.2.2.3 1.8.2.2.4 1.8.2.3.1 1.8.2.3.2 1.8.2.3.3
1.8.2.3.4 1.8.2.4.1 1.8.2.4.2 1.8.2.4.3 1.8.2.4.4 1.8.2.5.1
1.8.2.5.2 1.8.2.5.3 1.8.2.5.4 1.8.2.6.1 1.8.2.6.2 1.8.2.6.3
1.8.2.6.4 1.8.2.7.1 1.8.2.7.2 1.8.2.7.3 1.8.2.7.4 1.8.2.8.1
1.8.2.8.2 1.8.2.8.3 1.8.2.8.4 1.8.3.1.1 1.8.3.1.2 1.8.3.1.3
1.8.3.1.4 1.8.3.2.1 1.8.3.2.2 1.8.3.2.3 1.8.3.2.4 1.8.3.3.1
1.8.3.3.2 1.8.3.3.3 1.8.3.3.4 1.8.3.4.1 1.8.3.4.2 1.8.3.4.3
1.8.3.4.4 1.8.3.5.1 1.8.3.5.2 1.8.3.5.3 1.8.3.5.4 1.8.3.6.1
1.8.3.6.2 1.8.3.6.3 1.8.3.6.4 1.8.3.7.1 1.8.3.7.2 1.8.3.7.3
1.8.3.7.4 1.8.3.8.1 1.8.3.8.2 1.8.3.8.3
1.8.3.8.4 1.8.4.1.1 1.8.4.1.2 1.8.4.1.3 1.8.4.1.4 1.8.4.2.1
1.8.4.2.2 1.8.4.2.3 1.8.4.2.4 1.8.4.3.1 1.8.4.3.2 1.8.4.3.3
1.8.4.3.4 1.8.4.4.1 1.8.4.4.2 1.8.4.4.3 1.8.4.4.4 1.8.4.5.1
1.8.4.5.2 1.8.4.5.3 1.8.4.5.4 1.8.4.6.1 1.8.4.6.2 1.8.4.6.3
1.8.4.6.4 1.8.4.7.1 1.8.4.7.2 1.8.4.7.3 1.8.4.7.4 1.8.4.8.1
1.8.4.8.2 1.8.4.8.3 1.8.4.8.4 2.1.1.1.1 2.1.1.1.2 2.1.1.1.3
2.1.1.1.4 2.1.1.2.1 2.1.1.2.2 2.1.1.2.3 2.1.1.2.4 2.1.1.3.1
2.1.1.3.2 2.1.1.3.3 2.1.1.3.4 2.1.1.4.1 2.1.1.4.2 2.1.1.4.3
2.1.1.4.4 2.1.1.5.1 2.1.1.5.2 2.1.1.5.3 2.1.1.5.4 2.1.1.6.1
2.1.1.6.2 2.1.1.6.3 2.1.1.6.4 2.1.1.7.1 2.1.1.7.2 2.1.1.7.3
2.1.1.7.4 2.1.1.8.1 2.1.1.8.2 2.1.1.8.3 2.1.1.8.4 2.1.2.1.1
2.1.2.1.2 2.1.2.1.3 2.1.2.1.4 2.1.2.2.1 2.1.2.2.2 2.1.2.2.3
2.1.2.2.4 2.1.2.3.1 2.1.2.3.2 2.1.2.3.3 2.1.2.3.4 2.1.2.4.1
2.1.2.4.2 2.1.2.4.3 2.1.2.4.4 2.1.2.5.1 2.1.2.5.2 2.1.2.5.3
2.1.2.5.4 2.1.2.6.1 2.1.2.6.2 2.1.2.6.3 2.1.2.6.4 2.1.2.7.1
2.1.2.7.2 2.1.2.7.3 2.1.2.7.4 2.1.2.8.1 2.1.2.8.2 2.1.2.8.3
2.1.2.8.4 2.1.3.1.1 2.1.3.1.2 2.1.3.1.3 2.1.3.1.4 2.1.3.2.1
2.1.3.2.2 2.1.3.2.3 2.1.3.2.4 2.1.3.3.1 2.1.3.3.2 2.1.3.3.3
2.1.3.3.4 2.1.3.4.1 2.1.3.4.2 2.1.3.4.3 2.1.3.4.4 2.1.3.5.1
2.1.3.5.2 2.1.3.5.3 2.1.3.5.4 2.1.3.6.1 2.1.3.6.2 2.1.3.6.3
2.1.3.6.4 2.1.3.7.1 2.1.3.7.2 2.1.3.7.3 2.1.3.7.4 2.1.3.8.1
2.1.3.8.2 2.1.3.8.3 2.1.3.8.4 2.1.4.1.1 2.1.4.1.2 2.1.4.1.3
2.1.4.1.4 2.1.4.2.1 2.1.4.2.2 2.1.4.2.3 2.1.4.2.4 2.1.4.3.1
2.1.4.3.2 2.1.4.3.3 2.1.4.3.4 2.1.4.4.1 2.1.4.4.2 2.1.4.4.3
2.1.4.4.4 2.1.4.5.1 2.1.4.5.2 2.1.4.5.3 2.1.4.5.4 2.1.4.6.1
2.1.4.6.2 2.1.4.6.3 2.1.4.6.4 2.1.4.7.1 2.1.4.7.2 2.1.4.7.3
2.1.4.7.4 2.1.4.8.1 2.1.4.8.2 2.1.4.8.3 2.1.4.8.4 2.2.1.1.1
2.2.1.1.2 2.2.1.1.3 2.2.1.1.4 2.2.1.2.1 2.2.1.2.2 2.2.1.2.3
2.2.1.2.4 2.2.1.3.1 2.2.1.3.2 2.2.1.3.3 2.2.1.3.4 2.2.1.4.1
2.2.1.4.2 2.2.1.4.3 2.2.1.4.4 2.2.1.5.1 2.2.1.5.2 2.2.1.5.3
2.2.1.5.4 2.2.1.6.1 2.2.1.6.2 2.2.1.6.3 2.2.1.6.4 2.2.1.7.1
2.2.1.7.2 2.2.1.7.3 2.2.1.7.4 2.2.1.8.1 2.2.1.8.2 2.2.1.8.3
2.2.1.8.4 2.2.2.1.1 2.2.2.1.2 2.2.2.1.3 2.2.2.1.4 2.2.2.2.1
2.2.2.2.2 2.2.2.2.3 2.2.2.2.4 2.2.2.3.1 2.2.2.3.2 2.2.2.3.3
2.2.2.3.4 2.2.2.4.1 2.2.2.4.2 2.2.2.4.3 2.2.2.4.4 2.2.2.5.1
2.2.2.5.2 2.2.2.5.3 2.2.2.5.4 2.2.2.6.1 2.2.2.6.2 2.2.2.6.3
2.2.2.6.4 2.2.2.7.1 2.2.2.7.2 2.2.2.7.3 2.2.2.7.4 2.2.2.8.1
2.2.2.8.2 2.2.2.8.3 2.2.2.8.4 2.2.3.1.1 2.2.3.1.2 2.2.3.1.3
2.2.3.1.4 2.2.3.2.1 2.2.3.2.2 2.2.3.2.3 2.2.3.2.4 2.2.3.3.1
2.2.3.3.2 2.2.3.3.3 2.2.3.3.4 2.2.3.4.1 2.2.3.4.2 2.2.3.4.3
2.2.3.4.4 2.2.3.5.1 2.2.3.5.2 2.2.3.5.3 2.2.3.5.4 2.2.3.6.1
2.2.3.6.2 2.2.3.6.3 2.2.3.6.4 2.2.3.7.1 2.2.3.7.2 2.2.3.7.3
2.2.3.7.4 2.2.3.8.1 2.2.3.8.2 2.2.3.8.3 2.2.3.8.4 2.2.4.1.1
2.2.4.1.2 2.2.4.1.3 2.2.4.1.4 2.2.4.2.1 2.2.4.2.2 2.2.4.2.3
2.2.4.2.4 2.2.4.3.1 2.2.4.3.2 2.2.4.3.3 2.2.4.3.4 2.2.4.4.1
2.2.4.4.2 2.2.4.4.3 2.2.4.4.4 2.2.4.5.1 2.2.4.5.2 2.2.4.5.3
2.2.4.5.4 2.2.4.6.1 2.2.4.6.2 2.2.4.6.3 2.2.4.6.4 2.2.4.7.1
2.2.4.7.2 2.2.4.7.3 2.2.4.7.4 2.2.4.8.1 2.2.4.8.2 2.2.4.8.3
2.2.4.8.4 2.3.1.1.1 2.3.1.1.2 2.3.1.1.3 2.3.1.1.4 2.3.1.2.1
2.3.1.2.2 2.3.1.2.3 2.3.1.2.4 2.3.1.3.1 2.3.1.3.2 2.3.1.3.3
2.3.1.3.4 2.3.1.4.1 2.3.1.4.2 2.3.1.4.3 2.3.1.4.4 2.3.1.5.1
2.3.1.5.2 2.3.1.5.3 2.3.1.5.4 2.3.1.6.1 2.3.1.6.2 2.3.1.6.3
2.3.1.6.4 2.3.1.7.1 2.3.1.7.2 2.3.1.7.3 2.3.1.7.4 2.3.1.8.1
2.3.1.8.2 2.3.1.8.3 2.3.1.8.4 2.3.2.1.1 2.3.2.1.2 2.3.2.1.3
2.3.2.1.4 2.3.2.2.1 2.3.2.2.2 2.3.2.2.3 2.3.2.2.4 2.3.2.3.1
2.3.2.3.2 2.3.2.3.3 2.3.2.3.4 2.3.2.4.1 2.3.2.4.2 2.3.2.4.3
2.3.2.4.4 2.3.2.5.1 2.3.2.5.2 2.3.2.5.3 2.3.2.5.4 2.3.2.6.1
2.3.2.6.2 2.3.2.6.3 2.3.2.6.4 2.3.2.7.1 2.3.2.7.2 2.3.2.7.3
2.3.2.7.4 2.3.2.8.1 2.3.2.8.2 2.3.2.8.3 2.3.2.8.4 2.3.3.1.1
2.3.3.1.2 2.3.3.1.3 2.3.3.1.4 2.3.3.2.1 2.3.3.2.2 2.3.3.2.3
2.3.3.2.4 2.3.3.3.1 2.3.3.3.2 2.3.3.3.3 2.3.3.3.4 2.3.3.4.1
2.3.3.4.2 2.3.3.4.3 2.3.3.4.4 2.3.3.5.1 2.3.3.5.2 2.3.3.5.3
2.3.3.5.4 2.3.3.6.1 2.3.3.6.2 2.3.3.6.3 2.3.3.6.4 2.3.3.7.1
2.3.3.7.2 2.3.3.7.3 2.3.3.7.4 2.3.3.8.1 2.3.3.8.2 2.3.3.8.3
2.3.3.8.4 2.3.4.1.1 2.3.4.1.2 2.3.4.1.3 2.3.4.1.4 2.3.4.2.1
2.3.4.2.2 2.3.4.2.3 2.3.4.2.4 2.3.4.3.1 2.3.4.3.2 2.3.4.3.3
2.3.4.3.4 2.3.4.4.1 2.3.4.4.2 2.3.4.4.3 2.3.4.4.4 2.3.4.5.1
2.3.4.5.2 2.3.4.5.3 2.3.4.5.4 2.3.4.6.1 2.3.4.6.2 2.3.4.6.3
2.3.4.6.4 2.3.4.7.1 2.3.4.7.2 2.3.4.7.3 2.3.4.7.4 2.3.4.8.1
2.3.4.8.2 2.3.4.8.3 2.3.4.8.4 2.4.1.1.1 2.4.1.1.2 2.4.1.1.3
2.4.1.1.4 2.4.1.2.1 2.4.1.2.2 2.4.1.2.3 2.4.1.2.4 2.4.1.3.1
2.4.1.3.2 2.4.1.3.3 2.4.1.3.4 2.4.1.4.1 2.4.1.4.2 2.4.1.4.3
2.4.1.4.4 2.4.1.5.1 2.4.1.5.2 2.4.1.5.3 2.4.1.5.4 2.4.1.6.1
2.4.1.6.2 2.4.1.6.3 2.4.1.6.4 2.4.1.7.1 2.4.1.7.2 2.4.1.7.3
2.4.1.7.4 2.4.1.8.1 2.4.1.8.2 2.4.1.8.3 2.4.1.8.4 2.4.2.1.1
2.4.2.1.2 2.4.2.1.3 2.4.2.1.4 2.4.2.2.1 2.4.2.2.2 2.4.2.2.3
2.4.2.2.4 2.4.2.3.1 2.4.2.3.2 2.4.2.3.3 2.4.2.3.4 2.4.2.4.1
2.4.2.4.2 2.4.2.4.3 2.4.2.4.4 2.4.2.5.1 2.4.2.5.2 2.4.2.5.3
2.4.2.5.4 2.4.2.6.1 2.4.2.6.2 2.4.2.6.3 2.4.2.6.4 2.4.2.7.1
2.4.2.7.2 2.4.2.7.3 2.4.2.7.4 2.4.2.8.1 2.4.2.8.2 2.4.2.8.3
2.4.2.8.4 2.4.3.1.1 2.4.3.1.2 2.4.3.1.3 2.4.3.1.4 2.4.3.2.1
2.4.3.2.2 2.4.3.2.3 2.4.3.2.4 2.4.3.3.1 2.4.3.3.2 2.4.3.3.3
2.4.3.3.4 2.4.3.4.1 2.4.3.4.2 2.4.3.4.3 2.4.3.4.4 2.4.3.5.1
2.4.3.5.2 2.4.3.5.3 2.4.3.5.4 2.4.3.6.1 2.4.3.6.2 2.4.3.6.3
2.4.3.6.4 2.4.3.7.1 2.4.3.7.2 2.4.3.7.3 2.4.3.7.4 2.4.3.8.1
2.4.3.8.2 2.4.3.8.3 2.4.3.8.4 2.4.4.1.1 2.4.4.1.2 2.4.4.1.3
2.4.4.1.4 2.4.4.2.1 2.4.4.2.2 2.4.4.2.3 2.4.4.2.4 2.4.4.3.1
2.4.4.3.2 2.4.4.3.3 2.4.4.3.4 2.4.4.4.1 2.4.4.4.2 2.4.4.4.3
2.4.4.4.4 2.4.4.5.1 2.4.4.5.2 2.4.4.5.3 2.4.4.5.4 2.4.4.6.1
2.4.4.6.2 2.4.4.6.3 2.4.4.6.4 2.4.4.7.1 2.4.4.7.2 2.4.4.7.3
2.4.4.7.4 2.4.4.8.1 2.4.4.8.2 2.4.4.8.3 2.4.4.8.4 2.5.1.1.1
2.5.1.1.2 2.5.1.1.3 2.5.1.1.4 2.5.1.2.1 2.5.1.2.2 2.5.1.2.3
2.5.1.2.4 2.5.1.3.1 2.5.1.3.2 2.5.1.3.3 2.5.1.3.4 2.5.1.4.1
2.5.1.4.2 2.5.1.4.3 2.5.1.4.4 2.5.1.5.1 2.5.1.5.2 2.5.1.5.3
2.5.1.5.4 2.5.1.6.1 2.5.1.6.2 2.5.1.6.3 2.5.1.6.4 2.5.1.7.1
2.5.1.7.2 2.5.1.7.3 2.5.1.7.4 2.5.1.8.1 2.5.1.8.2 2.5.1.8.3
2.5.1.8.4 2.5.2.1.1 2.5.2.1.2 2.5.2.1.3 2.5.2.1.4 2.5.2.2.1
2.5.2.2.2 2.5.2.2.3 2.5.2.2.4 2.5.2.3.1 2.5.2.3.2 2.5.2.3.3
2.5.2.3.4 2.5.2.4.1 2.5.2.4.2 2.5.2.4.3 2.5.2.4.4 2.5.2.5.1
2.5.2.5.2 2.5.2.5.3 2.5.2.5.4 2.5.2.6.1 2.5.2.6.2 2.5.2.6.3
2.5.2.6.4 2.5.2.7.1 2.5.2.7.2 2.5.2.7.3 2.5.2.7.4 2.5.2.8.1
2.5.2.8.2 2.5.2.8.3 2.5.2.8.4 2.5.3.1.1 2.5.3.1.2 2.5.3.1.3
2.5.3.1.4 2.5.3.2.1 2.5.3.2.2 2.5.3.2.3 2.5.3.2.4 2.5.3.3.1
2.5.3.3.2 2.5.3.3.3 2.5.3.3.4 2.5.3.4.1 2.5.3.4.2 2.5.3.4.3
2.5.3.4.4 2.5.3.5.1 2.5.3.5.2 2.5.3.5.3 2.5.3.5.4 2.5.3.6.1
2.5.3.6.2 2.5.3.6.3 2.5.3.6.4 2.5.3.7.1 2.5.3.7.2 2.5.3.7.3
2.5.3.7.4 2.5.3.8.1 2.5.3.8.2 2.5.3.8.3 2.5.3.8.4 2.5.4.1.1
2.5.4.1.2 2.5.4.1.3 2.5.4.1.4 2.5.4.2.1 2.5.4.2.2 2.5.4.2.3
2.5.4.2.4 2.5.4.3.1 2.5.4.3.2 2.5.4.3.3 2.5.4.3.4 2.5.4.4.1
2.5.4.4.2 2.5.4.4.3 2.5.4.4.4 2.5.4.5.1 2.5.4.5.2 2.5.4.5.3
2.5.4.5.4 2.5.4.6.1 2.5.4.6.2 2.5.4.6.3 2.5.4.6.4 2.5.4.7.1
2.5.4.7.2 2.5.4.7.3 2.5.4.7.4 2.5.4.8.1 2.5.4.8.2 2.5.4.8.3
2.5.4.8.4 2.6.1.1.1 2.6.1.1.2 2.6.1.1.3 2.6.1.1.4 2.6.1.2.1
2.6.1.2.2 2.6.1.2.3 2.6.1.2.4 2.6.1.3.1 2.6.1.3.2 2.6.1.3.3
2.6.1.3.4 2.6.1.4.1 2.6.1.4.2 2.6.1.4.3 2.6.1.4.4 2.6.1.5.1
2.6.1.5.2 2.6.1.5.3 2.6.1.5.4 2.6.1.6.1 2.6.1.6.2 2.6.1.6.3
2.6.1.6.4 2.6.1.7.1 2.6.1.7.2 2.6.1.7.3 2.6.1.7.4 2.6.1.8.1
2.6.1.8.2 2.6.1.8.3 2.6.1.8.4 2.6.2.1.1 2.6.2.1.2 2.6.2.1.3
2.6.2.1.4 2.6.2.2.1 2.6.2.2.2 2.6.2.2.3 2.6.2.2.4 2.6.2.3.1
2.6.2.3.2 2.6.2.3.3 2.6.2.3.4 2.6.2.4.1 2.6.2.4.2 2.6.2.4.3
2.6.2.4.4 2.6.2.5.1 2.6.2.5.2 2.6.2.5.3 2.6.2.5.4 2.6.2.6.1
2.6.2.6.2 2.6.2.6.3 2.6.2.6.4 2.6.2.7.1 2.6.2.7.2 2.6.2.7.3
2.6.2.7.4 2.6.2.8.1 2.6.2.8.2 2.6.2.8.3 2.6.2.8.4 2.6.3.1.1
2.6.3.1.2 2.6.3.1.3 2.6.3.1.4 2.6.3.2.1 2.6.3.2.2 2.6.3.2.3
2.6.3.2.4 2.6.3.3.1 2.6.3.3.2 2.6.3.3.3 2.6.3.3.4 2.6.3.4.1
2.6.3.4.2 2.6.3.4.3 2.6.3.4.4 2.6.3.5.1 2.6.3.5.2 2.6.3.5.3
2.6.3.5.4 2.6.3.6.1 2.6.3.6.2 2.6.3.6.3 2.6.3.6.4 2.6.3.7.1
2.6.3.7.2 2.6.3.7.3 2.6.3.7.4 2.6.3.8.1 2.6.3.8.2 2.6.3.8.3
2.6.3.8.4 2.6.4.1.1 2.6.4.1.2 2.6.4.1.3 2.6.4.1.4 2.6.4.2.1
2.6.4.2.2 2.6.4.2.3 2.6.4.2.4 2.6.4.3.1 2.6.4.3.2 2.6.4.3.3
2.6.4.3.4 2.6.4.4.1 2.6.4.4.2 2.6.4.4.3 2.6.4.4.4 2.6.4.5.1
2.6.4.5.2 2.6.4.5.3 2.6.4.5.4 2.6.4.6.1 2.6.4.6.2 2.6.4.6.3
2.6.4.6.4 2.6.4.7.1 2.6.4.7.2 2.6.4.7.3 2.6.4.7.4 2.6.4.8.1
2.6.4.8.2 2.6.4.8.3 2.6.4.8.4 2.7.1.1.1 2.7.1.1.2 2.7.1.1.3
2.7.1.1.4 2.7.1.2.1 2.7.1.2.2 2.7.1.2.3 2.7.1.2.4 2.7.1.3.1
2.7.1.3.2 2.7.1.3.3 2.7.1.3.4 2.7.1.4.1 2.7.1.4.2 2.7.1.4.3
2.7.1.4.4 2.7.1.5.1 2.7.1.5.2 2.7.1.5.3 2.7.1.5.4 2.7.1.6.1
2.7.1.6.2 2.7.1.6.3 2.7.1.6.4 2.7.1.7.1 2.7.1.7.2 2.7.1.7.3
2.7.1.7.4 2.7.1.8.1 2.7.1.8.2 2.7.1.8.3 2.7.1.8.4 2.7.2.1.1
2.7.2.1.2 2.7.2.1.3 2.7.2.1.4 2.7.2.2.1 2.7.2.2.2 2.7.2.2.3
2.7.2.2.4 2.7.2.3.1 2.7.2.3.2 2.7.2.3.3 2.7.2.3.4 2.7.2.4.1
2.7.2.4.2 2.7.2.4.3 2.7.2.4.4 2.7.2.5.1 2.7.2.5.2 2.7.2.5.3
2.7.2.5.4 2.7.2.6.1 2.7.2.6.2 2.7.2.6.3 2.7.2.6.4 2.7.2.7.1
2.7.2.7.2 2.7.2.7.3 2.7.2.7.4 2.7.2.8.1 2.7.2.8.2 2.7.2.8.3
2.7.2.8.4 2.7.3.1.1 2.7.3.1.2 2.7.3.1.3 2.7.3.1.4 2.7.3.2.1
2.7.3.2.2 2.7.3.2.3 2.7.3.2.4 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3
2.7.3.3.4 2.7.3.4.1 2.7.3.4.2 2.7.3.4.3 2.7.3.4.4 2.7.3.5.1
2.7.3.5.2 2.7.3.5.3 2.7.3.5.4 2.7.3.6.1 2.7.3.6.2 2.7.3.6.3
2.7.3.6.4 2.7.3.7.1 2.7.3.7.2 2.7.3.7.3 2.7.3.7.4 2.7.3.8.1
2.7.3.8.2 2.7.3.8.3 2.7.3.8.4 2.7.4.1.1 2.7.4.1.2 2.7.4.1.3
2.7.4.1.4 2.7.4.2.1 2.7.4.2.2 2.7.4.2.3 2.7.4.2.4 2.7.4.3.1
2.7.4.3.2 2.7.4.3.3 2.7.4.3.4 2.7.4.4.1 2.7.4.4.2 2.7.4.4.3
2.7.4.4.4 2.7.4.5.1 2.7.4.5.2 2.7.4.5.3 2.7.4.5.4 2.7.4.6.1
2.7.4.6.2 2.7.4.6.3 2.7.4.6.4 2.7.4.7.1 2.7.4.7.2 2.7.4.7.3
2.7.4.7.4 2.7.4.8.1 2.7.4.8.2 2.7.4.8.3 2.7.4.8.4 2.8.1.1.1
2.8.1.1.2 2.8.1.1.3 2.8.1.1.4 2.8.1.2.1 2.8.1.2.2 2.8.1.2.3
2.8.1.2.4 2.8.1.3.1 2.8.1.3.2 2.8.1.3.3 2.8.1.3.4 2.8.1.4.1
2.8.1.4.2 2.8.1.4.3 2.8.1.4.4 2.8.1.5.1 2.8.1.5.2 2.8.1.5.3
2.8.1.5.4 2.8.1.6.1 2.8.1.6.2 2.8.1.6.3 2.8.1.6.4 2.8.1.7.1
2.8.1.7.2 2.8.1.7.3 2.8.1.7.4 2.8.1.8.1 2.8.1.8.2 2.8.1.8.3
2.8.1.8.4 2.8.2.1.1 2.8.2.1.2 2.8.2.1.3 2.8.2.1.4 2.8.2.2.1
2.8.2.2.2 2.8.2.2.3 2.8.2.2.4 2.8.2.3.1 2.8.2.3.2 2.8.2.3.3
2.8.2.3.4 2.8.2.4.1 2.8.2.4.2 2.8.2.4.3 2.8.2.4.4 2.8.2.5.1
2.8.2.5.2 2.8.2.5.3 2.8.2.5.4 2.8.2.6.1 2.8.2.6.2 2.8.2.6.3
2.8.2.6.4 2.8.2.7.1 2.8.2.7.2 2.8.2.7.3 2.8.2.7.4 2.8.2.8.1
2.8.2.8.2 2.8.2.8.3 2.8.2.8.4 2.8.3.1.1 2.8.3.1.2 2.8.3.1.3
2.8.3.1.4 2.8.3.2.1 2.8.3.2.2 2.8.3.2.3 2.8.3.2.4
2.8.3.3.1 2.8.3.3.2 2.8.3.3.3 2.8.3.3.4 2.8.3.4.1 2.8.3.4.2
2.8.3.4.3 2.8.3.4.4 2.8.3.5.1 2.8.3.5.2 2.8.3.5.3 2.8.3.5.4
2.8.3.6.1 2.8.3.6.2 2.8.3.6.3 2.8.3.6.4 2.8.3.7.1 2.8.3.7.2
2.8.3.7.3 2.8.3.7.4 2.8.3.8.1 2.8.3.8.2 2.8.3.8.3 2.8.3.8.4
2.8.4.1.1 2.8.4.1.2 2.8.4.1.3 2.8.4.1.4 2.8.4.2.1 2.8.4.2.2
2.8.4.2.3 2.8.4.2.4 2.8.4.3.1 2.8.4.3.2 2.8.4.3.3 2.8.4.3.4
2.8.4.4.1 2.8.4.4.2 2.8.4.4.3 2.8.4.4.4 2.8.4.5.1 2.8.4.5.2
2.8.4.5.3 2.8.4.5.4 2.8.4.6.1 2.8.4.6.2 2.8.4.6.3 2.8.4.6.4
2.8.4.7.1 2.8.4.7.2 2.8.4.7.3 2.8.4.7.4 2.8.4.8.1 2.8.4.8.2
2.8.4.8.3 2.8.4.8.4 3.1.1.1.1 3.1.1.1.2 3.1.1.1.3 3.1.1.1.4
3.1.1.2.1 3.1.1.2.2 3.1.1.2.3 3.1.1.2.4 3.1.1.3.1 3.1.1.3.2
3.1.1.3.3 3.1.1.3.4 3.1.1.4.1 3.1.1.4.2 3.1.1.4.3 3.1.1.4.4
3.1.1.5.1 3.1.1.5.2 3.1.1.5.3 3.1.1.5.4 3.1.1.6.1 3.1.1.6.2
3.1.1.6.3 3.1.1.6.4 3.1.1.7.1 3.1.1.7.2 3.1.1.7.3 3.1.1.7.4
3.1.1.8.1 3.1.1.8.2 3.1.1.8.3 3.1.1.8.4 3.1.2.1.1 3.1.2.1.2
3.1.2.1.3 3.1.2.1.4 3.1.2.2.1 3.1.2.2.2 3.1.2.2.3 3.1.2.2.4
3.1.2.3.1 3.1.2.3.2 3.1.2.3.3 3.1.2.3.4 3.1.2.4.1 3.1.2.4.2
3.1.2.4.3 3.1.2.4.4 3.1.2.5.1 3.1.2.5.2 3.1.2.5.3 3.1.2.5.4
3.1.2.6.1 3.1.2.6.2 3.1.2.6.3 3.1.2.6.4 3.1.2.7.1 3.1.2.7.2
3.1.2.7.3 3.1.2.7.4 3.1.2.8.1 3.1.2.8.2 3.1.2.8.3 3.1.2.8.4
3.1.3.1.1 3.1.3.1.2 3.1.3.1.3 3.1.3.1.4 3.1.3.2.1 3.1.3.2.2
3.1.3.2.3 3.1.3.2.4 3.1.3.3.1 3.1.3.3.2 3.1.3.3.3 3.1.3.3.4
3.1.3.4.1 3.1.3.4.2 3.1.3.4.3 3.1.3.4.4 3.1.3.5.1 3.1.3.5.2
3.1.3.5.3 3.1.3.5.4 3.1.3.6.1 3.1.3.6.2 3.1.3.6.3 3.1.3.6.4
3.1.3.7.1 3.1.3.7.2 3.1.3.7.3 3.1.3.7.4 3.1.3.8.1 3.1.3.8.2
3.1.3.8.3 3.1.3.8.4 3.1.4.1.1 3.1.4.1.2 3.1.4.1.3 3.1.4.1.4
3.1.4.2.1 3.1.4.2.2 3.1.4.2.3 3.1.4.2.4 3.1.4.3.1 3.1.4.3.2
3.1.4.3.3 3.1.4.3.4 3.1.4.4.1 3.1.4.4.2 3.1.4.4.3 3.1.4.4.4
3.1.4.5.1 3.1.4.5.2 3.1.4.5.3 3.1.4.5.4 3.1.4.6.1 3.1.4.6.2
3.1.4.6.3 3.1.4.6.4 3.1.4.7.1 3.1.4.7.2 3.1.4.7.3 3.1.4.7.4
3.1.4.8.1 3.1.4.8.2 3.1.4.8.3 3.1.4.8.4 3.2.1.1.1 3.2.1.1.2
3.2.1.1.3 3.2.1.1.4 3.2.1.2.1 3.2.1.2.2 3.2.1.2.3 3.2.1.2.4
3.2.1.3.1 3.2.1.3.2 3.2.1.3.3 3.2.1.3.4 3.2.1.4.1 3.2.1.4.2
3.2.1.4.3 3.2.1.4.4 3.2.1.5.1 3.2.1.5.2 3.2.1.5.3 3.2.1.5.4
3.2.1.6.1 3.2.1.6.2 3.2.1.6.3 3.2.1.6.4 3.2.1.7.1 3.2.1.7.2
3.2.1.7.3 3.2.1.7.4 3.2.1.8.1 3.2.1.8.2 3.2.1.8.3 3.2.1.8.4
3.2.2.1.1 3.2.2.1.2 3.2.2.1.3 3.2.2.1.4 3.2.2.2.1 3.2.2.2.2
3.2.2.2.3 3.2.2.2.4 3.2.2.3.1 3.2.2.3.2 3.2.2.3.3 3.2.2.3.4
3.2.2.4.1 3.2.2.4.2 3.2.2.4.3 3.2.2.4.4 3.2.2.5.1 3.2.2.5.2
3.2.2.5.3 3.2.2.5.4 3.2.2.6.1 3.2.2.6.2 3.2.2.6.3 3.2.2.6.4
3.2.2.7.1 3.2.2.7.2 3.2.2.7.3 3.2.2.7.4 3.2.2.8.1 3.2.2.8.2
3.2.2.8.3 3.2.2.8.4 3.2.3.1.1 3.2.3.1.2 3.2.3.1.3 3.2.3.1.4
3.2.3.2.1 3.2.3.2.2 3.2.3.2.3 3.2.3.2.4 3.2.3.3.1 3.2.3.3.2
3.2.3.3.3 3.2.3.3.4 3.2.3.4.1 3.2.3.4.2 3.2.3.4.3 3.2.3.4.4
3.2.3.5.1 3.2.3.5.2 3.2.3.5.3 3.2.3.5.4 3.2.3.6.1 3.2.3.6.2
3.2.3.6.3 3.2.3.6.4 3.2.3.7.1 3.2.3.7.2 3.2.3.7.3 3.2.3.7.4
3.2.3.8.1 3.2.3.8.2 3.2.3.8.3 3.2.3.8.4 3.2.4.1.1 3.2.4.1.2
3.2.4.1.3 3.2.4.1.4 3.2.4.2.1 3.2.4.2.2 3.2.4.2.3 3.2.4.2.4
3.2.4.3.1 3.2.4.3.2 3.2.4.3.3 3.2.4.3.4 3.2.4.4.1 3.2.4.4.2
3.2.4.4.3 3.2.4.4.4 3.2.4.5.1 3.2.4.5.2 3.2.4.5.3 3.2.4.5.4
3.2.4.6.1 3.2.4.6.2 3.2.4.6.3 3.2.4.6.4 3.2.4.7.1 3.2.4.7.2
3.2.4.7.3 3.2.4.7.4 3.2.4.8.1 3.2.4.8.2 3.2.4.8.3 3.2.4.8.4
3.3.1.1.1 3.3.1.1.2 3.3.1.1.3 3.3.1.1.4 3.3.1.2.1 3.3.1.2.2
3.3.1.2.3 3.3.1.2.4 3.3.1.3.1 3.3.1.3.2 3.3.1.3.3 3.3.1.3.4
3.3.1.4.1 3.3.1.4.2 3.3.1.4.3 3.3.1.4.4 3.3.1.5.1 3.3.1.5.2
3.3.1.5.3 3.3.1.5.4 3.3.1.6.1 3.3.1.6.2 3.3.1.6.3 3.3.1.6.4
3.3.1.7.1 3.3.1.7.2 3.3.1.7.3 3.3.1.7.4 3.3.1.8.1 3.3.1.8.2
3.3.1.8.3 3.3.1.8.4 3.3.2.1.1 3.3.2.1.2 3.3.2.1.3 3.3.2.1.4
3.3.2.2.1 3.3.2.2.2 3.3.2.2.3 3.3.2.2.4 3.3.2.3.1 3.3.2.3.2
3.3.2.3.3 3.3.2.3.4 3.3.2.4.1 3.3.2.4.2 3.3.2.4.3 3.3.2.4.4
3.3.2.5.1 3.3.2.5.2 3.3.2.5.3 3.3.2.5.4 3.3.2.6.1 3.3.2.6.2
3.3.2.6.3 3.3.2.6.4 3.3.2.7.1 3.3.2.7.2 3.3.2.7.3 3.3.2.7.4
3.3.2.8.1 3.3.2.8.2 3.3.2.8.3 3.3.2.8.4 3.3.3.1.1 3.3.3.1.2
3.3.3.1.3 3.3.3.1.4 3.3.3.2.1 3.3.3.2.2 3.3.3.2.3 3.3.3.2.4
3.3.3.3.1 3.3.3.3.2 3.3.3.3.3 3.3.3.3.4 3.3.3.4.1 3.3.3.4.2
3.3.3.4.3 3.3.3.4.4 3.3.3.5.1 3.3.3.5.2 3.3.3.5.3 3.3.3.5.4
3.3.3.6.1 3.3.3.6.2 3.3.3.6.3 3.3.3.6.4 3.3.3.7.1 3.3.3.7.2
3.3.3.7.3 3.3.3.7.4 3.3.3.8.1 3.3.3.8.2 3.3.3.8.3 3.3.3.8.4
3.3.4.1.1 3.3.4.1.2 3.3.4.1.3 3.3.4.1.4 3.3.4.2.1 3.3.4.2.2
3.3.4.2.3 3.3.4.2.4 3.3.4.3.1 3.3.4.3.2 3.3.4.3.3 3.3.4.3.4
3.3.4.4.1 3.3.4.4.2 3.3.4.4.3 3.3.4.4.4 3.3.4.5.1 3.3.4.5.2
3.3.4.5.3 3.3.4.5.4 3.3.4.6.1 3.3.4.6.2 3.3.4.6.3 3.3.4.6.4
3.3.4.7.1 3.3.4.7.2 3.3.4.7.3 3.3.4.7.4 3.3.4.8.1 3.3.4.8.2
3.3.4.8.3 3.3.4.8.4 3.4.1.1.1 3.4.1.1.2 3.4.1.1.3 3.4.1.1.4
3.4.1.2.1 3.4.1.2.2 3.4.1.2.3 3.4.1.2.4 3.4.1.3.1 3.4.1.3.2
3.4.1.3.3 3.4.1.3.4 3.4.1.4.1 3.4.1.4.2 3.4.1.4.3 3.4.1.4.4
3.4.1.5.1 3.4.1.5.2 3.4.1.5.3 3.4.1.5.4 3.4.1.6.1 3.4.1.6.2
3.4.1.6.3 3.4.1.6.4 3.4.1.7.1 3.4.1.7.2 3.4.1.7.3 3.4.1.7.4
3.4.1.8.1 3.4.1.8.2 3.4.1.8.3 3.4.1.8.4 3.4.2.1.1 3.4.2.1.2
3.4.2.1.3 3.4.2.1.4 3.4.2.2.1 3.4.2.2.2 3.4.2.2.3 3.4.2.2.4
3.4.2.3.1 3.4.2.3.2 3.4.2.3.3 3.4.2.3.4 3.4.2.4.1 3.4.2.4.2
3.4.2.4.3 3.4.2.4.4 3.4.2.5.1 3.4.2.5.2 3.4.2.5.3 3.4.2.5.4
3.4.2.6.1 3.4.2.6.2 3.4.2.6.3 3.4.2.6.4 3.4.2.7.1 3.4.2.7.2
3.4.2.7.3 3.4.2.7.4 3.4.2.8.1 3.4.2.8.2 3.4.2.8.3 3.4.2.8.4
3.4.3.1.1 3.4.3.1.2 3.4.3.1.3 3.4.3.1.4 3.4.3.2.1 3.4.3.2.2
3.4.3.2.3 3.4.3.2.4 3.4.3.3.1 3.4.3.3.2 3.4.3.3.3 3.4.3.3.4
3.4.3.4.1 3.4.3.4.2 3.4.3.4.3 3.4.3.4.4 3.4.3.5.1 3.4.3.5.2
3.4.3.5.3 3.4.3.5.4 3.4.3.6.1 3.4.3.6.2 3.4.3.6.3 3.4.3.6.4
3.4.3.7.1 3.4.3.7.2 3.4.3.7.3 3.4.3.7.4 3.4.3.8.1 3.4.3.8.2
3.4.3.8.3 3.4.3.8.4 3.4.4.1.1 3.4.4.1.2 3.4.4.1.3 3.4.4.1.4
3.4.4.2.1 3.4.4.2.2 3.4.4.2.3 3.4.4.2.4 3.4.4.3.1 3.4.4.3.2
3.4.4.3.3 3.4.4.3.4 3.4.4.4.1 3.4.4.4.2 3.4.4.4.3 3.4.4.4.4
3.4.4.5.1 3.4.4.5.2 3.4.4.5.3 3.4.4.5.4 3.4.4.6.1 3.4.4.6.2
3.4.4.6.3 3.4.4.6.4 3.4.4.7.1 3.4.4.7.2 3.4.4.7.3 3.4.4.7.4
3.4.4.8.1 3.4.4.8.2 3.4.4.8.3 3.4.4.8.4 3.5.1.1.1 3.5.1.1.2
3.5.1.1.3 3.5.1.1.4 3.5.1.2.1 3.5.1.2.2 3.5.1.2.3 3.5.1.2.4
3.5.1.3.1 3.5.1.3.2 3.5.1.3.3 3.5.1.3.4 3.5.1.4.1 3.5.1.4.2
3.5.1.4.3 3.5.1.4.4 3.5.1.5.1 3.5.1.5.2 3.5.1.5.3 3.5.1.5.4
3.5.1.6.1 3.5.1.6.2 3.5.1.6.3 3.5.1.6.4 3.5.1.7.1 3.5.1.7.2
3.5.1.7.3 3.5.1.7.4 3.5.1.8.1 3.5.1.8.2 3.5.1.8.3 3.5.1.8.4
3.5.2.1.1 3.5.2.1.2 3.5.2.1.3 3.5.2.1.4 3.5.2.2.1 3.5.2.2.2
3.5.2.2.3 3.5.2.2.4 3.5.2.3.1 3.5.2.3.2 3.5.2.3.3 3.5.2.3.4
3.5.2.4.1 3.5.2.4.2 3.5.2.4.3 3.5.2.4.4 3.5.2.5.1 3.5.2.5.2
3.5.2.5.3 3.5.2.5.4 3.5.2.6.1 3.5.2.6.2 3.5.2.6.3 3.5.2.6.4
3.5.2.7.1 3.5.2.7.2 3.5.2.7.3 3.5.2.7.4 3.5.2.8.1 3.5.2.8.2
3.5.2.8.3 3.5.2.8.4 3.5.3.1.1 3.5.3.1.2 3.5.3.1.3 3.5.3.1.4
3.5.3.2.1 3.5.3.2.2 3.5.3.2.3 3.5.3.2.4 3.5.3.3.1 3.5.3.3.2
3.5.3.3.3 3.5.3.3.4 3.5.3.4.1 3.5.3.4.2 3.5.3.4.3 3.5.3.4.4
3.5.3.5.1 3.5.3.5.2 3.5.3.5.3 3.5.3.5.4 3.5.3.6.1 3.5.3.6.2
3.5.3.6.3 3.5.3.6.4 3.5.3.7.1 3.5.3.7.2 3.5.3.7.3 3.5.3.7.4
3.5.3.8.1 3.5.3.8.2 3.5.3.8.3 3.5.3.8.4 3.5.4.1.1 3.5.4.1.2
3.5.4.1.3 3.5.4.1.4 3.5.4.2.1 3.5.4.2.2 3.5.4.2.3 3.5.4.2.4
3.5.4.3.1 3.5.4.3.2 3.5.4.3.3 3.5.4.3.4 3.5.4.4.1 3.5.4.4.2
3.5.4.4.3 3.5.4.4.4 3.5.4.5.1 3.5.4.5.2 3.5.4.5.3 3.5.4.5.4
3.5.4.6.1 3.5.4.6.2 3.5.4.6.3 3.5.4.6.4 3.5.4.7.1 3.5.4.7.2
3.5.4.7.3 3.5.4.7.4 3.5.4.8.1 3.5.4.8.2 3.5.4.8.3 3.5.4.8.4
3.6.1.1.1 3.6.1.1.2 3.6.1.1.3 3.6.1.1.4 3.6.1.2.1 3.6.1.2.2
3.6.1.2.3 3.6.1.2.4 3.6.1.3.1 3.6.1.3.2 3.6.1.3.3 3.6.1.3.4
3.6.1.4.1 3.6.1.4.2 3.6.1.4.3 3.6.1.4.4 3.6.1.5.1 3.6.1.5.2
3.6.1.5.3 3.6.1.5.4 3.6.1.6.1 3.6.1.6.2 3.6.1.6.3 3.6.1.6.4
3.6.1.7.1 3.6.1.7.2 3.6.1.7.3 3.6.1.7.4 3.6.1.8.1 3.6.1.8.2
3.6.1.8.3 3.6.1.8.4 3.6.2.1.1 3.6.2.1.2 3.6.2.1.3 3.6.2.1.4
3.6.2.2.1 3.6.2.2.2 3.6.2.2.3 3.6.2.2.4 3.6.2.3.1 3.6.2.3.2
3.6.2.3.3 3.6.2.3.4 3.6.2.4.1 3.6.2.4.2 3.6.2.4.3 3.6.2.4.4
3.6.2.5.1 3.6.2.5.2 3.6.2.5.3 3.6.2.5.4 3.6.2.6.1 3.6.2.6.2
3.6.2.6.3 3.6.2.6.4 3.6.2.7.1 3.6.2.7.2 3.6.2.7.3 3.6.2.7.4
3.6.2.8.1 3.6.2.8.2 3.6.2.8.3 3.6.2.8.4 3.6.3.1.1 3.6.3.1.2
3.6.3.1.3 3.6.3.1.4 3.6.3.2.1 3.6.3.2.2 3.6.3.2.3 3.6.3.2.4
3.6.3.3.1 3.6.3.3.2 3.6.3.3.3 3.6.3.3.4 3.6.3.4.1 3.6.3.4.2
3.6.3.4.3 3.6.3.4.4 3.6.3.5.1 3.6.3.5.2 3.6.3.5.3 3.6.3.5.4
3.6.3.6.1 3.6.3.6.2 3.6.3.6.3 3.6.3.6.4 3.6.3.7.1 3.6.3.7.2
3.6.3.7.3 3.6.3.7.4 3.6.3.8.1 3.6.3.8.2 3.6.3.8.3 3.6.3.8.4
3.6.4.1.1 3.6.4.1.2 3.6.4.1.3 3.6.4.1.4 3.6.4.2.1 3.6.4.2.2
3.6.4.2.3 3.6.4.2.4 3.6.4.3.1 3.6.4.3.2 3.6.4.3.3 3.6.4.3.4
3.6.4.4.1 3.6.4.4.2 3.6.4.4.3 3.6.4.4.4 3.6.4.5.1 3.6.4.5.2
3.6.4.5.3 3.6.4.5.4 3.6.4.6.1 3.6.4.6.2 3.6.4.6.3 3.6.4.6.4
3.6.4.7.1 3.6.4.7.2 3.6.4.7.3 3.6.4.7.4 3.6.4.8.1 3.6.4.8.2
3.6.4.8.3 3.6.4.8.4 3.7.1.1.1 3.7.1.1.2 3.7.1.1.3 3.7.1.1.4
3.7.1.2.1 3.7.1.2.2 3.7.1.2.3 3.7.1.2.4 3.7.1.3.1 3.7.1.3.2
3.7.1.3.3 3.7.1.3.4 3.7.1.4.1 3.7.1.4.2 3.7.1.4.3 3.7.1.4.4
3.7.1.5.1 3.7.1.5.2 3.7.1.5.3 3.7.1.5.4 3.7.1.6.1 3.7.1.6.2
3.7.1.6.3 3.7.1.6.4 3.7.1.7.1 3.7.1.7.2 3.7.1.7.3 3.7.1.7.4
3.7.1.8.1 3.7.1.8.2 3.7.1.8.3 3.7.1.8.4 3.7.2.1.1 3.7.2.1.2
3.7.2.1.3 3.7.2.1.4 3.7.2.2.1 3.7.2.2.2 3.7.2.2.3 3.7.2.2.4
3.7.2.3.1 3.7.2.3.2 3.7.2.3.3 3.7.2.3.4 3.7.2.4.1 3.7.2.4.2
3.7.2.4.3 3.7.2.4.4 3.7.2.5.1 3.7.2.5.2 3.7.2.5.3 3.7.2.5.4
3.7.2.6.1 3.7.2.6.2 3.7.2.6.3 3.7.2.6.4 3.7.2.7.1 3.7.2.7.2
3.7.2.7.3 3.7.2.7.4 3.7.2.8.1 3.7.2.8.2 3.7.2.8.3 3.7.2.8.4
3.7.3.1.1 3.7.3.1.2 3.7.3.1.3 3.7.3.1.4 3.7.3.2.1 3.7.3.2.2
3.7.3.2.3 3.7.3.2.4 3.7.3.3.1 3.7.3.3.2 3.7.3.3.3 3.7.3.3.4
3.7.3.4.1 3.7.3.4.2 3.7.3.4.3 3.7.3.4.4 3.7.3.5.1 3.7.3.5.2
3.7.3.5.3 3.7.3.5.4 3.7.3.6.1 3.7.3.6.2 3.7.3.6.3 3.7.3.6.4
3.7.3.7.1 3.7.3.7.2 3.7.3.7.3 3.7.3.7.4 3.7.3.8.1 3.7.3.8.2
3.7.3.8.3 3.7.3.8.4 3.7.4.1.1 3.7.4.1.2 3.7.4.1.3 3.7.4.1.4
3.7.4.2.1 3.7.4.2.2 3.7.4.2.3 3.7.4.2.4 3.7.4.3.1 3.7.4.3.2
3.7.4.3.3 3.7.4.3.4 3.7.4.4.1 3.7.4.4.2 3.7.4.4.3 3.7.4.4.4
3.7.4.5.1 3.7.4.5.2 3.7.4.5.3 3.7.4.5.4 3.7.4.6.1 3.7.4.6.2
3.7.4.6.3 3.7.4.6.4 3.7.4.7.1 3.7.4.7.2 3.7.4.7.3 3.7.4.7.4
3.7.4.8.1 3.7.4.8.2 3.7.4.8.3 3.7.4.8.4 3.8.1.1.1 3.8.1.1.2
3.8.1.1.3 3.8.1.1.4 3.8.1.2.1 3.8.1.2.2 3.8.1.2.3 3.8.1.2.4
3.8.1.3.1 3.8.1.3.2 3.8.1.3.3 3.8.1.3.4 3.8.1.4.1 3.8.1.4.2
3.8.1.4.3 3.8.1.4.4 3.8.1.5.1 3.8.1.5.2 3.8.1.5.3 3.8.1.5.4
3.8.1.6.1 3.8.1.6.2 3.8.1.6.3 3.8.1.6.4 3.8.1.7.1 3.8.1.7.2
3.8.1.7.3 3.8.1.7.4 3.8.1.8.1 3.8.1.8.2 3.8.1.8.3 3.8.1.8.4
3.8.2.1.1 3.8.2.1.2 3.8.2.1.3 3.8.2.1.4 3.8.2.2.1 3.8.2.2.2
3.8.2.2.3 3.8.2.2.4 3.8.2.3.1 3.8.2.3.2 3.8.2.3.3 3.8.2.3.4
3.8.2.4.1 3.8.2.4.2 3.8.2.4.3 3.8.2.4.4 3.8.2.5.1 3.8.2.5.2
3.8.2.5.3 3.8.2.5.4 3.8.2.6.1 3.8.2.6.2 3.8.2.6.3
3.8.2.6.4 3.8.2.7.1 3.8.2.7.2 3.8.2.7.3 3.8.2.7.4 3.8.2.8.1
3.8.2.8.2 3.8.2.8.3 3.8.2.8.4 3.8.3.1.1 3.8.3.1.2 3.8.3.1.3
3.8.3.1.4 3.8.3.2.1 3.8.3.2.2 3.8.3.2.3 3.8.3.2.4 3.8.3.3.1
3.8.3.3.2 3.8.3.3.3 3.8.3.3.4 3.8.3.4.1 3.8.3.4.2 3.8.3.4.3
3.8.3.4.4 3.8.3.5.1 3.8.3.5.2 3.8.3.5.3 3.8.3.5.4 3.8.3.6.1
3.8.3.6.2 3.8.3.6.3 3.8.3.6.4 3.8.3.7.1 3.8.3.7.2 3.8.3.7.3
3.8.3.7.4 3.8.3.8.1 3.8.3.8.2 3.8.3.8.3 3.8.3.8.4 3.8.4.1.1
3.8.4.1.2 3.8.4.1.3 3.8.4.1.4 3.8.4.2.1 3.8.4.2.2 3.8.4.2.3
3.8.4.2.4 3.8.4.3.1 3.8.4.3.2 3.8.4.3.3 3.8.4.3.4 3.8.4.4.1
3.8.4.4.2 3.8.4.4.3 3.8.4.4.4 3.8.4.5.1 3.8.4.5.2 3.8.4.5.3
3.8.4.5.4 3.8.4.6.1 3.8.4.6.2 3.8.4.6.3 3.8.4.6.4 3.8.4.7.1
3.8.4.7.2 3.8.4.7.3 3.8.4.7.4 3.8.4.8.1 3.8.4.8.2 3.8.4.8.3
3.8.4.8.4 4.1.1.1.1 4.1.1.1.2 4.1.1.1.3 4.1.1.1.4 4.1.1.2.1
4.1.1.2.2 4.1.1.2.3 4.1.1.2.4 4.1.1.3.1 4.1.1.3.2 4.1.1.3.3
4.1.1.3.4 4.1.1.4.1 4.1.1.4.2 4.1.1.4.3 4.1.1.4.4 4.1.1.5.1
4.1.1.5.2 4.1.1.5.3 4.1.1.5.4 4.1.1.6.1 4.1.1.6.2 4.1.1.6.3
4.1.1.6.4 4.1.1.7.1 4.1.1.7.2 4.1.1.7.3 4.1.1.7.4 4.1.1.8.1
4.1.1.8.2 4.1.1.8.3 4.1.1.8.4 4.1.2.1.1 4.1.2.1.2 4.1.2.1.3
4.1.2.1.4 4.1.2.2.1 4.1.2.2.2 4.1.2.2.3 4.1.2.2.4 4.1.2.3.1
4.1.2.3.2 4.1.2.3.3 4.1.2.3.4 4.1.2.4.1 4.1.2.4.2 4.1.2.4.3
4.1.2.4.4 4.1.2.5.1 4.1.2.5.2 4.1.2.5.3 4.1.2.5.4 4.1.2.6.1
4.1.2.6.2 4.1.2.6.3 4.1.2.6.4 4.1.2.7.1 4.1.2.7.2 4.1.2.7.3
4.1.2.7.4 4.1.2.8.1 4.1.2.8.2 4.1.2.8.3 4.1.2.8.4 4.1.3.1.1
4.1.3.1.2 4.1.3.1.3 4.1.3.1.4 4.1.3.2.1 4.1.3.2.2 4.1.3.2.3
4.1.3.2.4 4.1.3.3.1 4.1.3.3.2 4.1.3.3.3 4.1.3.3.4 4.1.3.4.1
4.1.3.4.2 4.1.3.4.3 4.1.3.4.4 4.1.3.5.1 4.1.3.5.2 4.1.3.5.3
4.1.3.5.4 4.1.3.6.1 4.1.3.6.2 4.1.3.6.3 4.1.3.6.4 4.1.3.7.1
4.1.3.7.2 4.1.3.7.3 4.1.3.7.4 4.1.3.8.1 4.1.3.8.2 4.1.3.8.3
4.1.3.8.4 4.1.4.1.1 4.1.4.1.2 4.1.4.1.3 4.1.4.1.4 4.1.4.2.1
4.1.4.2.2 4.1.4.2.3 4.1.4.2.4 4.1.4.3.1 4.1.4.3.2 4.1.4.3.3
4.1.4.3.4 4.1.4.4.1 4.1.4.4.2 4.1.4.4.3 4.1.4.4.4 4.1.4.5.1
4.1.4.5.2 4.1.4.5.3 4.1.4.5.4 4.1.4.6.1 4.1.4.6.2 4.1.4.6.3
4.1.4.6.4 4.1.4.7.1 4.1.4.7.2 4.1.4.7.3 4.1.4.7.4 4.1.4.8.1
4.1.4.8.2 4.1.4.8.3 4.1.4.8.4 4.2.1.1.1 4.2.1.1.2 4.2.1.1.3
4.2.1.1.4 4.2.1.2.1 4.2.1.2.2 4.2.1.2.3 4.2.1.2.4 4.2.1.3.1
4.2.1.3.2 4.2.1.3.3 4.2.1.3.4 4.2.1.4.1 4.2.1.4.2 4.2.1.4.3
4.2.1.4.4 4.2.1.5.1 4.2.1.5.2 4.2.1.5.3 4.2.1.5.4 4.2.1.6.1
4.2.1.6.2 4.2.1.6.3 4.2.1.6.4 4.2.1.7.1 4.2.1.7.2 4.2.1.7.3
4.2.1.7.4 4.2.1.8.1 4.2.1.8.2 4.2.1.8.3 4.2.1.8.4 4.2.2.1.1
4.2.2.1.2 4.2.2.1.3 4.2.2.1.4 4.2.2.2.1 4.2.2.2.2 4.2.2.2.3
4.2.2.2.4 4.2.2.3.1 4.2.2.3.2 4.2.2.3.3 4.2.2.3.4 4.2.2.4.1
4.2.2.4.2 4.2.2.4.3 4.2.2.4.4 4.2.2.5.1 4.2.2.5.2 4.2.2.5.3
4.2.2.5.4 4.2.2.6.1 4.2.2.6.2 4.2.2.6.3 4.2.2.6.4 4.2.2.7.1
4.2.2.7.2 4.2.2.7.3 4.2.2.7.4 4.2.2.8.1 4.2.2.8.2 4.2.2.8.3
4.2.2.8.4 4.2.3.1.1 4.2.3.1.2 4.2.3.1.3 4.2.3.1.4 4.2.3.2.1
4.2.3.2.2 4.2.3.2.3 4.2.3.2.4 4.2.3.3.1 4.2.3.3.2 4.2.3.3.3
4.2.3.3.4 4.2.3.4.1 4.2.3.4.2 4.2.3.4.3 4.2.3.4.4 4.2.3.5.1
4.2.3.5.2 4.2.3.5.3 4.2.3.5.4 4.2.3.6.1 4.2.3.6.2 4.2.3.6.3
4.2.3.6.4 4.2.3.7.1 4.2.3.7.2 4.2.3.7.3 4.2.3.7.4 4.2.3.8.1
4.2.3.8.2 4.2.3.8.3 4.2.3.8.4 4.2.4.1.1 4.2.4.1.2 4.2.4.1.3
4.2.4.1.4 4.2.4.2.1 4.2.4.2.2 4.2.4.2.3 4.2.4.2.4 4.2.4.3.1
4.2.4.3.2 4.2.4.3.3 4.2.4.3.4 4.2.4.4.1 4.2.4.4.2 4.2.4.4.3
4.2.4.4.4 4.2.4.5.1 4.2.4.5.2 4.2.4.5.3 4.2.4.5.4 4.2.4.6.1
4.2.4.6.2 4.2.4.6.3 4.2.4.6.4 4.2.4.7.1 4.2.4.7.2 4.2.4.7.3
4.2.4.7.4 4.2.4.8.1 4.2.4.8.2 4.2.4.8.3 4.2.4.8.4 4.3.1.1.1
4.3.1.1.2 4.3.1.1.3 4.3.1.1.4 4.3.1.2.1 4.3.1.2.2 4.3.1.2.3
4.3.1.2.4 4.3.1.3.1 4.3.1.3.2 4.3.1.3.3 4.3.1.3.4 4.3.1.4.1
4.3.1.4.2 4.3.1.4.3 4.3.1.4.4 4.3.1.5.1 4.3.1.5.2 4.3.1.5.3
4.3.1.5.4 4.3.1.6.1 4.3.1.6.2 4.3.1.6.3 4.3.1.6.4 4.3.1.7.1
4.3.1.7.2 4.3.1.7.3 4.3.1.7.4 4.3.1.8.1 4.3.1.8.2 4.3.1.8.3
4.3.1.8.4 4.3.2.1.1 4.3.2.1.2 4.3.2.1.3 4.3.2.1.4 4.3.2.2.1
4.3.2.2.2 4.3.2.2.3 4.3.2.2.4 4.3.2.3.1 4.3.2.3.2 4.3.2.3.3
4.3.2.3.4 4.3.2.4.1 4.3.2.4.2 4.3.2.4.3 4.3.2.4.4 4.3.2.5.1
4.3.2.5.2 4.3.2.5.3 4.3.2.5.4 4.3.2.6.1 4.3.2.6.2 4.3.2.6.3
4.3.2.6.4 4.3.2.7.1 4.3.2.7.2 4.3.2.7.3 4.3.2.7.4 4.3.2.8.1
4.3.2.8.2 4.3.2.8.3 4.3.2.8.4 4.3.3.1.1 4.3.3.1.2 4.3.3.1.3
4.3.3.1.4 4.3.3.2.1 4.3.3.2.2 4.3.3.2.3 4.3.3.2.4 4.3.3.3.1
4.3.3.3.2 4.3.3.3.3 4.3.3.3.4 4.3.3.4.1 4.3.3.4.2 4.3.3.4.3
4.3.3.4.4 4.3.3.5.1 4.3.3.5.2 4.3.3.5.3 4.3.3.5.4 4.3.3.6.1
4.3.3.6.2 4.3.3.6.3 4.3.3.6.4 4.3.3.7.1 4.3.3.7.2 4.3.3.7.3
4.3.3.7.4 4.3.3.8.1 4.3.3.8.2 4.3.3.8.3 4.3.3.8.4 4.3.4.1.1
4.3.4.1.2 4.3.4.1.3 4.3.4.1.4 4.3.4.2.1 4.3.4.2.2 4.3.4.2.3
4.3.4.2.4 4.3.4.3.1 4.3.4.3.2 4.3.4.3.3 4.3.4.3.4 4.3.4.4.1
4.3.4.4.2 4.3.4.4.3 4.3.4.4.4 4.3.4.5.1 4.3.4.5.2 4.3.4.5.3
4.3.4.5.4 4.3.4.6.1 4.3.4.6.2 4.3.4.6.3 4.3.4.6.4 4.3.4.7.1
4.3.4.7.2 4.3.4.7.3 4.3.4.7.4 4.3.4.8.1 4.3.4.8.2 4.3.4.8.3
4.3.4.8.4 4.4.1.1.1 4.4.1.1.2 4.4.1.1.3 4.4.1.1.4 4.4.1.2.1
4.4.1.2.2 4.4.1.2.3 4.4.1.2.4 4.4.1.3.1 4.4.1.3.2 4.4.1.3.3
4.4.1.3.4 4.4.1.4.1 4.4.1.4.2 4.4.1.4.3 4.4.1.4.4 4.4.1.5.1
4.4.1.5.2 4.4.1.5.3 4.4.1.5.4 4.4.1.6.1 4.4.1.6.2 4.4.1.6.3
4.4.1.6.4 4.4.1.7.1 4.4.1.7.2 4.4.1.7.3 4.4.1.7.4 4.4.1.8.1
4.4.1.8.2 4.4.1.8.3 4.4.1.8.4 4.4.2.1.1 4.4.2.1.2 4.4.2.1.3
4.4.2.1.4 4.4.2.2.1 4.4.2.2.2 4.4.2.2.3 4.4.2.2.4 4.4.2.3.1
4.4.2.3.2 4.4.2.3.3 4.4.2.3.4 4.4.2.4.1 4.4.2.4.2 4.4.2.4.3
4.4.2.4.4 4.4.2.5.1 4.4.2.5.2 4.4.2.5.3 4.4.2.5.4 4.4.2.6.1
4.4.2.6.2 4.4.2.6.3 4.4.2.6.4 4.4.2.7.1 4.4.2.7.2 4.4.2.7.3
4.4.2.7.4 4.4.2.8.1 4.4.2.8.2 4.4.2.8.3 4.4.2.8.4 4.4.3.1.1
4.4.3.1.2 4.4.3.1.3 4.4.3.1.4 4.4.3.2.1 4.4.3.2.2 4.4.3.2.3
4.4.3.2.4 4.4.3.3.1 4.4.3.3.2 4.4.3.3.3 4.4.3.3.4 4.4.3.4.1
4.4.3.4.2 4.4.3.4.3 4.4.3.4.4 4.4.3.5.1 4.4.3.5.2 4.4.3.5.3
4.4.3.5.4 4.4.3.6.1 4.4.3.6.2 4.4.3.6.3 4.4.3.6.4 4.4.3.7.1
4.4.3.7.2 4.4.3.7.3 4.4.3.7.4 4.4.3.8.1 4.4.3.8.2 4.4.3.8.3
4.4.3.8.4 4.4.4.1.1 4.4.4.1.2 4.4.4.1.3 4.4.4.1.4 4.4.4.2.1
4.4.4.2.2 4.4.4.2.3 4.4.4.2.4 4.4.4.3.1 4.4.4.3.2 4.4.4.3.3
4.4.4.3.4 4.4.4.4.1 4.4.4.4.2 4.4.4.4.3 4.4.4.4.4 4.4.4.5.1
4.4.4.5.2 4.4.4.5.3 4.4.4.5.4 4.4.4.6.1 4.4.4.6.2 4.4.4.6.3
4.4.4.6.4 4.4.4.7.1 4.4.4.7.2 4.4.4.7.3 4.4.4.7.4 4.4.4.8.1
4.4.4.8.2 4.4.4.8.3 4.4.4.8.4 4.5.1.1.1 4.5.1.1.2 4.5.1.1.3
4.5.1.1.4 4.5.1.2.1 4.5.1.2.2 4.5.1.2.3 4.5.1.2.4 4.5.1.3.1
4.5.1.3.2 4.5.1.3.3 4.5.1.3.4 4.5.1.4.1 4.5.1.4.2 4.5.1.4.3
4.5.1.4.4 4.5.1.5.1 4.5.1.5.2 4.5.1.5.3 4.5.1.5.4 4.5.1.6.1
4.5.1.6.2 4.5.1.6.3 4.5.1.6.4 4.5.1.7.1 4.5.1.7.2 4.5.1.7.3
4.5.1.7.4 4.5.1.8.1 4.5.1.8.2 4.5.1.8.3 4.5.1.8.4 4.5.2.1.1
4.5.2.1.2 4.5.2.1.3 4.5.2.1.4 4.5.2.2.1 4.5.2.2.2 4.5.2.2.3
4.5.2.2.4 4.5.2.3.1 4.5.2.3.2 4.5.2.3.3 4.5.2.3.4 4.5.2.4.1
4.5.2.4.2 4.5.2.4.3 4.5.2.4.4 4.5.2.5.1 4.5.2.5.2 4.5.2.5.3
4.5.2.5.4 4.5.2.6.1 4.5.2.6.2 4.5.2.6.3 4.5.2.6.4 4.5.2.7.1
4.5.2.7.2 4.5.2.7.3 4.5.2.7.4 4.5.2.8.1 4.5.2.8.2 4.5.2.8.3
4.5.2.8.4 4.5.3.1.1 4.5.3.1.2 4.5.3.1.3 4.5.3.1.4 4.5.3.2.1
4.5.3.2.2 4.5.3.2.3 4.5.3.2.4 4.5.3.3.1 4.5.3.3.2 4.5.3.3.3
4.5.3.3.4 4.5.3.4.1 4.5.3.4.2 4.5.3.4.3 4.5.3.4.4 4.5.3.5.1
4.5.3.5.2 4.5.3.5.3 4.5.3.5.4 4.5.3.6.1 4.5.3.6.2 4.5.3.6.3
4.5.3.6.4 4.5.3.7.1 4.5.3.7.2 4.5.3.7.3 4.5.3.7.4 4.5.3.8.1
4.5.3.8.2 4.5.3.8.3 4.5.3.8.4 4.5.4.1.1 4.5.4.1.2 4.5.4.1.3
4.5.4.1.4 4.5.4.2.1 4.5.4.2.2 4.5.4.2.3 4.5.4.2.4 4.5.4.3.1
4.5.4.3.2 4.5.4.3.3 4.5.4.3.4 4.5.4.4.1 4.5.4.4.2 4.5.4.4.3
4.5.4.4.4 4.5.4.5.1 4.5.4.5.2 4.5.4.5.3 4.5.4.5.4 4.5.4.6.1
4.5.4.6.2 4.5.4.6.3 4.5.4.6.4 4.5.4.7.1 4.5.4.7.2 4.5.4.7.3
4.5.4.7.4 4.5.4.8.1 4.5.4.8.2 4.5.4.8.3 4.5.4.8.4 4.6.1.1.1
4.6.1.1.2 4.6.1.1.3 4.6.1.1.4 4.6.1.2.1 4.6.1.2.2 4.6.1.2.3
4.6.1.2.4 4.6.1.3.1 4.6.1.3.2 4.6.1.3.3 4.6.1.3.4 4.6.1.4.1
4.6.1.4.2 4.6.1.4.3 4.6.1.4.4 4.6.1.5.1 4.6.1.5.2 4.6.1.5.3
4.6.1.5.4 4.6.1.6.1 4.6.1.6.2 4.6.1.6.3 4.6.1.6.4 4.6.1.7.1
4.6.1.7.2 4.6.1.7.3 4.6.1.7.4 4.6.1.8.1 4.6.1.8.2 4.6.1.8.3
4.6.1.8.4 4.6.2.1.1 4.6.2.1.2 4.6.2.1.3 4.6.2.1.4 4.6.2.2.1
4.6.2.2.2 4.6.2.2.3 4.6.2.2.4 4.6.2.3.1 4.6.2.3.2 4.6.2.3.3
4.6.2.3.4 4.6.2.4.1 4.6.2.4.2 4.6.2.4.3 4.6.2.4.4 4.6.2.5.1
4.6.2.5.2 4.6.2.5.3 4.6.2.5.4 4.6.2.6.1 4.6.2.6.2 4.6.2.6.3
4.6.2.6.4 4.6.2.7.1 4.6.2.7.2 4.6.2.7.3 4.6.2.7.4 4.6.2.8.1
4.6.2.8.2 4.6.2.8.3 4.6.2.8.4 4.6.3.1.1 4.6.3.1.2 4.6.3.1.3
4.6.3.1.4 4.6.3.2.1 4.6.3.2.2 4.6.3.2.3 4.6.3.2.4 4.6.3.3.1
4.6.3.3.2 4.6.3.3.3 4.6.3.3.4 4.6.3.4.1 4.6.3.4.2 4.6.3.4.3
4.6.3.4.4 4.6.3.5.1 4.6.3.5.2 4.6.3.5.3 4.6.3.5.4 4.6.3.6.1
4.6.3.6.2 4.6.3.6.3 4.6.3.6.4 4.6.3.7.1 4.6.3.7.2 4.6.3.7.3
4.6.3.7.4 4.6.3.8.1 4.6.3.8.2 4.6.3.8.3 4.6.3.8.4 4.6.4.1.1
4.6.4.1.2 4.6.4.1.3 4.6.4.1.4 4.6.4.2.1 4.6.4.2.2 4.6.4.2.3
4.6.4.2.4 4.6.4.3.1 4.6.4.3.2 4.6.4.3.3 4.6.4.3.4 4.6.4.4.1
4.6.4.4.2 4.6.4.4.3 4.6.4.4.4 4.6.4.5.1 4.6.4.5.2 4.6.4.5.3
4.6.4.5.4 4.6.4.6.1 4.6.4.6.2 4.6.4.6.3 4.6.4.6.4 4.6.4.7.1
4.6.4.7.2 4.6.4.7.3 4.6.4.7.4 4.6.4.8.1 4.6.4.8.2 4.6.4.8.3
4.6.4.8.4 4.7.1.1.1 4.7.1.1.2 4.7.1.1.3 4.7.1.1.4 4.7.1.2.1
4.7.1.2.2 4.7.1.2.3 4.7.1.2.4 4.7.1.3.1 4.7.1.3.2 4.7.1.3.3
4.7.1.3.4 4.7.1.4.1 4.7.1.4.2 4.7.1.4.3 4.7.1.4.4 4.7.1.5.1
4.7.1.5.2 4.7.1.5.3 4.7.1.5.4 4.7.1.6.1 4.7.1.6.2 4.7.1.6.3
4.7.1.6.4 4.7.1.7.1 4.7.1.7.2 4.7.1.7.3 4.7.1.7.4 4.7.1.8.1
4.7.1.8.2 4.7.1.8.3 4.7.1.8.4 4.7.2.1.1 4.7.2.1.2 4.7.2.1.3
4.7.2.1.4 4.7.2.2.1 4.7.2.2.2 4.7.2.2.3 4.7.2.2.4 4.7.2.3.1
4.7.2.3.2 4.7.2.3.3 4.7.2.3.4 4.7.2.4.1 4.7.2.4.2 4.7.2.4.3
4.7.2.4.4 4.7.2.5.1 4.7.2.5.2 4.7.2.5.3 4.7.2.5.4 4.7.2.6.1
4.7.2.6.2 4.7.2.6.3 4.7.2.6.4 4.7.2.7.1 4.7.2.7.2 4.7.2.7.3
4.7.2.7.4 4.7.2.8.1 4.7.2.8.2 4.7.2.8.3 4.7.2.8.4 4.7.3.1.1
4.7.3.1.2 4.7.3.1.3 4.7.3.1.4 4.7.3.2.1 4.7.3.2.2 4.7.3.2.3
4.7.3.2.4 4.7.3.3.1 4.7.3.3.2 4.7.3.3.3 4.7.3.3.4 4.7.3.4.1
4.7.3.4.2 4.7.3.4.3 4.7.3.4.4 4.7.3.5.1 4.7.3.5.2 4.7.3.5.3
4.7.3.5.4 4.7.3.6.1 4.7.3.6.2 4.7.3.6.3 4.7.3.6.4 4.7.3.7.1
4.7.3.7.2 4.7.3.7.3 4.7.3.7.4 4.7.3.8.1 4.7.3.8.2 4.7.3.8.3
4.7.3.8.4 4.7.4.1.1 4.7.4.1.2 4.7.4.1.3 4.7.4.1.4 4.7.4.2.1
4.7.4.2.2 4.7.4.2.3 4.7.4.2.4 4.7.4.3.1 4.7.4.3.2 4.7.4.3.3
4.7.4.3.4 4.7.4.4.1 4.7.4.4.2 4.7.4.4.3 4.7.4.4.4 4.7.4.5.1
4.7.4.5.2 4.7.4.5.3 4.7.4.5.4 4.7.4.6.1 4.7.4.6.2 4.7.4.6.3
4.7.4.6.4 4.7.4.7.1 4.7.4.7.2 4.7.4.7.3 4.7.4.7.4 4.7.4.8.1
4.7.4.8.2 4.7.4.8.3 4.7.4.8.4 4.8.1.1.1 4.8.1.1.2 4.8.1.1.3
4.8.1.1.4 4.8.1.2.1 4.8.1.2.2 4.8.1.2.3 4.8.1.2.4 4.8.1.3.1
4.8.1.3.2 4.8.1.3.3 4.8.1.3.4 4.8.1.4.1 4.8.1.4.2 4.8.1.4.3
4.8.1.4.4 4.8.1.5.1 4.8.1.5.2 4.8.1.5.3 4.8.1.5.4 4.8.1.6.1
4.8.1.6.2 4.8.1.6.3 4.8.1.6.4 4.8.1.7.1 4.8.1.7.2 4.8.1.7.3
4.8.1.7.4 4.8.1.8.1 4.8.1.8.2 4.8.1.8.3 4.8.1.8.4
4.8.2.1.1 4.8.2.1.2 4.8.2.1.3 4.8.2.1.4 4.8.2.2.1 4.8.2.2.2
4.8.2.2.3 4.8.2.2.4 4.8.2.3.1 4.8.2.3.2 4.8.2.3.3 4.8.2.3.4
4.8.2.4.1 4.8.2.4.2 4.8.2.4.3 4.8.2.4.4 4.8.2.5.1 4.8.2.5.2
4.8.2.5.3 4.8.2.5.4 4.8.2.6.1 4.8.2.6.2 4.8.2.6.3 4.8.2.6.4
4.8.2.7.1 4.8.2.7.2 4.8.2.7.3 4.8.2.7.4 4.8.2.8.1 4.8.2.8.2
4.8.2.8.3 4.8.2.8.4 4.8.3.1.1 4.8.3.1.2 4.8.3.1.3 4.8.3.1.4
4.8.3.2.1 4.8.3.2.2 4.8.3.2.3 4.8.3.2.4 4.8.3.3.1 4.8.3.3.2
4.8.3.3.3 4.8.3.3.4 4.8.3.4.1 4.8.3.4.2 4.8.3.4.3 4.8.3.4.4
4.8.3.5.1 4.8.3.5.2 4.8.3.5.3 4.8.3.5.4 4.8.3.6.1 4.8.3.6.2
4.8.3.6.3 4.8.3.6.4 4.8.3.7.1 4.8.3.7.2 4.8.3.7.3 4.8.3.7.4
4.8.3.8.1 4.8.3.8.2 4.8.3.8.3 4.8.3.8.4 4.8.4.1.1 4.8.4.1.2
4.8.4.1.3 4.8.4.1.4 4.8.4.2.1 4.8.4.2.2 4.8.4.2.3 4.8.4.2.4
4.8.4.3.1 4.8.4.3.2 4.8.4.3.3 4.8.4.3.4 4.8.4.4.1 4.8.4.4.2
4.8.4.4.3 4.8.4.4.4 4.8.4.5.1 4.8.4.5.2 4.8.4.5.3 4.8.4.5.4
4.8.4.6.1 4.8.4.6.2 4.8.4.6.3 4.8.4.6.4 4.8.4.7.1 4.8.4.7.2
4.8.4.7.3 4.8.4.7.4 4.8.4.8.1 4.8.4.8.2 4.8.4.8.3 4.8.4.8.4
5.1.1.1.1 5.1.1.1.2 5.1.1.1.3 5.1.1.1.4 5.1.1.2.1 5.1.1.2.2
5.1.1.2.3 5.1.1.2.4 5.1.1.3.1 5.1.1.3.2 5.1.1.3.3 5.1.1.3.4
5.1.1.4.1 5.1.1.4.2 5.1.1.4.3 5.1.1.4.4 5.1.1.5.1 5.1.1.5.2
5.1.1.5.3 5.1.1.5.4 5.1.1.6.1 5.1.1.6.2 5.1.1.6.3 5.1.1.6.4
5.1.1.7.1 5.1.1.7.2 5.1.1.7.3 5.1.1.7.4 5.1.1.8.1 5.1.1.8.2
5.1.1.8.3 5.1.1.8.4 5.1.2.1.1 5.1.2.1.2 5.1.2.1.3 5.1.2.1.4
5.1.2.2.1 5.1.2.2.2 5.1.2.2.3 5.1.2.2.4 5.1.2.3.1 5.1.2.3.2
5.1.2.3.3 5.1.2.3.4 5.1.2.4.1 5.1.2.4.2 5.1.2.4.3 5.1.2.4.4
5.1.2.5.1 5.1.2.5.2 5.1.2.5.3 5.1.2.5.4 5.1.2.6.1 5.1.2.6.2
5.1.2.6.3 5.1.2.6.4 5.1.2.7.1 5.1.2.7.2 5.1.2.7.3 5.1.2.7.4
5.1.2.8.1 5.1.2.8.2 5.1.2.8.3 5.1.2.8.4 5.1.3.1.1 5.1.3.1.2
5.1.3.1.3 5.1.3.1.4 5.1.3.2.1 5.1.3.2.2 5.1.3.2.3 5.1.3.2.4
5.1.3.3.1 5.1.3.3.2 5.1.3.3.3 5.1.3.3.4 5.1.3.4.1 5.1.3.4.2
5.1.3.4.3 5.1.3.4.4 5.1.3.5.1 5.1.3.5.2 5.1.3.5.3 5.1.3.5.4
5.1.3.6.1 5.1.3.6.2 5.1.3.6.3 5.1.3.6.4 5.1.3.7.1 5.1.3.7.2
5.1.3.7.3 5.1.3.7.4 5.1.3.8.1 5.1.3.8.2 5.1.3.8.3 5.1.3.8.4
5.1.4.1.1 5.1.4.1.2 5.1.4.1.3 5.1.4.1.4 5.1.4.2.1 5.1.4.2.2
5.1.4.2.3 5.1.4.2.4 5.1.4.3.1 5.1.4.3.2 5.1.4.3.3 5.1.4.3.4
5.1.4.4.1 5.1.4.4.2 5.1.4.4.3 5.1.4.4.4 5.1.4.5.1 5.1.4.5.2
5.1.4.5.3 5.1.4.5.4 5.1.4.6.1 5.1.4.6.2 5.1.4.6.3 5.1.4.6.4
5.1.4.7.1 5.1.4.7.2 5.1.4.7.3 5.1.4.7.4 5.1.4.8.1 5.1.4.8.2
5.1.4.8.3 5.1.4.8.4 5.2.1.1.1 5.2.1.1.2 5.2.1.1.3 5.2.1.1.4
5.2.1.2.1 5.2.1.2.2 5.2.1.2.3 5.2.1.2.4 5.2.1.3.1 5.2.1.3.2
5.2.1.3.3 5.2.1.3.4 5.2.1.4.1 5.2.1.4.2 5.2.1.4.3 5.2.1.4.4
5.2.1.5.1 5.2.1.5.2 5.2.1.5.3 5.2.1.5.4 5.2.1.6.1 5.2.1.6.2
5.2.1.6.3 5.2.1.6.4 5.2.1.7.1 5.2.1.7.2 5.2.1.7.3 5.2.1.7.4
5.2.1.8.1 5.2.1.8.2 5.2.1.8.3 5.2.1.8.4 5.2.2.1.1 5.2.2.1.2
5.2.2.1.3 5.2.2.1.4 5.2.2.2.1 5.2.2.2.2 5.2.2.2.3 5.2.2.2.4
5.2.2.3.1 5.2.2.3.2 5.2.2.3.3 5.2.2.3.4 5.2.2.4.1 5.2.2.4.2
5.2.2.4.3 5.2.2.4.4 5.2.2.5.1 5.2.2.5.2 5.2.2.5.3 5.2.2.5.4
5.2.2.6.1 5.2.2.6.2 5.2.2.6.3 5.2.2.6.4 5.2.2.7.1 5.2.2.7.2
5.2.2.7.3 5.2.2.7.4 5.2.2.8.1 5.2.2.8.2 5.2.2.8.3 5.2.2.8.4
5.2.3.1.1 5.2.3.1.2 5.2.3.1.3 5.2.3.1.4 5.2.3.2.1 5.2.3.2.2
5.2.3.2.3 5.2.3.2.4 5.2.3.3.1 5.2.3.3.2 5.2.3.3.3 5.2.3.3.4
5.2.3.4.1 5.2.3.4.2 5.2.3.4.3 5.2.3.4.4 5.2.3.5.1 5.2.3.5.2
5.2.3.5.3 5.2.3.5.4 5.2.3.6.1 5.2.3.6.2 5.2.3.6.3 5.2.3.6.4
5.2.3.7.1 5.2.3.7.2 5.2.3.7.3 5.2.3.7.4 5.2.3.8.1 5.2.3.8.2
5.2.3.8.3 5.2.3.8.4 5.2.4.1.1 5.2.4.1.2 5.2.4.1.3 5.2.4.1.4
5.2.4.2.1 5.2.4.2.2 5.2.4.2.3 5.2.4.2.4 5.2.4.3.1 5.2.4.3.2
5.2.4.3.3 5.2.4.3.4 5.2.4.4.1 5.2.4.4.2 5.2.4.4.3 5.2.4.4.4
5.2.4.5.1 5.2.4.5.2 5.2.4.5.3 5.2.4.5.4 5.2.4.6.1 5.2.4.6.2
5.2.4.6.3 5.2.4.6.4 5.2.4.7.1 5.2.4.7.2 5.2.4.7.3 5.2.4.7.4
5.2.4.8.1 5.2.4.8.2 5.2.4.8.3 5.2.4.8.4 5.3.1.1.1 5.3.1.1.2
5.3.1.1.3 5.3.1.1.4 5.3.1.2.1 5.3.1.2.2 5.3.1.2.3 5.3.1.2.4
5.3.1.3.1 5.3.1.3.2 5.3.1.3.3 5.3.1.3.4 5.3.1.4.1 5.3.1.4.2
5.3.1.4.3 5.3.1.4.4 5.3.1.5.1 5.3.1.5.2 5.3.1.5.3 5.3.1.5.4
5.3.1.6.1 5.3.1.6.2 5.3.1.6.3 5.3.1.6.4 5.3.1.7.1 5.3.1.7.2
5.3.1.7.3 5.3.1.7.4 5.3.1.8.1 5.3.1.8.2 5.3.1.8.3 5.3.1.8.4
5.3.2.1.1 5.3.2.1.2 5.3.2.1.3 5.3.2.1.4 5.3.2.2.1 5.3.2.2.2
5.3.2.2.3 5.3.2.2.4 5.3.2.3.1 5.3.2.3.2 5.3.2.3.3 5.3.2.3.4
5.3.2.4.1 5.3.2.4.2 5.3.2.4.3 5.3.2.4.4 5.3.2.5.1 5.3.2.5.2
5.3.2.5.3 5.3.2.5.4 5.3.2.6.1 5.3.2.6.2 5.3.2.6.3 5.3.2.6.4
5.3.2.7.1 5.3.2.7.2 5.3.2.7.3 5.3.2.7.4 5.3.2.8.1 5.3.2.8.2
5.3.2.8.3 5.3.2.8.4 5.3.3.1.1 5.3.3.1.2 5.3.3.1.3 5.3.3.1.4
5.3.3.2.1 5.3.3.2.2 5.3.3.2.3 5.3.3.2.4 5.3.3.3.1 5.3.3.3.2
5.3.3.3.3 5.3.3.3.4 5.3.3.4.1 5.3.3.4.2 5.3.3.4.3 5.3.3.4.4
5.3.3.5.1 5.3.3.5.2 5.3.3.5.3 5.3.3.5.4 5.3.3.6.1 5.3.3.6.2
5.3.3.6.3 5.3.3.6.4 5.3.3.7.1 5.3.3.7.2 5.3.3.7.3 5.3.3.7.4
5.3.3.8.1 5.3.3.8.2 5.3.3.8.3 5.3.3.8.4 5.3.4.1.1 5.3.4.1.2
5.3.3.1.3 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
5.7.2.5.1 5.7.2.5.2 5.7.2.5.3 5.7.2.5.4 5.7.2.6.1 5.7.2.6.2
5.7.2.6.3 5.7.2.6.4 5.7.2.7.1 5.7.2.7.2 5.7.2.7.3 5.7.2.7.4
5.7.2.8.1 5.7.2.8.2 5.7.2.8.3 5.7.2.8.4 5.7.3.1.1 5.7.3.1.2
5.7.3.1.3 5.7.3.1.4 5.7.3.2.1 5.7.3.2.2 5.7.3.2.3 5.7.3.2.4
5.7.3.3.1 5.7.3.3.2 5.7.3.3.3 5.7.3.3.4 5.7.3.4.1 5.7.3.4.2
5.7.3.4.3 5.7.3.4.4 5.7.3.5.1 5.7.3.5.2 5.7.3.5.3 5.7.3.5.4
5.7.3.6.1 5.7.3.6.2 5.7.3.6.3 5.7.3.6.4 5.7.3.7.1 5.7.3.7.2
5.7.3.7.3 5.7.3.7.4 5.7.3.8.1 5.7.3.8.2 5.7.3.8.3 5.7.3.8.4
5.7.4.1.1 5.7.4.1.2 5.7.4.1.3 5.7.4.1.4 5.7.4.2.1 5.7.4.2.2
5.7.4.2.3 5.7.4.2.4 5.7.4.3.1 5.7.4.3.2 5.7.4.3.3 5.7.4.3.4
5.7.4.4.1 5.7.4.4.2 5.7.4.4.3 5.7.4.4.4 5.7.4.5.1 5.7.4.5.2
5.7.4.5.3 5.7.4.5.4 5.7.4.6.1 5.7.4.6.2 5.7.4.6.3 5.7.4.6.4
5.7.4.7.1 5.7.4.7.2 5.7.4.7.3 5.7.4.7.4 5.7.4.8.1 5.7.4.8.2
5.7.4.8.3 5.7.4.8.4 5.8.1.1.1 5.8.1.1.2 5.8.1.1.3 5.8.1.1.4
5.8.1.2.1 5.8.1.2.2 5.8.1.2.3 5.8.1.2.4 5.8.1.3.1 5.8.1.3.2
5.8.1.3.3 5.8.1.3.4 5.8.1.4.1 5.8.1.4.2 5.8.1.4.3
5.8.1.4.4 5.8.1.5.1 5.8.1.5.2 5.8.1.5.3 5.8.1.5.4 5.8.1.6.1
5.8.1.6.2 5.8.1.6.3 5.8.1.6.4 5.8.1.7.1 5.8.1.7.2 5.8.1.7.3
5.8.1.7.4 5.8.1.8.1 5.8.1.8.2 5.8.1.8.3 5.8.1.8.4 5.8.2.1.1
5.8.2.1.2 5.8.2.1.3 5.8.2.1.4 5.8.2.2.1 5.8.2.2.2 5.8.2.2.3
5.8.2.2.4 5.8.2.3.1 5.8.2.3.2 5.8.2.3.3 5.8.2.3.4 5.8.2.4.1
5.8.2.4.2 5.8.2.4.3 5.8.2.4.4 5.8.2.5.1 5.8.2.5.2 5.8.2.5.3
5.8.2.5.4 5.8.2.6.1 5.8.2.6.2 5.8.2.6.3 5.8.2.6.4 5.8.2.7.1
5.8.2.7.2 5.8.2.7.3 5.8.2.7.4 5.8.2.3.1 5.8.2.3.2 5.8.2.3.3
5.8.2.3.4 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 6.8.4.3.4 7.1.1.1.1 7.1.1.1.2
7.1.1.1.3 7.1.1.1.4 7.1.1.2.1 7.1.1.2.2 7.1.1.2.3 7.1.1.2.4
7.1.1.3.1 7.1.1.3.2 7.1.1.3.3 7.1.1.3.4 7.1.1.4.1 7.1.1.4.2
7.1.1.4.3 7.1.1.4.4 7.1.1.5.1 7.1.1.5.2 7.1.1.5.3 7.1.1.5.4
7.1.1.6.1 7.1.1.6.2 7.1.1.6.3 7.1.1.6.4 7.1.1.7.1 7.1.1.7.2
7.1.1.7.3 7.1.1.7.4 7.1.1.8.1 7.1.1.8.2 7.1.1.8.3 7.1.1.8.4
7.1.2.1.1 7.1.2.1.2 7.1.2.1.3 7.1.2.1.4 7.1.2.2.1 7.1.2.2.2
7.1.2.2.3 7.1.2.2.4 7.1.2.3.1 7.1.2.3.2 7.1.2.3.3 7.1.2.3.4
7.1.2.4.1 7.1.2.4.2 7.1.2.4.3 7.1.2.4.4 7.1.2.5.1 7.1.2.5.2
7.1.2.5.3 7.1.2.5.4 7.1.2.6.1 7.1.2.6.2 7.1.2.6.3 7.1.2.6.4
7.1.2.7.1 7.1.2.7.2 7.1.2.7.3 7.1.2.7.4 7.1.2.8.1 7.1.2.8.2
7.1.2.8.3 7.1.2.8.4 7.1.3.1.1 7.1.3.1.2 7.1.3.1.3 7.1.3.1.4
7.1.3.2.1 7.1.3.2.2 7.1.3.2.3 7.1.3.2.4 7.1.3.3.1 7.1.3.3.2
7.1.3.3.3 7.1.3.3.4 7.1.3.4.1 7.1.3.4.2 7.1.3.4.3 7.1.3.4.4
7.1.3.5.1 7.1.3.5.2 7.1.3.5.3 7.1.3.5.4 7.1.3.6.1 7.1.3.6.2
7.1.3.6.3 7.1.3.6.4 7.1.3.7.1 7.1.3.7.2 7.1.3.7.3 7.1.3.7.4
7.1.3.8.1 7.1.3.8.2 7.1.3.8.3 7.1.3.8.4 7.1.4.1.1 7.1.4.1.2
7.1.4.1.3 7.1.4.1.4 7.1.4.2.1 7.1.4.2.2 7.1.4.2.3 7.1.4.2.4
7.1.4.3.1 7.1.4.3.2 7.1.4.3.3 7.1.4.3.4 7.1.4.4.1 7.1.4.4.2
7.1.4.4.3 7.1.4.4.4 7.1.4.5.1 7.1.4.5.2 7.1.4.5.3 7.1.4.5.4
7.1.4.6.1 7.1.4.6.2 7.1.4.6.3 7.1.4.6.4 7.1.4.7.1 7.1.4.7.2
7.1.4.7.3 7.1.4.7.4 7.1.4.8.1 7.1.4.8.2 7.1.4.8.3 7.1.4.8.4
7.2.1.1.1 7.2.1.1.2 7.2.1.1.3 7.2.1.1.4 7.2.1.2.1 7.2.1.2.2
7.2.1.2.3 7.2.1.2.4 7.2.1.3.1 7.2.1.3.2 7.2.1.3.3 7.2.1.3.4
7.2.1.4.1 7.2.1.4.2 7.2.1.4.3 7.2.1.4.4 7.2.1.5.1 7.2.1.5.2
7.2.1.5.3 7.2.1.5.4 7.2.1.6.1 7.2.1.6.2 7.2.1.6.3 7.2.1.6.4
7.2.1.7.1 7.2.1.7.2 7.2.1.7.3 7.2.1.7.4 7.2.1.8.1 7.2.1.8.2
7.2.1.8.3 7.2.1.8.4 7.2.2.1.1 7.2.2.1.2 7.2.2.1.3 7.2.2.1.4
7.2.2.2.1 7.2.2.2.2 7.2.2.2.3 7.2.2.2.4 7.2.2.3.1 7.2.2.3.2
7.2.2.3.3 7.2.2.3.4 7.2.2.4.1 7.2.2.4.2 7.2.2.4.3 7.2.2.4.4
7.2.2.5.1 7.2.2.5.2 7.2.2.5.3 7.2.2.5.4 7.2.2.6.1 7.2.2.6.2
7.2.2.6.3 7.2.2.6.4 7.2.2.7.1 7.2.2.7.2 7.2.2.7.3 7.2.2.7.4
7.2.2.8.1 7.2.2.8.2 7.2.2.8.3 7.2.2.8.4 7.2.3.1.1 7.2.3.1.2
7.2.3.1.3 7.2.3.1.4 7.2.3.2.1 7.2.3.2.2 7.2.3.2.3 7.2.3.2.4
7.2.3.3.1 7.2.3.3.2 7.2.3.3.3 7.2.3.3.4 7.2.3.4.1 7.2.3.4.2
7.2.3.4.3 7.2.3.4.4 7.2.3.5.1 7.2.3.5.2 7.2.3.5.3 7.2.3.5.4
7.2.3.6.1 7.2.3.6.2 7.2.3.6.3 7.2.3.6.4 7.2.3.7.1 7.2.3.7.2
7.2.3.7.3 7.2.3.7.4 7.2.3.8.1 7.2.3.8.2 7.2.3.8.3 7.2.3.8.4
7.2.4.1.1 7.2.4.1.2 7.2.4.1.3 7.2.4.1.4 7.2.4.2.1 7.2.4.2.2
7.2.4.2.3 7.2.4.2.4 7.2.4.3.1 7.2.4.3.2 7.2.4.3.3 7.2.4.3.4
7.2.4.4.1 7.2.4.4.2 7.2.4.4.3 7.2.4.4.4 7.2.4.5.1 7.2.4.5.2
7.2.4.5.3 7.2.4.5.4 7.2.4.6.1 7.2.4.6.2 7.2.4.6.3 7.2.4.6.4
7.2.4.7.1 7.2.4.7.2 7.2.4.7.3 7.2.4.7.4 7.2.4.8.1 7.2.4.8.2
7.2.4.8.3 7.2.4.8.4 7.3.1.1.1 7.3.1.1.2 7.3.1.1.3 7.3.1.1.4
7.3.1.2.1 7.3.1.2.2 7.3.1.2.3 7.3.1.2.4 7.3.1.3.1 7.3.1.3.2
7.3.1.3.3 7.3.1.3.4 7.3.1.4.1 7.3.1.4.2 7.3.1.4.3 7.3.1.4.4
7.3.1.5.1 7.3.1.5.2 7.3.1.5.3 7.3.1.5.4 7.3.1.6.1 7.3.1.6.2
7.3.1.6.3 7.3.1.6.4 7.3.1.7.1 7.3.1.7.2 7.3.1.7.3 7.3.1.7.4
7.3.1.8.1 7.3.1.8.2 7.3.1.8.3 7.3.1.8.4 7.3.2.1.1 7.3.2.1.2
7.3.2.1.3 7.3.2.1.4 7.3.2.2.1 7.3.2.2.2 7.3.2.2.3 7.3.2.2.4
7.3.2.3.1 7.3.2.3.2 7.3.2.3.3 7.3.2.3.4 7.3.2.4.1 7.3.2.4.2
7.3.2.4.3 7.3.2.4.4 7.3.2.5.1 7.3.2.5.2 7.3.2.5.3 7.3.2.5.4
7.3.2.6.1 7.3.2.6.2 7.3.2.6.3 7.3.2.6.4 7.3.2.7.1 7.3.2.7.2
7.3.2.7.3 7.3.2.7.4 7.3.2.8.1 7.3.2.8.2 7.3.2.8.3 7.3.2.8.4
7.3.3.1.1 7.3.3.1.2 7.3.3.1.3 7.3.3.1.4 7.3.3.2.1 7.3.3.2.2
7.3.3.2.3 7.3.3.2.4 7.3.3.3.1 7.3.3.3.2 7.3.3.3.3 7.3.3.3.4
7.3.3.4.1 7.3.3.4.2 7.3.3.4.3 7.3.3.4.4 7.3.3.5.1 7.3.3.5.2
7.3.3.5.3 7.3.3.5.4 7.3.3.6.1 7.3.3.6.2 7.3.3.6.3 7.3.3.6.4
7.3.3.7.1 7.3.3.7.2 7.3.3.7.3 7.3.3.7.4 7.3.3.8.1 7.3.3.8.2
7.3.3.8.3 7.3.3.8.4 7.3.4.1.1 7.3.4.1.2 7.3.4.1.3 7.3.4.1.4
7.3.4.2.1 7.3.4.2.2 7.3.4.2.3 7.3.4.2.4 7.3.4.3.1 7.3.4.3.2
7.3.4.3.3 7.3.4.3.4 7.3.4.4.1 7.3.4.4.2 7.3.4.4.3 7.3.4.4.4
7.3.4.5.1 7.3.4.5.2 7.3.4.5.3 7.3.4.5.4 7.3.4.6.1 7.3.4.6.2
7.3.4.6.3 7.3.4.6.4 7.3.4.7.1 7.3.4.7.2 7.3.4.7.3 7.3.4.7.4
7.3.4.8.1 7.3.4.8.2 7.3.4.8.3 7.3.4.8.4 7.4.1.1.1 7.4.1.1.2
7.4.1.1.3 7.4.1.1.4 7.4.1.2.1 7.4.1.2.2 7.4.1.2.3 7.4.1.2.4
7.4.1.3.1 7.4.1.3.2 7.4.1.3.3 7.4.1.3.4 7.4.1.4.1 7.4.1.4.2
7.4.1.4.3 7.4.1.4.4 7.4.1.5.1 7.4.1.5.2 7.4.1.5.3 7.4.1.5.4
7.4.1.6.1 7.4.1.6.2 7.4.1.6.3 7.4.1.6.4 7.4.1.7.1 7.4.1.7.2
7.4.1.7.3 7.4.1.7.4 7.4.1.8.1 7.4.1.8.2 7.4.1.8.3 7.4.1.8.4
7.4.2.1.1 7.4.2.1.2 7.4.2.1.3 7.4.2.1.4 7.4.2.2.1 7.4.2.2.2
7.4.2.2.3 7.4.2.2.4 7.4.2.3.1 7.4.2.3.2 7.4.2.3.3 7.4.2.3.4
7.4.2.4.1 7.4.2.4.2 7.4.2.4.3 7.4.2.4.4 7.4.2.5.1 7.4.2.5.2
7.4.2.5.3 7.4.2.5.4 7.4.2.6.1 7.4.2.6.2 7.4.2.6.3 7.4.2.6.4
7.4.2.7.1 7.4.2.7.2 7.4.2.7.3 7.4.2.7.4 7.4.2.8.1 7.4.2.8.2
7.4.2.8.3 7.4.2.8.4 7.4.3.1.1 7.4.3.1.2 7.4.3.1.3 7.4.3.1.4
7.4.3.2.1 7.4.3.2.2 7.4.3.2.3 7.4.3.2.4 7.4.3.3.1 7.4.3.3.2
7.4.3.3.3 7.4.3.3.4 7.4.3.4.1 7.4.3.4.2 7.4.3.4.3 7.4.3.4.4
7.4.3.5.1 7.4.3.5.2 7.4.3.5.3 7.4.3.5.4 7.4.3.6.1 7.4.3.6.2
7.4.3.6.3 7.4.3.6.4 7.4.3.7.1 7.4.3.7.2 7.4.3.7.3 7.4.3.7.4
7.4.3.8.1 7.4.3.8.2 7.4.3.8.3 7.4.3.8.4 7.4.4.1.1 7.4.4.1.2
7.4.4.1.3 7.4.4.1.4 7.4.4.2.1 7.4.4.2.2 7.4.4.2.3 7.4.4.2.4
7.4.4.3.1 7.4.4.3.2 7.4.4.3.3 7.4.4.3.4 7.4.4.4.1 7.4.4.4.2
7.4.4.4.3 7.4.4.4.4 7.4.4.5.1 7.4.4.5.2 7.4.4.5.3 7.4.4.5.4
7.4.4.6.1 7.4.4.6.2 7.4.4.6.3 7.4.4.6.4 7.4.4.7.1 7.4.4.7.2
7.4.4.7.3 7.4.4.7.4 7.4.4.8.1 7.4.4.8.2 7.4.4.8.3 7.4.4.8.4
7.5.1.1.1 7.5.1.1.2 7.5.1.1.3 7.5.1.1.4 7.5.1.2.1 7.5.1.2.2
7.5.1.2.3 7.5.1.2.4 7.5.1.3.1 7.5.1.3.2 7.5.1.3.3 7.5.1.3.4
7.5.1.4.1 7.5.1.4.2 7.5.1.4.3 7.5.1.4.4 7.5.1.5.1 7.5.1.5.2
7.5.1.5.3 7.5.1.5.4 7.5.1.6.1 7.5.1.6.2 7.5.1.6.3 7.5.1.6.4
7.5.1.7.1 7.5.1.7.2 7.5.1.7.3 7.5.1.7.4 7.5.1.8.1 7.5.1.8.2
7.5.1.8.3 7.5.1.8.4 7.5.2.1.1 7.5.2.1.2 7.5.2.1.3 7.5.2.1.4
7.5.2.2.1 7.5.2.2.2 7.5.2.2.3 7.5.2.2.4 7.5.2.3.1 7.5.2.3.2
7.5.2.3.3 7.5.2.3.4 7.5.2.4.1 7.5.2.4.2 7.5.2.4.3 7.5.2.4.4
7.5.2.5.1 7.5.2.5.2 7.5.2.5.3 7.5.2.5.4 7.5.2.6.1 7.5.2.6.2
7.5.2.6.3 7.5.2.6.4 7.5.2.7.1 7.5.2.7.2 7.5.2.7.3 7.5.2.7.4
7.5.2.8.1 7.5.2.8.2 7.5.2.8.3 7.5.2.8.4 7.5.3.1.1 7.5.3.1.2
7.5.3.1.3 7.5.3.1.4 7.5.3.2.1 7.5.3.2.2 7.5.3.2.3 7.5.3.2.4
7.5.3.3.1 7.5.3.3.2 7.5.3.3.3 7.5.3.3.4 7.5.3.4.1 7.5.3.4.2
7.5.3.4.3 7.5.3.4.4 7.5.3.5.1 7.5.3.5.2 7.5.3.5.3 7.5.3.5.4
7.5.3.6.1 7.5.3.6.2 7.5.3.6.3 7.5.3.6.4 7.5.3.7.1 7.5.3.7.2
7.5.3.7.3 7.5.3.7.4 7.5.3.8.1 7.5.3.8.2 7.5.3.8.3 7.5.3.8.4
7.5.4.1.1 7.5.4.1.2 7.5.4.1.3 7.5.4.1.4 7.5.4.2.1 7.5.4.2.2
7.5.4.2.3 7.5.4.2.4 7.5.4.3.1 7.5.4.3.2 7.5.4.3.3 7.5.4.3.4
7.5.4.4.1 7.5.4.4.2 7.5.4.4.3 7.5.4.4.4 7.5.4.5.1 7.5.4.5.2
7.5.4.5.3 7.5.4.5.4 7.5.4.6.1 7.5.4.6.2 7.5.4.6.3 7.5.4.6.4
7.5.4.7.1 7.5.4.7.2 7.5.4.7.3 7.5.4.7.4 7.5.4.8.1 7.5.4.8.2
7.5.4.8.3 7.5.4.8.4 7.6.1.1.1 7.6.1.1.2 7.6.1.1.3 7.6.1.1.4
7.6.1.2.1 7.6.1.2.2 7.6.1.2.3 7.6.1.2.4 7.6.1.3.1 7.6.1.3.2
7.6.1.3.3 7.6.1.3.4 7.6.1.4.1 7.6.1.4.2 7.6.1.4.3 7.6.1.4.4
7.6.1.5.1 7.6.1.5.2 7.6.1.5.3 7.6.1.5.4 7.6.1.6.1 7.6.1.6.2
7.6.1.6.3 7.6.1.6.4 7.6.1.7.1 7.6.1.7.2 7.6.1.7.3 7.6.1.7.4
7.6.1.8.1 7.6.1.8.2 7.6.1.8.3 7.6.1.8.4 7.6.2.1.1 7.6.2.1.2
7.6.2.1.3 7.6.2.1.4 7.6.2.2.1 7.6.2.2.2 7.6.2.2.3 7.6.2.2.4
7.6.2.3.1 7.6.2.3.2 7.6.2.3.3 7.6.2.3.4 7.6.2.4.1 7.6.2.4.2
7.6.2.4.3 7.6.2.4.4 7.6.2.5.1 7.6.2.5.2 7.6.2.5.3 7.6.2.5.4
7.6.2.6.1 7.6.2.6.2 7.6.2.6.3 7.6.2.6.4 7.6.2.7.1 7.6.2.7.2
7.6.2.7.3 7.6.2.7.4 7.6.2.8.1 7.6.2.8.2 7.6.2.8.3 7.6.2.8.4
7.6.3.1.1 7.6.3.1.2 7.6.3.1.3 7.6.3.1.4 7.6.3.2.1 7.6.3.2.2
7.6.3.2.3 7.6.3.2.4 7.6.3.3.1 7.6.3.3.2 7.6.3.3.3 7.6.3.3.4
7.6.3.4.1 7.6.3.4.2 7.6.3.4.3 7.6.3.4.4 7.6.3.5.1 7.6.3.5.2
7.6.3.5.3 7.6.3.5.4 7.6.3.6.1 7.6.3.6.2 7.6.3.6.3 7.6.3.6.4
7.6.3.7.1 7.6.3.7.2 7.6.3.7.3 7.6.3.7.4 7.6.3.8.1 7.6.3.8.2
7.6.3.8.3 7.6.3.8.4 7.6.4.1.1 7.6.4.1.2 7.6.4.1.3 7.6.4.1.4
7.6.4.2.1 7.6.4.2.2 7.6.4.2.3 7.6.4.2.4 7.6.4.3.1 7.6.4.3.2
7.6.4.3.3 7.6.4.3.4 7.6.4.4.1 7.6.4.4.2 7.6.4.4.3 7.6.4.4.4
7.6.4.5.1 7.6.4.5.2 7.6.4.5.3 7.6.4.5.4 7.6.4.6.1 7.6.4.6.2
7.6.4.6.3 7.6.4.6.4 7.6.4.7.1 7.6.4.7.2 7.6.4.7.3 7.6.4.7.4
7.6.4.8.1 7.6.4.8.2 7.6.4.8.3 7.6.4.8.4 7.7.1.1.1 7.7.1.1.2
7.7.1.1.3 7.7.1.1.4 7.7.1.2.1 7.7.1.2.2 7.7.1.2.3 7.7.1.2.4
7.7.1.3.1 7.7.1.3.2 7.7.1.3.3 7.7.1.3.4 7.7.1.4.1 7.7.1.4.2
7.7.1.4.3 7.7.1.4.4 7.7.1.5.1 7.7.1.5.2 7.7.1.5.3 7.7.1.5.4
7.7.1.6.1 7.7.1.6.2 7.7.1.6.3 7.7.1.6.4 7.7.1.7.1 7.7.1.7.2
7.7.1.7.3 7.7.1.7.4 7.7.1.8.1 7.7.1.8.2 7.7.1.8.3 7.7.1.8.4
7.7.2.1.1 7.7.2.1.2 7.7.2.1.3 7.7.2.1.4 7.7.2.2.1 7.7.2.2.2
7.7.2.2.3 7.7.2.2.4 7.7.2.3.1 7.7.2.3.2 7.7.2.3.3 7.7.2.3.4
7.7.2.4.1 7.7.2.4.2 7.7.2.4.3 7.7.2.4.4 7.7.2.5.1 7.7.2.5.2
7.7.2.5.3 7.7.2.5.4 7.7.2.6.1 7.7.2.6.2 7.7.2.6.3 7.7.2.6.4
7.7.2.7.1 7.7.2.7.2 7.7.2.7.3 7.7.2.7.4 7.7.2.8.1 7.7.2.8.2
7.7.2.8.3 7.7.2.8.4 7.7.3.1.1 7.7.3.1.2 7.7.3.1.3 7.7.3.1.4
7.7.3.2.1 7.7.3.2.2 7.7.3.2.3 7.7.3.2.4 7.7.3.3.1 7.7.3.3.2
7.7.3.3.3 7.7.3.3.4 7.7.3.4.1 7.7.3.4.2 7.7.3.4.3 7.7.3.4.4
7.7.3.5.1 7.7.3.5.2 7.7.3.5.3 7.7.3.5.4 7.7.3.6.1 7.7.3.6.2
7.7.3.6.3 7.7.3.6.4 7.7.3.7.1 7.7.3.7.2 7.7.3.7.3 7.7.3.7.4
7.7.3.8.1 7.7.3.8.2 7.7.3.8.3 7.7.3.8.4 7.7.4.1.1 7.7.4.1.2
7.7.4.1.3 7.7.4.1.4 7.7.4.2.1 7.7.4.2.2 7.7.4.2.3
7.7.4.2.4 7.7.4.3.1 7.7.4.3.2 7.7.4.3.3 7.7.4.3.4 7.7.4.4.1
7.7.4.4.2 7.7.4.4.3 7.7.4.4.4 7.7.4.5.1 7.7.4.5.2 7.7.4.5.3
7.7.4.5.4 7.7.4.6.1 7.7.4.6.2 7.7.4.6.3 7.7.4.6.4 7.7.4.7.1
7.7.4.7.2 7.7.4.7.3 7.7.4.7.4 7.7.4.8.1 7.7.4.8.2 7.7.4.8.3
7.7.4.8.4 7.8.1.1.1 7.8.1.1.2 7.8.1.1.3 7.8.1.1.4 7.8.1.2.1
7.8.1.2.2 7.8.1.2.3 7.8.1.2.4 7.8.1.3.1 7.8.1.3.2 7.8.1.3.3
7.8.1.3.4 7.8.1.4.1 7.8.1.4.2 7.8.1.4.3 7.8.1.4.4 7.8.1.5.1
7.8.1.5.2 7.8.1.5.3 7.8.1.5.4 7.8.1.6.1 7.8.1.6.2 7.8.1.6.3
7.8.1.6.4 7.8.1.7.1 7.8.1.7.2 7.8.1.7.3 7.8.1.7.4 7.8.1.8.1
7.8.1.8.2 7.8.1.8.3 7.8.1.8.4 7.8.2.1.1 7.8.2.1.2 7.8.2.1.3
7.8.2.1.4 7.8.2.2.1 7.8.2.2.2 7.8.2.2.3 7.8.2.2.4 7.8.2.3.1
7.8.2.3.2 7.8.2.3.3 7.8.2.3.4 7.8.2.4.1 7.8.2.4.2 7.8.2.4.3
7.8.2.4.4 7.8.2.5.1 7.8.2.5.2 7.8.2.5.3 7.8.2.5.4 7.8.2.6.1
7.8.2.6.2 7.8.2.6.3 7.8.2.6.4 7.8.2.7.1 7.8.2.7.2 7.8.2.7.3
7.8.2.7.4 7.8.2.8.1 7.8.2.8.2 7.8.2.8.3 7.8.2.8.4 7.8.3.1.1
7.8.3.1.2 7.8.3.1.3 7.8.3.1.4 7.8.3.2.1 7.8.3.2.2 7.8.3.2.3
7.8.3.2.4 7.8.3.3.1 7.8.3.3.2 7.8.3.3.3 7.8.3.3.4 7.8.3.4.1
7.8.3.4.2 7.8.3.4.3 7.8.3.4.4 7.8.3.5.1 7.8.3.5.2 7.8.3.5.3
7.8.3.5.4 7.8.3.6.1 7.8.3.6.2 7.8.3.6.3 7.8.3.6.4 7.8.3.7.1
7.8.3.7.2 7.8.3.7.3 7.8.3.7.4 7.8.3.8.1 7.8.3.8.2 7.8.3.8.3
7.8.3.8.4 7.8.4.1.1 7.8.4.1.2 7.8.4.1.3 7.8.4.1.4 7.8.4.2.1
7.8.4.2.2 7.8.4.2.3 7.8.4.2.4 7.8.4.3.1 7.8.4.3.2 7.8.4.3.3
7.8.4.3.4 7.8.4.4.1 7.8.4.4.2 7.8.4.4.3 7.8.4.4.4 7.8.4.5.1
7.8.4.5.2 7.8.4.5.3 7.8.4.5.4 7.8.4.6.1 7.8.4.6.2 7.8.4.6.3
7.8.4.6.4 7.8.4.7.1 7.8.4.7.2 7.8.4.7.3 7.8.4.7.4 7.8.4.8.1
7.8.4.8.2 7.8.4.8.3 7.8.4.8.4 8.1.1.1.1 8.1.1.1.2 8.1.1.1.3
8.1.1.1.4 8.1.1.2.1 8.1.1.2.2 8.1.1.2.3 8.1.1.2.4 8.1.1.3.1
8.1.1.3.2 8.1.1.3.3 8.1.1.3.4 8.1.1.4.1 8.1.1.4.2 8.1.1.4.3
8.1.1.4.4 8.1.1.5.1 8.1.1.5.2 8.1.1.5.3 8.1.1.5.4 8.1.1.6.1
8.1.1.6.2 8.1.1.6.3 8.1.1.6.4 8.1.1.7.1 8.1.1.7.2 8.1.1.7.3
8.1.1.7.4 8.1.1.8.1 8.1.1.8.2 8.1.1.8.3 8.1.1.8.4 8.1.2.1.1
8.1.2.1.2 8.1.2.1.3 8.1.2.1.4 8.1.2.2.1 8.1.2.2.2 8.1.2.2.3
8.1.2.2.4 8.1.2.3.1 8.1.2.3.2 8.1.2.3.3 8.1.2.3.4 8.1.2.4.1
8.1.2.4.2 8.1.2.4.3 8.1.2.4.4 8.1.2.5.1 8.1.2.5.2 8.1.2.5.3
8.1.2.5.4 8.1.2.6.1 8.1.2.6.2 8.1.2.6.3 8.1.2.6.4 8.1.2.7.1
8.1.2.7.2 8.1.2.7.3 8.1.2.7.4 8.1.2.8.1 8.1.2.8.2 8.1.2.8.3
8.1.2.8.4 8.1.3.1.1 8.1.3.1.2 8.1.3.1.3 8.1.3.1.4 8.1.3.2.1
8.1.3.2.2 8.1.3.2.3 8.1.3.2.4 8.1.3.3.1 8.1.3.3.2 8.1.3.3.3
8.1.3.3.4 8.1.3.4.1 8.1.3.4.2 8.1.3.4.3 8.1.3.4.4 8.1.3.5.1
8.1.3.5.2 8.1.3.5.3 8.1.3.5.4 8.1.3.6.1 8.1.3.6.2 8.1.3.6.3
8.1.3.6.4 8.1.3.7.1 8.1.3.7.2 8.1.3.7.3 8.1.3.7.4 8.1.3.8.1
8.1.3.8.2 8.1.3.8.3 8.1.3.8.4 8.1.4.1.1 8.1.4.1.2 8.1.4.1.3
8.1.4.1.4 8.1.4.2.1 8.1.4.2.2 8.1.4.2.3 8.1.4.2.4 8.1.4.3.1
8.1.4.3.2 8.1.4.3.3 8.1.4.3.4 8.1.4.4.1 8.1.4.4.2 8.1.4.4.3
8.1.4.4.4 8.1.4.5.1 8.1.4.5.2 8.1.4.5.3 8.1.4.5.4 8.1.4.6.1
8.1.4.6.2 8.1.4.6.3 8.1.4.6.4 8.1.4.7.1 8.1.4.7.2 8.1.4.7.3
8.1.4.7.4 8.1.4.8.1 8.1.4.8.2 8.1.4.8.3 8.1.4.8.4 8.2.1.1.1
8.2.1.1.2 8.2.1.1.3 8.2.1.1.4 8.2.1.2.1 8.2.1.2.2 8.2.1.2.3
8.2.1.2.4 8.2.1.3.1 8.2.1.3.2 8.2.1.3.3 8.2.1.3.4 8.2.1.4.1
8.2.1.4.2 8.2.1.4.3 8.2.1.4.4 8.2.1.5.1 8.2.1.5.2 8.2.1.5.3
8.2.1.5.4 8.2.1.6.1 8.2.1.6.2 8.2.1.6.3 8.2.1.6.4 8.2.1.7.1
8.2.1.7.2 8.2.1.7.3 8.2.1.7.4 8.2.1.8.1 8.2.1.8.2 8.2.1.8.3
8.2.1.8.4 8.2.2.1.1 8.2.2.1.2 8.2.2.1.3 8.2.2.1.4 8.2.2.2.1
8.2.2.2.2 8.2.2.2.3 8.2.2.2.4 8.2.2.3.1 8.2.2.3.2 8.2.2.3.3
8.2.2.3.4 8.2.2.4.1 8.2.2.4.2 8.2.2.4.3 8.2.2.4.4 8.2.2.5.1
8.2.2.5.2 8.2.2.5.3 8.2.2.5.4 8.2.2.6.1 8.2.2.6.2 8.2.2.6.3
8.2.2.6.4 8.2.2.7.1 8.2.2.7.2 8.2.2.7.3 8.2.2.7.4 8.2.2.8.1
8.2.2.8.2 8.2.2.8.3 8.2.2.8.4 8.2.3.1.1 8.2.3.1.2 8.2.3.1.3
8.2.3.1.4 8.2.3.2.1 8.2.3.2.2 8.2.3.2.3 8.2.3.2.4 8.2.3.3.1
8.2.3.3.2 8.2.3.3.3 8.2.3.3.4 8.2.3.4.1 8.2.3.4.2 8.2.3.4.3
8.2.3.4.4 8.2.3.5.1 8.2.3.5.2 8.2.3.5.3 8.2.3.5.4 8.2.3.6.1
8.2.3.6.2 8.2.3.6.3 8.2.3.6.4 8.2.3.7.1 8.2.3.7.2 8.2.3.7.3
8.2.3.7.4 8.2.3.8.1 8.2.3.8.2 8.2.3.8.3 8.2.3.8.4 8.2.4.1.1
8.2.4.1.2 8.2.4.1.3 8.2.4.1.4 8.2.4.2.1 8.2.4.2.2 8.2.4.2.3
8.2.4.2.4 8.2.4.3.1 8.2.4.3.2 8.2.4.3.3 8.2.4.3.4 8.2.4.4.1
8.2.4.4.2 8.2.4.4.3 8.2.4.4.4 8.2.4.5.1 8.2.4.5.2 8.2.4.5.3
8.2.4.5.4 8.2.4.6.1 8.2.4.6.2 8.2.4.6.3 8.2.4.6.4 8.2.4.7.1
8.2.4.7.2 8.2.4.7.3 8.2.4.7.4 8.2.4.8.1 8.2.4.8.2 8.2.4.8.3
8.2.4.8.4 8.3.1.1.1 8.3.1.1.2 8.3.1.1.3 8.3.1.1.4 8.3.1.2.1
8.3.1.2.2 8.3.1.2.3 8.3.1.2.4 8.3.1.3.1 8.3.1.3.2 8.3.1.3.3
8.3.1.3.4 8.3.1.4.1 8.3.1.4.2 8.3.1.4.3 8.3.1.4.4 8.3.1.5.1
8.3.1.5.2 8.3.1.5.3 8.3.1.5.4 8.3.1.6.1 8.3.1.6.2 8.3.1.6.3
8.3.1.6.4 8.3.1.7.1 8.3.1.7.2 8.3.1.7.3 8.3.1.7.4 8.3.1.8.1
8.3.1.8.2 8.3.1.8.3 8.3.1.8.4 8.3.2.1.1 8.3.2.1.2 8.3.2.1.3
8.3.2.1.4 8.3.2.2.1 8.3.2.2.2 8.3.2.2.3 8.3.2.2.4 8.3.2.3.1
8.3.2.3.2 8.3.2.3.3 8.3.2.3.4 8.3.2.4.1 8.3.2.4.2 8.3.2.4.3
8.3.2.4.4 8.3.2.5.1 8.3.2.5.2 8.3.2.5.3 8.3.2.5.4 8.3.2.6.1
8.3.2.6.2 8.3.2.6.3 8.3.2.6.4 8.3.2.7.1 8.3.2.7.2 8.3.2.7.3
8.3.2.7.4 8.3.2.8.1 8.3.2.8.2 8.3.2.8.3 8.3.2.8.4 8.3.3.1.1
8.3.3.1.2 8.3.3.1.3 8.3.3.1.4 8.3.3.2.1 8.3.3.2.2 8.3.3.2.3
8.3.3.2.4 8.3.3.3.1 8.3.3.3.2 8.3.3.3.3 8.3.3.3.4 8.3.3.4.1
8.3.3.4.2 8.3.3.4.3 8.3.3.4.4 8.3.3.5.1 8.3.3.5.2 8.3.3.5.3
8.3.3.5.4 8.3.3.6.1 8.3.3.6.2 8.3.3.6.3 8.3.3.6.4 8.3.3.7.1
8.3.3.7.2 8.3.3.7.3 8.3.3.7.4 8.3.3.8.1 8.3.3.8.2 8.3.3.8.3
8.3.3.8.4 8.3.4.1.1 8.3.4.1.2 8.3.4.1.3 8.3.4.1.4 8.3.4.2.1
8.3.4.2.2 8.3.4.2.3 8.3.4.2.4 8.3.4.3.1 8.3.4.3.2 8.3.4.3.3
8.3.4.3.4 8.3.4.4.1 8.3.4.4.2 8.3.4.4.3 8.3.4.4.4 8.3.4.5.1
8.3.4.5.2 8.3.4.5.3 8.3.4.5.4 8.3.4.6.1 8.3.4.6.2 8.3.4.6.3
8.3.4.6.4 8.3.4.7.1 8.3.4.7.2 8.3.4.7.3 8.3.4.7.4 8.3.4.8.1
8.3.4.8.2 8.3.4.8.3 8.3.4.8.4 8.4.1.1.1 8.4.1.1.2 8.4.1.1.3
8.4.1.1.4 8.4.1.2.1 8.4.1.2.2 8.4.1.2.3 8.4.1.2.4 8.4.1.3.1
8.4.1.3.2 8.4.1.3.3 8.4.1.3.4 8.4.1.4.1 8.4.1.4.2 8.4.1.4.3
8.4.1.4.4 8.4.1.5.1 8.4.1.5.2 8.4.1.5.3 8.4.1.5.4 8.4.1.6.1
8.4.1.6.2 8.4.1.6.3 8.4.1.6.4 8.4.1.7.1 8.4.1.7.2 8.4.1.7.3
8.4.1.7.4 8.4.1.8.1 8.4.1.8.2 8.4.1.8.3 8.4.1.8.4 8.4.2.1.1
8.4.2.1.2 8.4.2.1.3 8.4.2.1.4 8.4.2.2.1 8.4.2.2.2 8.4.2.2.3
8.4.2.2.4 8.4.2.3.1 8.4.2.3.2 8.4.2.3.3 8.4.2.3.4 8.4.2.4.1
8.4.2.4.2 8.4.2.4.3 8.4.2.4.4 8.4.2.5.1 8.4.2.5.2 8.4.2.5.3
8.4.2.5.4 8.4.2.6.1 8.4.2.6.2 8.4.2.6.3 8.4.2.6.4 8.4.2.7.1
8.4.2.7.2 8.4.2.7.3 8.4.2.7.4 8.4.2.8.1 8.4.2.8.2 8.4.2.8.3
8.4.2.8.4 8.4.3.1.1 8.4.3.1.2 8.4.3.1.3 8.4.3.1.4 8.4.3.2.1
8.4.3.2.2 8.4.3.2.3 8.4.3.2.4 8.4.3.3.1 8.4.3.3.2 8.4.3.3.3
8.4.3.3.4 8.4.3.4.1 8.4.3.4.2 8.4.3.4.3 8.4.3.4.4 8.4.3.5.1
8.4.3.5.2 8.4.3.5.3 8.4.3.5.4 8.4.3.6.1 8.4.3.6.2 8.4.3.6.3
8.4.3.6.4 8.4.3.7.1 8.4.3.7.2 8.4.3.7.3 8.4.3.7.4 8.4.3.8.1
8.4.3.8.2 8.4.3.8.3 8.4.3.8.4 8.4.4.1.1 8.4.4.1.2 8.4.4.1.3
8.4.4.1.4 8.4.4.2.1 8.4.4.2.2 8.4.4.2.3 8.4.4.2.4 8.4.4.3.1
8.4.4.3.2 8.4.4.3.3 8.4.4.3.4 8.4.4.4.1 8.4.4.4.2 8.4.4.4.3
8.4.4.4.4 8.4.4.5.1 8.4.4.5.2 8.4.4.5.3 8.4.4.5.4 8.4.4.6.1
8.4.4.6.2 8.4.4.6.3 8.4.4.6.4 8.4.4.7.1 8.4.4.7.2 8.4.4.7.3
8.4.4.7.4 8.4.4.8.1 8.4.4.8.2 8.4.4.8.3 8.4.4.8.4 8.5.1.1.1
8.5.1.1.2 8.5.1.1.3 8.5.1.1.4 8.5.1.2.1 8.5.1.2.2 8.5.1.2.3
8.5.1.2.4 8.5.1.3.1 8.5.1.3.2 8.5.1.3.3 8.5.1.3.4 8.5.1.4.1
8.5.1.4.2 8.5.1.4.3 8.5.1.4.4 8.5.1.5.1 8.5.1.5.2 8.5.1.5.3
8.5.1.5.4 8.5.1.6.1 8.5.1.6.2 8.5.1.6.3 8.5.1.6.4 8.5.1.7.1
8.5.1.7.2 8.5.1.7.3 8.5.1.7.4 8.5.1.8.1 8.5.1.8.2 8.5.1.8.3
8.5.1.8.4 8.5.2.1.1 8.5.2.1.2 8.5.2.1.3 8.5.2.1.4 8.5.2.2.1
8.5.2.2.2 8.5.2.2.3 8.5.2.2.4 8.5.2.3.1 8.5.2.3.2 8.5.2.3.3
8.5.2.3.4 8.5.2.4.1 8.5.2.4.2 8.5.2.4.3 8.5.2.4.4 8.5.2.5.1
8.5.2.5.2 8.5.2.5.3 8.5.2.5.4 8.5.2.6.1 8.5.2.6.2 8.5.2.6.3
8.5.2.6.4 8.5.2.7.1 8.5.2.7.2 8.5.2.7.3 8.5.2.7.4 8.5.2.8.1
8.5.2.8.2 8.5.2.8.3 8.5.2.8.4 8.5.3.1.1 8.5.3.1.2 8.5.3.1.3
8.5.3.1.4 8.5.3.2.1 8.5.3.2.2 8.5.3.2.3 8.5.3.2.4 8.5.3.3.1
8.5.3.3.2 8.5.3.3.3 8.5.3.3.4 8.5.3.4.1 8.5.3.4.2 8.5.3.4.3
8.5.3.4.4 8.5.3.5.1 8.5.3.5.2 8.5.3.5.3 8.5.3.5.4 8.5.3.6.1
8.5.3.6.2 8.5.3.6.3 8.5.3.6.4 8.5.3.7.1 8.5.3.7.2 8.5.3.7.3
8.5.3.7.4 8.5.3.8.1 8.5.3.8.2 8.5.3.8.3 8.5.3.8.4 8.5.4.1.1
8.5.4.1.2 8.5.4.1.3 8.5.4.1.4 8.5.4.2.1 8.5.4.2.2 8.5.4.2.3
8.5.4.2.4 8.5.4.3.1 8.5.4.3.2 8.5.4.3.3 8.5.4.3.4 8.5.4.4.1
8.5.4.4.2 8.5.4.4.3 8.5.4.4.4 8.5.4.5.1 8.5.4.5.2 8.5.4.5.3
8.5.4.5.4 8.5.4.6.1 8.5.4.6.2 8.5.4.6.3 8.5.4.6.4 8.5.4.7.1
8.5.4.7.2 8.5.4.7.3 8.5.4.7.4 8.5.4.8.1 8.5.4.8.2 8.5.4.8.3
8.5.4.8.4 8.6.1.1.1 8.6.1.1.2 8.6.1.1.3 8.6.1.1.4 8.6.1.2.1
8.6.1.2.2 8.6.1.2.3 8.6.1.2.4 8.6.1.3.1 8.6.1.3.2 8.6.1.3.3
8.6.1.3.4 8.6.1.4.1 8.6.1.4.2 8.6.1.4.3 8.6.1.4.4 8.6.1.5.1
8.6.1.5.2 8.6.1.5.3 8.6.1.5.4 8.6.1.6.1 8.6.1.6.2 8.6.1.6.3
8.6.1.6.4 8.6.1.7.1 8.6.1.7.2 8.6.1.7.3 8.6.1.7.4 8.6.1.8.1
8.6.1.8.2 8.6.1.8.3 8.6.1.8.4 8.6.2.1.1 8.6.2.1.2 8.6.2.1.3
8.6.2.1.4 8.6.2.2.1 8.6.2.2.2 8.6.2.2.3 8.6.2.2.4 8.6.2.3.1
8.6.2.3.2 8.6.2.3.3 8.6.2.3.4 8.6.2.4.1 8.6.2.4.2 8.6.2.4.3
8.6.2.4.4 8.6.2.5.1 8.6.2.5.2 8.6.2.5.3 8.6.2.5.4 8.6.2.6.1
8.6.2.6.2 8.6.2.6.3 8.6.2.6.4 8.6.2.7.1 8.6.2.7.2 8.6.2.7.3
8.6.2.7.4 8.6.2.8.1 8.6.2.8.2 8.6.2.8.3 8.6.2.8.4 8.6.3.1.1
8.6.3.1.2 8.6.3.1.3 8.6.3.1.4 8.6.3.2.1 8.6.3.2.2 8.6.3.2.3
8.6.3.2.4 8.6.3.3.1 8.6.3.3.2 8.6.3.3.3 8.6.3.3.4 8.6.3.4.1
8.6.3.4.2 8.6.3.4.3 8.6.3.4.4 8.6.3.5.1 8.6.3.5.2 8.6.3.5.3
8.6.3.5.4 8.6.3.6.1 8.6.3.6.2 8.6.3.6.3 8.6.3.6.4 8.6.3.7.1
8.6.3.7.2 8.6.3.7.3 8.6.3.7.4 8.6.3.8.1 8.6.3.8.2 8.6.3.8.3
8.6.3.8.4 8.6.4.1.1 8.6.4.1.2 8.6.4.1.3 8.6.4.1.4 8.6.4.2.1
8.6.4.2.2 8.6.4.2.3 8.6.4.2.4 8.6.4.3.1 8.6.4.3.2 8.6.4.3.3
8.6.4.3.4 8.6.4.4.1 8.6.4.4.2 8.6.4.4.3 8.6.4.4.4 8.6.4.5.1
8.6.4.5.2 8.6.4.5.3 8.6.4.5.4 8.6.4.6.1 8.6.4.6.2 8.6.4.6.3
8.6.4.6.4 8.6.4.7.1 8.6.4.7.2 8.6.4.7.3 8.6.4.7.4 8.6.4.8.1
8.6.4.8.2 8.6.4.8.3 8.6.4.8.4 8.7.1.1.1 8.7.1.1.2 8.7.1.1.3
8.7.1.1.4 8.7.1.2.1 8.7.1.2.2 8.7.1.2.3 8.7.1.2.4 8.7.1.3.1
8.7.1.3.2 8.7.1.3.3 8.7.1.3.4 8.7.1.4.1 8.7.1.4.2 8.7.1.4.3
8.7.1.4.4 8.7.1.5.1 8.7.1.5.2 8.7.1.5.3 8.7.1.5.4 8.7.1.6.1
8.7.1.6.2 8.7.1.6.3 8.7.1.6.4 8.7.1.7.1 8.7.1.7.2 8.7.1.7.3
8.7.1.7.4 8.7.1.8.1 8.7.1.8.2 8.7.1.8.3 8.7.1.8.4 8.7.2.1.1
8.7.2.1.2 8.7.2.1.3 8.7.2.1.4 8.7.2.2.1 8.7.2.2.2 8.7.2.2.3
8.7.2.2.4 8.7.2.3.1 8.7.2.3.2 8.7.2.3.3 8.7.2.3.4 8.7.2.4.1
8.7.2.4.2 8.7.2.4.3 8.7.2.4.4 8.7.2.5.1 8.7.2.5.2 8.7.2.5.3
8.7.2.5.4 8.7.2.6.1 8.7.2.6.2 8.7.2.6.3 8.7.2.6.4 8.7.2.7.1
8.7.2.7.2 8.7.2.7.3 8.7.2.7.4 8.7.2.8.1 8.7.2.8.2 8.7.2.8.3
8.7.2.8.4 8.7.3.1.1 8.7.3.1.2 8.7.3.1.3 8.7.3.1.4 8.7.3.2.1
8.7.3.2.2 8.7.3.2.3 8.7.3.2.4 8.7.3.3.1 8.7.3.3.2 8.7.3.3.3
8.7.3.3.4 8.7.3.4.1 8.7.3.4.2 8.7.3.4.3 8.7.3.4.4
8.7.3.5.1 8.7.3.5.2 8.7.3.5.3 8.7.3.5.4 8.7.3.6.1 8.7.3.6.2
8.7.3.6.3 8.7.3.6.4 8.7.3.7.1 8.7.3.7.2 8.7.3.7.3 8.7.3.7.4
8.7.3.8.1 8.7.3.8.2 8.7.3.8.3 8.7.3.8.4 8.7.4.1.1 8.7.4.1.2
8.7.4.1.3 8.7.4.1.4 8.7.4.2.1 8.7.4.2.2 8.7.4.2.3 8.7.4.2.4
8.7.4.3.1 8.7.4.3.2 8.7.4.3.3 8.7.4.3.4 8.7.4.4.1 8.7.4.4.2
8.7.4.4.3 8.7.4.4.4 8.7.4.5.1 8.7.4.5.2 8.7.4.5.3 8.7.4.5.4
8.7.4.6.1 8.7.4.6.2 8.7.4.6.3 8.7.4.6.4 8.7.4.7.1 8.7.4.7.2
8.7.4.7.3 8.7.4.7.4 8.7.4.8.1 8.7.4.8.2 8.7.4.8.3 8.7.4.8.4
8.8.1.1.1 8.8.1.1.2 8.8.1.1.3 8.8.1.1.4 8.8.1.2.1 8.8.1.2.2
8.8.1.2.3 8.8.1.2.4 8.9.1.3.1 8.8.1.3.2 8.8.1.3.3 8.8.1.3.4
8.8.1.4.1 8.8.1.4.2 8.8.1.4.3 8.8.1.4.4 8.8.1.5.1 8.8.1.5.2
8.8.1.5.3 8.8.1.5.4 8.8.1.6.1 8.8.1.6.2 8.8.1.6.3 8.8.1.6.4
8.8.1.7.1 8.8.1.7.2 8.8.1.7.3 8.8.1.7.4 8.8.1.8.1 8.8.1.8.2
8.8.1.8.3 8.8.1.8.4 8.8.2.1.1 8.8.2.1.2 8.8.2.1.3 8.8.2.1.4
8.8.2.2.1 8.8.2.2.2 8.8.2.2.3 8.8.2.2.4 8.8.2.3.1 8.8.2.3.2
8.8.2.3.3 8.8.2.3.4 8.8.2.4.1 8.8.2.4.2 8.8.2.4.3 8.8.2.4.4
8.8.2.5.1 8.8.2.5.2 8.8.2.5.3 8.8.2.5.4 8.8.2.6.1 8.8.2.6.2
8.8.2.6.3 8.8.2.6.4 8.8.2.7.1 8.8.2.7.2 8.8.2.7.3 8.8.2.7.4
8.8.2.8.1 8.8.2.8.2 8.8.2.8.3 8.8.2.8.4 8.8.3.1.1 8.8.3.1.2
8.8.3.1.3 8.8.3.1.4 8.8.3.2.1 8.8.3.2.2 8.8.3.2.3 8.8.3.2.4
8.8.3.3.1 8.8.3.3.2 8.8.3.3.3 8.8.3.3.4 8.8.3.4.1 8.8.3.4.2
8.8.3.4.3 8.8.3.4.4 8.8.3.5.1 8.8.3.5.2 8.8.3.5.3 8.8.3.5.4
8.8.3.6.1 8.8.3.6.2 8.8.3.6.3 8.8.3.6.4 8.8.3.7.1 8.8.3.7.2
8.8.3.7.3 8.8.3.7.4 8.8.3.8.1 8.8.3.8.2 8.8.3.8.3 8.8.3.8.4
8.8.4.1.1 8.8.4.1.2 8.8.4.1.3 8.8.4.1.4 8.8.4.2.1 8.8.4.2.2
8.8.4.2.3 8.8.4.2.4 8.8.4.3.1 8.8.4.3.2 8.8.4.3.3 8.8.4.3.4
8.8.4.4.1 8.8.4.4.2 8.8.4.4.3 8.8.4.4.4 8.8.4.5.1 8.8.4.5.2
8.8.4.5.3 8.8.4.5.4 8.8.4.6.1 8.8.4.6.2 8.8.4.6.3 8.8.4.6.4
8.8.4.7.1 8.8.4.7.2 8.8.4.7.3 8.8.4.7.4 8.8.4.8.1 8.8.4.8.2
8.8.4.8.3 8.8.4.8.4
[0667] Thus, the compound named in Table 3 of formula (v) having
substitutents from Group 1 of each variable B, X, D, and E named
2.4.1.1.1 specifies --NH.sub.2 as A, -Pr-n as B, furan-2,5-diyl as
X, --H as D and --H as E, and this compound is
2-amino-5-propyl-6-[2-(5-phosphono)furanyl]pyridine prepared in
Example 15 as compound 15.14. Compounds named in Table 3 of formula
(v) are compounds with a pyridinyl as R.sup.5 in formula I.
Analogously, the compound named 2.1.1.1.3 in Table 3 of formula (v)
using substitutents of Group 1 of each variable B, X, D, and E has
the structure of 2-amino-3-ethyl-6-[2-(5-phosphono)furanyl]pyridine
and was prepared in Example 15 as compound 15.12.
[0668] Compounds named in Table 3 of formula (vi) are compounds
with a pyrazinyl as R.sup.5 in formula I. One preferred pyrazinyl
compound named in Table 3 of formula (vi) is 2.1.1.0.4. Using Group
1 of each variable, 2.1.1.0.4 has the structure of
2-amino-3-propyl-6-[2-(phosphono)furanyl]pyrazine and was prepared
in Example 17 as compound 17.3. Similarly, compounds named in Table
3 of formula (vii) are compounds with a pyrimidinyl as R.sup.5 in
formula I. The formula (vii) compound named 2.4.1.1.0 in Table 3
using all Group 1 variables has the structure of
2-amino-5-propyl-6-[2-(phosphono)furanyl]pyrimidine and was
prepared in Example 16 as compound 16.1. Similarly, compounds named
in Table 3 of formula (viii) are compounds with a pyrimidinyl as
R.sup.5 in formula I. Thus, using Group 1 variable, the compound
named 1.0.1.1.1 in Table 3 has the structure of
2-[2-(5-phosphono)furanyl]pyrimidine and was prepared in Example 16
as compound 16.5.
[0669] Some of the exemplary embodiments of the compounds named in
Table 3 using Groups 1-4 for variable B, Groups 1-2 for variable X,
Groups 1-2 for variable D, and Groups 1-3 for variable E in the
compound of formulae (v), (vi), (vii), (viii) and (ix) are listed
in Table 4. TABLE-US-00024 TABLE 4 Compound Synthetic No. as
Example group group group group A.B.X.D.E No. Formula A No.* B No.*
X** No.* D No.* E 1.1.1.1.1 15.6 (v) H 1 H 1 furan-2,5-diyl 1 H 1 H
1.1.2.1.1. 12.1 (v) H 1 H 1 pyridin-2,6-diyl 1 H 1 H 6.1.4.2.1 13.1
(v) Me 1 H 5 CH2OCH2 2 Me 1 H 6.1.1.2.1 15.15 (v) Me 1 H 1
furan-2,5-diyl 1 Me 2 Br 4.1.1.1.1 15.9 (v) Cl 1 H 1 furan-2,5-diyl
1 H 1 H 1.8.1.1.2 15.10 (v) H 1 Cl 1 furan-2,5-diyl 1 H 2 Cl
6.7.1.1.1 15.5 (v) Me 1 Br 1 furan-2,5-diyl 1 H 1 H 2.1.1.1.1 15.1
(v) NH2 1 H 1 furan-2,5-diyl 1 H 1 H 2.7.1.1.1 15.2 (v) NH2 1 Br 1
furan-2,5-diyl 1 H 1 H 2.7.1.1.1 15.3 (v) NH2 1 Br 1 furan-2,5-diyl
1 H 2 Br 2.3.1.1.3 15.4 (v) NH2 1 Et 1 furan-2,5-diyl 1 H 1 Et
2.1.1.1.3 15.12 (v) NH2 1 H 1 furan-2,5-diyl 1 H 1 Et 2.3.1.1.1
15.13 (v) NH2 1 Et 1 furan-2,5-diyl 1 H 1 H 2.4.1.1.1 15.14 (v) NH2
1 Pr-n 1 furan-2,5-diyl 1 H 1 H 2.4.1.1.0 16.1 (vii) NH2 1 Pr-n 1
furan-2,5-diyl 1 H null 2.4.1.1.0 16.2 (vii) NH2 2 Bu-i 1
furan-2,5-diyl 1 H null 2.4.4.2.0 13.2 (vii) NH2 1 Pr-n 2 CH2OCH2 1
Me null 2.1.1.2.0 16.6 (vii) NH2 1 H 1 furan-2,5-diyl 1 Me null
6.1.1.1.0 16.8 (vii) Me 1 H 1 furan-2,5-diyl 1 H null 2.1.1.1.0
16.3 (vii) NH2 1 H 1 furan-2,5-diyl 1 H null 2.3.1.1.0 16.4 (vii)
NH2 1 Et 1 furan-2,5-diyl 1 H null 1.0.1.1.2 16.5 (viii) H null 1
furan-2,5-diyl 1 H 1 H 6.0.1.7.2 16.9 (viii) Me null 1
furan-2,5-diyl 1 Br 1 Me 6.2.1.0.1 17.1 (vi) Me 1 Me 1
furan-2,5-diyl null 1 H 4.1.1.0.1 17.2 (vi) Cl 1 H 1 furan-2,5-diyl
null 1 H 2.1.1.0.4 17.3 (vi) NH2 1 H 1 furan-2,5-diyl null 1 Pr-n
2.8.1.0.1 15.19 (vii) NH2 1 Cl 1 furan-2,5-diyl 1 H null 2.1.1.5.0
16.11 (vii) NH2 1 H 1 furan-2,5-diyl 1 SMe null 1.8.1.0.1 17.6 (vi)
H 2 SMe 1 furan-2,5-diyl null 1 H 2.7.1.5.0 16.12 (vii) NH2 1 Br 1
furan-2,5-diyl 1 SMe null 2.8.1.0.1 17.7 (vi) NH2 2 SMe 1
furan-2,5-diyl null 1 H 2.1.1.0.3 17.8 (vi) NH2 1 H 1
furan-2,5-diyl null 3 SMe 2.8.1.0.1 17.9 (vi) NH2 1 Cl 1
furan-2,5-diyl null 3 CO2Me 1.1.3.1.1 18.8 (v) H 1 H 1 C(O)NHCH2 1
H 1 H 1.1.1.1.1 18.9 (v) H 1 H 2 NHC(O)CH2 1 H 1 H 2.1.1.1.2 15.19
(v) NH2 1 H 1 furan-2,5-diyl 1 H 3 Pr-c 2.6.1.1.1 15.20 (v) NH2 1
Pr-c 1 furan-2,5-diyl 1 H 1 H 2.8.1.0.1 17.10 (vi) NH2 2 SMe 1
furan-2,5-diyl null 1 H 6.2.1.1.1 15.22 (v) Me 2 CN 1
furan-2,5-diyl 1 H 1 H 2.2.1.2.4 15.23 (v) NH2 2 CN 1
furan-2,5-diyl 1 Me 2 CN 1.1.3.1.1 30.1 (v) H 1 H 2 ethyn-1,2-diyl
1 H 1 H 2.1.1.1.1 18.23 (v) NH2 1 H 2 NHC(O)CH2 1 H 1 H 4.1.1.3.1
15.24 (v) Cl 1 H 1 furan-2,5-diyl 2 CN 1 H 2.0.1.8.1 16.14 (viii)
NH2 null 1 furan-2,5-diyl 1 Cl 1 H 2.1.1.1.1 18.25 (v) NH2 1 H 2
NHC(O)CH2 1 H 2 Br 2.7.1.1.1 18.26 (v) NH2 1 Br 2 NHC(O)CH2 1 H 2
Br 2.3.1.1.3 18.28 (v) NH2 1 Et 2 NHC(O)CH2 1 H 1 Et 2.8.1.2.0 33.1
(vii) NH2 1 Cl 1 furan-2,5-diyl 1 Me null 2.0.1.7.1 33.13 (viii)
NH2 null 1 furan-2,5-diyl 2 OMe 1 H 1.7.1.0.1 33.14 (vi) H 4 OMe 1
furan-2,5-diyl null 1 H 1.7.1.0.1 33.27 (vi) H 2 OEt 1
furan-2,5-diyl null 1 H 4.1.1.3.1 33.36 (v) Cl 1 H 1 furan-2,5-diyl
2 CN 1 H 4.1.1.6.1 33.38 (v) Cl 1 H 1 furan-2,5-diyl 2 C(O)NH2 1 H
4.1.1.4.1 33.39 (v) Cl 1 H 1 furan-2,5-diyl 1 CO2Et 1 H 4.1.1.2.4
33.41 (v) Cl 1 H 1 furan-2,5-diyl 1 Me 2 CN 4.1.1.8.4 33.43 (v) Cl
1 H 1 furan-2,5-diyl 2 CF3 2 CN 0.2.1.2.1 33.44 (ix) null 1 Me 1
furan-2,5-diyl 1 Me 2 Br 0.2.1.2.2 33.45 (ix) null 1 Me 1
furan-2,5-diyl 1 Me 2 Cl 3.2.1.1.0 33.46 (vii) Br 1 Me 1
furan-2,5-diyl 1 H null 3.7.1.1.0 33.47 (vii) Br 1 Br 1
furan-2,5-diyl 1 H null 3.1.1.2.0 33.48 (vii) Br 1 H 1
furan-2,5-diyl 1 Me null 3.8.1.7.0 33.50 (vii) Br 1 Cl 1
furan-2,5-diyl 1 Br null 2.1.1.7.0 33.52 (vii) NH2 1 H 1
furan-2,5-diyl 1 Br null 3.1.1.7.0 33.54 (vii) Br 1 H 1
furan-2,5-diyl 1 Br null 3.1.1.8.0 33.55 (vii) Br 1 H 1
furan-2,5-diyl 1 Cl null 1.7.1.0.1 33.56 (vi) H 1 Br 1
furan-2,5-diyl null 1 H 2.8.1.0.1 33.57 (vi) NH2 1 Cl 1
furan-2,5-diyl null 3 CO2Me 1.8.1.0.1 33.59 (vi) H 3 OPr-n 1
furan-2,5-diyl null 1 H 6.1.1.1.1 33.97 (v) Me 1 H 2 NHC(O)CH2 1 H
1 H 1.2.1.1.1 33.98 (v) H 1 Me 2 NHC(O)CH2 1 H 1 H 2.1.1.1.2 33.99
(v) NH2 1 H 2 NHC(O)CH2 1 H 2 Cl 2.8.1.1.1 33.100 (v) NH2 1 Cl 2
NHC(O)CH2 1 H 1 H 6.1.1.2.1 33.102 (v) Me 1 H 2 NHC(O)CH2 1 Me 1 H
1.1.1.1.2 33.103 (v) H 1 H 2 NHC(O)CH2 1 H 2 Cl 1.1.1.1.1 33.104
(v) H 1 H 2 NHC(O)CH2 1 H 2 Br 5.1.1.1.1 33.105 (v) Me 1 H 2
NHC(O)CH2 1 H 2 Br 1.1.1.1.1 33.106 (v) H 1 H 2 NHC(O)CH2 1 H 1 H
1.1.1.1.2 33.107 (v) H 1 H 2 NHC(O)CH2 1 H 1 Me 1.1.1.2.1 33.108
(v) H 1 H 2 NHC(O)CH2 1 Me 1 H 6.8.1.2.0 33.109 (vii) Me 1 Cl 2
NHC(O)CH2 1 Me null 4.1.1.0.1 33.110 (vi) Cl 1 H 2 NHC(O)CH2 1 null
1 H 1.7.1.1.2 33.111 (v) H 1 Br 2 NHC(O)CH2 1 H 1 Me 1.1.1.3.1
33.114 (v) H 1 H 2 NHC(O)CH2 1 Et 1 H 6.3.1.1.1 33.115 (v) Me 1 Et
2 NHC(O)CH2 1 H 1 H 6.1.1.1.1 33.116 (v) Me 1 H 2 NHC(O)CH2 1 H 2
Br 1.7.1.1.2 33.117 (v) H 1 Br 2 NHC(O)CH2 1 H 1 Me 1.2.1.1.1
33.118 (v) H 1 Me 2 NHC(O)CH2 1 H 2 Br 6.7.1.1.1 33.119 (v) Me 1 Br
2 NHC(O)CH2 1 H 2 Br 1.1.3.1.1 33.120 (v) H 1 H 1 C(O)NHCH2 1 H 1 H
6.1.3.1.1 33.121 (v) Me 1 H 1 C(O)NHCH2 1 H 1 H 3.1.3.1.1 33.123
(v) Br 1 H 1 C(O)NHCH2 1 H 1 H 4.1.3.1.1 33.124 (v) Cl 1 H 1
C(O)NHCH2 1 H 1 H 1.1.3.8.1 33.125 (v) H 1 H 1 C(O)NHCH2 1 Cl 1 H
1.1.3.0.1 33.127 (vi) H 1 H 1 C(O)NHCH2 null 1 H 1.8.3.1.1 33.130
(v) H 3 OPr-n 1 C(O)NHCH2 1 H 1 H 4.8.3.1.1 33.131 (v) Cl 1 Cl 1
C(O)NHCH2 1 H 1 H 4.7.3.1.1 33.132 (v) Cl 3 CF3 1 C(O)NHCH2 1 H 1 H
1.8.3.8.2 33.134 (v) H 1 Cl 1 C(O)NHCH2 1 Cl 2 Cl 1.1.3.0.2 33.140
(vi) H 1 H 1 C(O)NHCH2 null 1 Me 1.2.3.1.1 33.141 (v) H 1 Me 1
C(O)NHCH2 1 H 1 H 4.8.3.8.2 33.142 (v) Cl 1 Cl 1 C(O)NHCH2 1 Cl 2
Cl *The group number in front of B, X, D or E indicates the
compound group in which the corresponding B, X, D or E is selected.
**The direction of X groups is defined as going from R5 to the
phosphorus atom
[0670] The numbers designated in Table 3 also refer to preferred
benzothiazole and benzoxazole compounds of formula X. These
preferred compounds are shown in structures (x) and (xi), below:
##STR56##
[0671] The preferred compounds of formula (x) and formula (xi) are
listed in Table 3 by designated numbers assigned to B, X, A, D and
E in the above formulae (x) and (xi) according to the following
convention: B.X.A.D.E. For each moiety, structures are assigned to
a number shown in the following tables for B, X, A, D, and E.
[0672] Variable B is divided into two Groups, each listing eight
different substitutents. The substitutents for variable B of
formula (x) and formula (xi) in Table 3 are assigned the following
numbers:
[0673] The Group 1 substitutents for variable B in Table 3 for
formulae (x) and (xi) are assigned the following numbers:
TABLE-US-00025 1 2 3 4 5 6 7 8 B = H Me Et Pr-n Pr-c Pr-i Br Cl
[0674] The Group 2 substitutents for variable B are assigned the
following numbers: TABLE-US-00026 1 2 3 4 5 6 7 8 B = CN F OMe OEt
SMe SEt CH.sub.2OH C(O)OEt
[0675] Variable X is selected from eight different substitutents,
assigned with the following numbers: TABLE-US-00027 TABLE X 1 2 3 4
5 6 7 8 X = OCH.sub.2 SCH.sub.2 CH.sub.2CH.sub.2
CH.sub.2CH.sub.2CH.sub.2 CH.sub.2CF.sub.2 NHCH.sub.2 OC(O)
SC(O)
The direction of X groups is defined as going from the heterocycle
to the phosphorus atom as shown in formula (x) and formula
(xi).
[0676] Variable A is selected from four different substitutents
assigned with the following numbers: TABLE-US-00028 TABLE A 1 2 3 4
A = H NH.sub.2 Br Cl
[0677] Variable D is selected from eight different substitutents,
assigned with the following numbers: TABLE-US-00029 TABLE D 1 2 3 4
5 6 7 8 D = H Me Et C(O)OMe CH.sub.2OMe SMe SEt OMe
[0678] Variable E is selected from four different substitutents
assigned with the following numbers: TABLE-US-00030 TABLE E 1 2 3 4
E = H Me Et F
[0679] Thus, using Group 1 for variable B, the compound of formula
(x) named in Table 3 as 1.1.2.1.1 specifies --H as B, --OCH.sub.2--
as X, --NH.sub.2 as A, --H as D and --H as E, and this compound is
2-amino-4-phosphonomethoxybenzothiazole prepared in Example 34 as
compound 34.2. Similarly, using group 1 for variable B, the
compound named in Table 3 of formula (x) as 1.2.2.1.1 specifies --H
as B, --SCH.sub.2-- as X, --NH.sub.2 as A, --H as D and --H as E,
and this compound is 2-amino-4-phosphonomethylthiobenzothiazole in
Example 46 as compound 46.1.
[0680] Likewise, using Group 2 for variable B, the compound named
8.1.2.1.1 in Table 3 of formula (x) is
2-amino-7-ethoxycarbonyl-4-phosphonomethoxybenzothiazole in Example
37 prepared as compound 37.4.
[0681] Examples of preferred compounds of formula X also include,
but not limited to the pharmaceutically acceptable salts and
prodrugs of the compounds named in Table 5: TABLE-US-00031 TABLE 5
##STR57## Synthetic Example No. A Y' B D E X 36.1 NH2 S C7(CH2)4C6
C7(CH2)4C6 H OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 Me OCH2 NH2 S
C7(CH2)4C6 C7(CH2)4C6 Et OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 Pr-n OCH2
NH2 S C7(CH2)4C6 C7(CH2)4C6 Pr-c OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6
Ph OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 C(O)OMe OCH2 NH2 S C7(CH2)4C6
C7(CH2)4C6 C(O)OEt OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 C(O)NH2 OCH2
NH2 S C7(CH2)4C6 C7(CH2)4C6 OMe OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 Br
OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 Cl OCH2 NH2 S C7(CH2)4C6
C7(CH2)4C6 I OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 F OCH2 NH2 S
C7(CH2)4C6 C7(CH2)4C6 CF3 OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 CN OCH2
NH2 S C7(CH2)4C6 C7(CH2)4C6 SMe OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6
SEt OCH2 NH2 S C7(CH2)4C6 C7(CH2)4C6 NEt2 OCH2 NH2 S C7(CH2)4C6
C7(CH2)4C6 NMe2 OCH2 NH2 O C7(CH2)4C6 C7(CH2)4C6 H OCH2 NH2 O
C7(CH2)4C6 C7(CH2)4C6 Me OCH2 NH2 O C7(CH2)4C6 C7(CH2)4C6 Et OCH2
NH2 O C7(CH2)4C6 C7(CH2)4C6 Pr-n OCH2 NH2 O C7(CH2)4C6 C7(CH2)4C6
Br OCH2 NH2 O C7(CH2)4C6 C7(CH2)4C6 Cl OCH2 NH2 O C7(CH2)4C6
C7(CH2)4C6 I OCH2 NH2 O C7(CH2)4C6 C7(CH2)4C6 Ph OCH2 NH2 O
C7(CH2)4C6 C7(CH2)4C6 F OCH2 NH2 O C7(CH2)4C6 C7(CH2)4C6 NMe2 OCH2
NH2 O C7(CH2)4C6 C7(CH2)4C6 OH OCH2 45.1 H S C7(CH2)4C6 C7(CH2)4C6
H OCH2 H S C7(CH2)4C6 C7(CH2)4C6 Me OCH2 H S C7(CH2)4C6 C7(CH2)4C6
Et OCH2 H S C7(CH2)4C6 C7(CH2)4C6 Pr-n OCH2 H S C7(CH2)4C6
C7(CH2)4C6 Br OCH2 H S C7(CH2)4C6 C7(CH2)4C6 Cl OCH2 H S C7(CH2)4C6
C7(CH2)4C6 I OCH2 H S C7(CH2)4C6 C7(CH2)4C6 F OCH2 H S C7(CH2)4C6
C7(CH2)4C6 Ph OCH2 H S C7(CH2)4C6 C7(CH2)4C6 NMe2 OCH2 H O
C7(CH2)4C6 C7(CH2)4C6 H OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 H OCH2 NH2
S C7(CH2)3C6 C7(CH2)3C6 Me OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 Et OCH2
NH2 S C7(CH2)3C6 C7(CH2)3C6 Ph OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6
Pr-i OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 Pr-c OCH2 NH2 S C7(CH2)3C6
C7(CH2)3C6 Br OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 Cl OCH2 NH2 S
C7(CH2)3C6 C7(CH2)3C6 F OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 I OCH2 NH2
S C7(CH2)3C6 C7(CH2)3C6 NMe2 OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6
C(O)OEt OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 C(O)NH2 OCH2 NH2 S
C7(CH2)3C6 C7(CH2)3C6 OMe OCH2 NH2 S C7(CH2)3C6 C7(CH2)3C6 OH OCH2
H S C7(CH2)3C6 C7(CH2)3C6 H OCH2 H S C7(CH2)3C6 C7(CH2)3C6 Me OCH2
H S C7(CH2)3C6 C7(CH2)3C6 Et OCH2 H S C7(CH2)3C6 C7(CH2)3C6 Ph OCH2
H S C7(CH2)3C6 C7(CH2)3C6 OMe OCH2 H S C7(CH2)3C6 C7(CH2)3C6
C(O)OMe OCH2 H S C7(CH2)3C6 C7(CH2)3C6 Br OCH2 H S C7(CH2)3C6
C7(CH2)3C6 OH OCH2 36.2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 H OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Me OCH2
NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
Et OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Pr-i OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Pr-c
OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 OMe OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Br OCH2
NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 I
OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Cl OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 F OCH2
NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
NMe2 OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C(O)OMe OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C(O)OEt
OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Ph OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 CF3
OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 CN OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C(O)NH2
OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 SMe OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 SEt
OCH2 NH2 S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 CO2H OCH2 NH2 S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 OH OCH2
H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 H
OCH2 H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Me OCH2 H S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 H OCH2
H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Me
OCH2 H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Et OCH2 H S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 OMe
OCH2 H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Ph OCH2 H S
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Br OCH2
H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 Cl
OCH2 H S C7(CH.dbd.CH.dbd.CH.dbd.CH)C6
C7(CH.dbd.CH.dbd.CH.dbd.CH)C6 OH OCH2 NH2 S C7OCH.dbd.CHC6
C7OCH.dbd.CHC6 H OCH2 NH2 S C7O--CH.dbd.CHC6 C7O--CH.dbd.CHC6 Me
OCH2 NH2 S C7O--CH.dbd.CHC6 C7O--CH.dbd.CHC6 Ph OCH2 NH2 S
C7O--CH.dbd.CHC6 C7O--CH.dbd.CHC6 Br OCH2 NH2 S C7O--CH.dbd.CHC6
C7O--CH.dbd.CHC6 OH OCH2 NH2 S C7O--CH.dbd.CHC6 C7O--CH.dbd.CHC6
OMe OCH2 NH2 S C7CH.dbd.CH--OC6 C7CH.dbd.CH--OC6 H OCH2 NH2 S
C7CH.dbd.CH--OC6 C7CH.dbd.CH--OC6 Me OCH2 NH2 S C7CH.dbd.CH--OC6
C7CH.dbd.CH--OC6 Br OCH2 NH2 S C7CH.dbd.CH--OC6 C7CH.dbd.CH--OC6 Ph
OCH2 NH2 S C7CH.dbd.CH--OC6 C7CH.dbd.CH--OC6 OH OCH2 NH2 S
C7CH.dbd.CH--OC6 C7CH.dbd.CH--OC6 OMe OCH2 NH2 S C7S--CH.dbd.CHC6
C7S--CH.dbd.CHC6 H OCH2 NH2 S C7S--CH.dbd.CHC6 C7S--CH.dbd.CHC6 Me
OCH2 NH2 S C7S--CH.dbd.CHC6 C7S--CH.dbd.CHC6 Ph OCH2 NH2 S
C7S--CH.dbd.CHC6 C7S--CH.dbd.CHC6 OH OCH2 NH2 S C7S--CH.dbd.CHC6
C7S--CH.dbd.CHC6 OMe OCH2 NH2 S C7S--CH.dbd.CHC6 C7S--CH.dbd.CHC6
isobutyl OCH2 NH2 S Me C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2 NH2 S Et
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2
NH2 S Pr-n C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2 NH2 S OMe
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2
NH2 S OH C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2 NH2 S OCH3
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2
NH2 S Cl C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2 NH2 S Br
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2
NH2 S F C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
OCH2 NH2 S CH2OH C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2 NH2 S H
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2
NH2 S C(O)OMe C6(CH.dbd.CH.dbd.CH.dbd.CH)C5
C6(CH.dbd.CH.dbd.CH.dbd.CH)C5 OCH2 NH2 S H C6(CH2)4C5 C6(CH2)4C5
OCH2 NH2 S Me C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S Et C6(CH2)4C5
C6(CH2)4C5 OCH2 NH2 S OH C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S OMe
C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S CH2OH C6(CH2)4C5 C6(CH2)4C5 OCH2
NH2 S Br C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S Cl C6(CH2)4C5 C6(CH2)4C5
OCH2 NH2 S C(O)OMe C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S H
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S Me C6O--CH.dbd.CHC5
C6O--CH.dbd.CHC5 OCH2 NH2 S Et C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5
OCH2 NH2 S CH2OH C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S Br
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S Cl C6O--CH.dbd.CHC5
C6O--CH.dbd.CHC5 OCH2 NH2 S Ph C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5
OCH2 NH2 S OMe C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S Pr-n
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S C(O)OMe
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S H C6O--CH.dbd.CHC5
C6O--CH.dbd.CHC5 OCH2 NH2 S Me C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5
OCH2 NH2 S Et C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S OH
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S OMe C6O--CH.dbd.CHC5
C6O--CH.dbd.CHC5 OCH2 NH2 S CH2OH C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5
OCH2 NH2 S Br C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S Cl
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S C(O)OMe
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 NH2 S Ph C6O--CH.dbd.CHC5
C6O--CH.dbd.CHC5 OCH2 H S Me C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2
H S Br C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 H S Me
C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2 H S Br C6O--CH.dbd.CHC5
C6O--CH.dbd.CHC5 OCH2 H S H C6O--CH.dbd.CHC5 C6O--CH.dbd.CHC5 OCH2
Cl S C7(CH2)4C6 C7(CH2)4C6 H OCH2 Cl S C7(CH2)4C6 C7(CH2)4C6 Me
OCH2 Cl S C7(CH2)4C6 C7(CH2)4C6 Et OCH2 Cl S C7(CH2)4C6 C7(CH2)4C6
Pr-n OCH2 Cl S C7(CH2)4C6 C7(CH2)4C6 Ph OCH2 Cl S C7(CH2)4C6
C7(CH2)4C6 Br OCH2 Cl S C7(CH2)4C6 C7(CH2)4C6 Cl OCH2 Cl S
C7(CH2)4C6 C7(CH2)4C6 C(O)OMe OCH2 Cl S C7(CH2)4C6 C7(CH2)4C6 OH
OCH2 Me S C7(CH2)4C6 C7(CH2)4C6 H OCH2 Me S C7(CH2)4C6 C7(CH2)4C6
Me OCH2 Me S C7(CH2)4C6 C7(CH2)4C6 Et OCH2 Me S C7(CH2)4C6
C7(CH2)4C6 Pr-n OCH2 Me S C7(CH2)4C6 C7(CH2)4C6 Ph OCH2 Me S
C7(CH2)4C6 C7(CH2)4C6 OH OCH2 Me S C7(CH2)4C6 C7(CH2)4C6 Br OCH2 Me
S C7(CH2)4C6 C7(CH2)4C6 Cl OCH2 Me S C7(CH2)4C6 C7(CH2)4C6 C(O)OMe
OCH2 Me S C7(CH2)4C6 C7(CH2)4C6 NMe2 OCH2 NH2 S H C6(CH2)4C5
C6(CH2)4C5 OCH2 NH2 S Me C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S Et
C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S Pr-n C6(CH2)4C5 C6(CH2)4C5 OCH2
NH2 S Br C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S Cl C6(CH2)4C5 C6(CH2)4C5
OCH2 NH2 S OH C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S CF3 C6(CH2)4C5
C6(CH2)4C5 OCH2 NH2 S C(O)OMe C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S Ph
C6(CH2)4C5 C6(CH2)4C5 OCH2 NH2 S NMe2 C6(CH2)4C5 C6(CH2)4C5 OCH2
44.1 Br S C7(CH2)4C6 C7(CH2)4C6 H OCH2
[0682] The numbers designated in Table 1 also represent preferred
prodrugs of compounds of formula I as shown in formula (xii) and
(xiii), below: ##STR58##
[0683] In the above formulae (xii) and (xiii), Ar stands for aryl
including heteroaryl and is substituted by R.sup.25. The preferred
compounds of formula (xii) and formula (xiii) are listed in Table 1
designated by numbers assigned to X, R.sup.5, R.sup.25, and Ar in
the above formulae (xii) and (xiii) according to the following
convention: X.R.sup.5.R.sup.25.Ar.
[0684] Variable X is selected from seven different substitutents,
assigned the following numbers: TABLE-US-00032 TABLE X 1 2 3 4 5 6
7 X = Furan- C(O)OCH.sub.2 C(O)NHCH.sub.2 NHC(O)CH.sub.2 Pyridin-
CH.sub.2OCH.sub.2 C(O)SCH.sub.2 2,5-diyl 2,6-diyl
[0685] Variable R.sup.5 is selected from nine different
substitutents assigned the following numbers: TABLE-US-00033 TABLE
R.sup.5 1 2 3 4 5 R.sup.5 = ##STR59## ##STR60## ##STR61## ##STR62##
6 7 8 9 R.sup.5 = ##STR63## ##STR64## ##STR65## ##STR66##
[0686] Variable R.sup.25 is selected from nine different
substitutents assigned the following numbers: TABLE-US-00034 TABLE
R.sup.25 1 2 3 4 5 6 7 8 9 R.sup.25 = F Cl Br CN CF.sub.3 Me Et OMe
NHAc
[0687] Variable Ar is selected from six different substitutents
assigned the following numbers: TABLE-US-00035 TABLE Ar 1 2 3 4 5 6
Ar = ##STR67## ##STR68## ##STR69## ##STR70## ##STR71##
##STR72##
[0688] The compounds named in Table 1 of formula (xii) or formula
(xiii) each number listed in Table 1 of formula (xii) or formula
(xiii) are shown without depictions of stereochemistry since the
compounds are biologically active as the diastereomeric mixture or
as a single stereoisomer.
[0689] Using the variable for X, R.sup.5, R.sup.25, and Ar, the
compound of formula (xii) named 1.2.2.2 in Table 1 specifies
furan-2,5-diyl as X, 4-(2-amino-5-isobutyl)thiazolyl as R.sup.5,
chloro as R.sup.25, and 3-chlorophenyl as Ar, and this compound is
the diastereomers of
2-amino-5-isobutyl-4-{2-[5-(1-(3-chlorophenyl)-1,3-propyl)phosphono]furan-
yl}thiazoles prepared in Example 19 as compound 19.46 (major
isomer) and 19.45 (minor isomer).
[0690] The numbers designated in Table 3 also represent preferred
prodrugs of compounds of formula I as shown in the following
formulae (xiv) and (xv): ##STR73##
[0691] In the compounds of formulae (xiv) and (xv), Ar represents
aryl and heteroaryl and is substituted by R.sup.25. The preferred
compounds of formula (xiv) and formula (xv) are listed named in
Table 3 by designated numbers assigned to R.sup.5, R.sup.23, Ar,
R.sup.25 and X in the above formulae (xiv) and (xv) according to
the following convention: R.sup.5.R.sup.23.Ar.R.sup.25.X. For each
moiety, structures are assigned to a number shown in the following
tables for R.sup.5, R.sup.23, Ar, R.sup.25 and X.
[0692] The Variable R.sup.5 is selected from eight different
substitutents assigned the following numbers: TABLE-US-00036 TABLE
R.sup.5 1 2 3 4 5 R.sup.5 = ##STR74## ##STR75## ##STR76## ##STR77##
##STR78## 6 7 8 R.sup.5 = ##STR79## ##STR80## ##STR81##
[0693] The variable R.sup.23 is selected from eight different
substitutents assigned the following number: TABLE-US-00037 TABLE
R.sup.23 1 2 3 4 5 6 7 8 R.sup.23 = ##STR82## ##STR83## ##STR84##
##STR85## ##STR86## ##STR87## ##STR88## ##STR89##
[0694] The variable Ar is selected from four different
substitutents assigned the following numbers: TABLE-US-00038 TABLE
Ar 1 2 3 4 Ar = ##STR90## ##STR91## ##STR92## ##STR93##
[0695] The variable R.sup.25 is selected from eight different
substitutents assigned the following numbers: TABLE-US-00039 TABLE
R.sup.25 1 2 3 4 5 6 7 8 R.sup.25 = F Cl Br NHAc CF.sub.3 Me
CO.sub.2Et OMe
[0696] The variable X is selected from four different substitutents
assigned the following numbers: TABLE-US-00040 TABLE X 1 2 3 4 X =
Furan-2,5-diyl C(O)OCH.sub.2 C(O)NHCH.sub.2 NHC(O)CH.sub.2
[0697] Thus, using the variables for R.sup.5, R.sup.23, Ar,
R.sup.25, and X, the compound of formula (viv) named in Table 3 as
2.7.2.2.1 specifies 4-(2-amino-5-isobutyl)thiazolyl as R.sup.5,
--CH(Me)CO.sub.2Me as R.sup.23, 3-chlorophenyl as Ar, chloro as
R.sup.25, and furan-2,5-diyl as X, and this compound is
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-(1-(1-methoxycarbonyl)ethyl)phosph-
ono]furanyl}thiazole prepared in Example 31 as compound 31.6.
[0698] The numbers designated in Table 3 also represent preferred
prodrugs of compounds of formula I as shown in the following
formulae (xvi) and (xvii): ##STR94##
[0699] In the above formuale (xvi) and (xvii), Ar stands for aryl
including heteroaryl, and is substituted by R.sup.24 and R.sup.25.
The preferred compounds of formula (xvi) and formula (xvii) are
listed in Table 3 by designated numbers assigned to R.sup.24,
R.sup.25, Ar, R.sup.5, and R.sup.23 in the above formula according
to the following convention, R.sup.24.R.sup.25.Ar.R.sup.5.R.sup.23.
For each moiety, structures are assigned to a number shown in the
following tables for R.sup.24, R.sup.25, Ar, R.sup.5 and
R.sup.23.
[0700] Variable R.sup.24 is selected from eight different
substitutents assigned the following numbers: TABLE-US-00041 TABLE
R.sup.24 1 2 3 4 5 6 7 8 R.sup.24 = F Cl Br NHAc CF.sub.3 Me
CO.sub.2Et OMe
[0701] Variable R.sup.25 is selected from eight different
substitutents assigned the following numbers: TABLE-US-00042 TABLE
R.sup.25 1 2 3 4 5 6 7 8 R.sup.25 = F Cl Br NHAc CF.sub.3 Me
CO.sub.2Et OMe
[0702] Variable Ar is divided into two Groups, each listing four
different substituents. The Group 1 substitutents for variable Ar
are assigned the following numbers: ##STR95##
[0703] The Group 2 substitutents for variable Ar are assigned the
following numbers: ##STR96##
[0704] Variable R.sup.5 is selected from eight different
substitutents assigned the following numbers: TABLE-US-00043 TABLE
R.sup.5 1 2 3 4 5 R.sup.5 = ##STR97## ##STR98## ##STR99##
##STR100## ##STR101## 6 7 8 R.sup.5 = ##STR102## ##STR103##
##STR104##
[0705] Variable R.sup.23 is divided into two Groups, each listing
four different substitutents. The Group 1 substitutents for
variable R.sup.23 are assigned the following numbers:
##STR105##
[0706] The Group 2 substitutents for variable R.sup.23 are assigned
the following numbers: ##STR106##
[0707] Variable R.sup.5 is selected from eight different
substitutents assigned the following numbers, TABLE-US-00044 TABLE
R.sup.5 1 2 3 4 5 R.sup.5 = ##STR107## ##STR108## ##STR109##
##STR110## ##STR111## 6 7 8 R.sup.5 = ##STR112## ##STR113##
##STR114##
[0708] Variable X is selected from four different substitutents
assigned the following numbers: TABLE-US-00045 TABLE X 1 2 3 4 X =
Furan-2,5-diyl C(O)OCH.sub.2 C(O)NHCH.sub.2 NHC(O)CH.sub.2
[0709] Examples of preferred prodrugs of compounds of formula I are
named in Table 6 as shown in the following prodrug formula (xi):
R.sup.5--X--P' (xix)
[0710] The preferred compounds of formula (xix) are listed in Table
6 by designated numbers assigned to P', R.sup.5, and X in the above
formula (xix) according to the following convention, P'.R.sup.5.X.
For each moiety, structures are assigned to a number in the
following tables for P', R.sup.5 and X.
[0711] Variable P' is divided into two Groups, each listing seven
different substituents. The Group 1 substitutents for variable P'
are assigned the following numbers: TABLE-US-00046 TABLE P' 1 2 3 4
P' = ##STR115## ##STR116## ##STR117## ##STR118## 5 6 7 P' =
##STR119## ##STR120## ##STR121##
[0712] The Group 2 substitutents for variable P' are assigned the
following numbers: TABLE-US-00047 1 2 P' = ##STR122## ##STR123## 3
4 P' = ##STR124## ##STR125## 5 P' = ##STR126## 6 7 P' = ##STR127##
##STR128##
[0713] Variable R.sup.5 is selected from nine different
substitutents assigned the following numbers: TABLE-US-00048 TABLE
R.sup.5 1 2 3 4 5 R.sup.5 = ##STR129## ##STR130## ##STR131##
##STR132## ##STR133## 6 7 8 9 R.sup.5 = ##STR134## ##STR135##
##STR136## ##STR137##
[0714] Variable X is selected from six different substitutents
assigned the following numbers: TABLE-US-00049 TABLE X 1 2 3 4 5 6
X = Furan-2,5-diyl C(O)OCH.sub.2 C(O)NHCH.sub.2 NHC(O)CH.sub.2
Pyridin-2,6-diyl CH.sub.2OCH.sub.2
[0715] TABLE-US-00050 TABLE 6 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6
1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.2.6 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5
1.3.6 1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 1.4.6 1.5.1 1.5.2 1.5.3 1.5.4
1.5.5 1.5.6 1.6.1 1.6.2 1.6.3 1.6.4 1.6.5 1.6.6 1.7.1 1.7.2 1.7.3
1.7.4 1.7.5 1.7.6 1.8.1 1.8.2 1.8.3 1.8.4 1.8.5 1.8.6 1.9.1 1.9.2
1.9.3 1.9.4 1.9.5 1.9.6 2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6 2.2.1
2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6
2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6 2.5.1 2.5.2 2.5.3 2.5.4 2.5.5
2.5.6 2.6.1 2.6.2 2.6.3 2.6.4 2.6.5 2.6.6 2.7.1 2.7.2 2.7.3 2.7.4
2.7.5 2.7.6 2.8.1 2.8.2 2.8.3 2.8.4 2.8.5 2.8.6 2.9.1 2.9.2 2.9.3
2.9.4 2.9.5 2.9.6 3.1.1 3.1.2 3.1.3 3.1.4 3.1.5 3.1.6 3.2.1 3.2.2
3.2.3 3.2.4 3.2.5 3.2.6 3.3.1 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.4.1
3.4.2 3.4.3 3.4.4 3.4.5 3.4.6 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5 3.5.6
3.6.1 3.6.2 3.6.3 3.6.4 3.6.5 3.6.6 3.7.1 3.7.2 3.7.3 3.7.4 3.7.5
3.7.6 3.8.1 3.8.2 3.8.3 3.8.4 3.8.5 3.8.6 3.9.1 3.9.2 3.9.3 3.9.4
3.9.5 3.9.6 4.1.1 4.1.2 4.1.3 4.1.4 4.1.5 4.1.6 4.2.1 4.2.2 4.2.3
4.2.4 4.2.5 4.2.6 4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6 4.4.1 4.4.2
4.4.3 4.4.4 4.4.5 4.4.6 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 4.5.6 4.6.1
4.6.2 4.6.3 4.6.4 4.6.5 4.6.6 4.7.1 4.7.2 4.7.3 4.7.4 4.7.5 4.7.6
4.8.1 4.8.2 4.8.3 4.8.4 4.8.5 4.8.6 4.9.1 4.9.2 4.9.3 4.9.4 4.9.5
4.9.6 5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.2.1 5.2.2 5.2.3 5.2.4
5.2.5 5.2.6 5.3.1 5.3.2 5.3.3 5.3.4 5.3.5 5.3.6 5.4.1 5.4.2 5.4.3
5.4.4 5.4.5 5.4.6 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.6.1 5.6.2
5.6.3 5.6.4 5.6.5 5.6.6 5.7.1 5.7.2 5.7.3 5.7.4 5.7.5 5.7.6 5.8.1
5.8.2 5.8.3 5.8.4 5.8.5 5.8.6 5.9.1 5.9.2 5.9.3 5.9.4 5.9.5 5.9.6
6.1.1 6.1.2 6.1.3 6.1.4 6.1.5 6.1.6 6.2.1 6.2.2 6.2.3 6.2.4 6.2.5
6.2.6 6.3.1 6.3.2 6.3.3 6.3.4 6.3.5 6.3.6 6.4.1 6.4.2 6.4.3 6.4.4
6.4.5 6.4.6 6.5.1 6.5.2 6.5.3 6.5.4 6.5.5 6.5.6 6.6.1 6.6.2 6.6.3
6.6.4 6.6.5 6.6.6 6.7.1 6.7.2 6.7.3 6.7.4 6.7.5 6.7.6 6.8.1 6.8.2
6.8.3 6.8.4 6.8.5 6.8.6 6.9.1 6.9.2 6.9.3 6.9.4 6.9.5 6.9.6 7.1.1
7.1.2 7.1.3 7.1.4 7.1.5 7.1.6 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.2.6
7.3.1 7.3.2 7.3.3 7.3.4 7.3.5 7.3.6 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5
7.4.6 7.5.1 7.5.2 7.5.3 7.5.4 7.5.5 7.5.6 7.6.1 7.6.2 7.6.3 7.6.4
7.6.5 7.6.6 7.7.1 7.7.2 7.7.3 7.7.4 7.7.5 7.7.6 7.8.1 7.8.2 7.8.3
7.8.4 7.8.5 7.8.6 7.9.1 7.9.2 7.9.3 7.9.4 7.9.5 7.9.6
[0716] The numbers designated in Table 1 also represent preferred
prodrugs of compounds of formula X as shown in the following
formula (xx): ##STR138##
[0717] In the above formula (xx), Ar stands for aryl including
heteroaryl, and is substituted with R.sup.25. The preferred
compounds of formula (xx) are listed in Table 1 by designated
numbers assigned to Ar', R.sup.25, R.sup.23, and Ar according to
the following convention: Ar'.R.sup.25.R.sup.23.Ar. For each
moiety, structures are assigned to a number in the following tables
for Ar', R.sup.25, R.sup.23 and Ar, wherein R.sup.25 is a
substitutent attached to Ar.
[0718] Variable Ar' is selected from seven different substitutents
assigned the following numbers: TABLE-US-00051 TABLE Ar' 1 2 3 4
Ar' ##STR139## ##STR140## ##STR141## ##STR142## 5 6 7 Ar'
##STR143## ##STR144## ##STR145##
[0719] Variable R.sup.25 is selected from nine different
substitutents assigned the following numbers: TABLE-US-00052 TABLE
R.sup.25 1 2 3 4 5 6 7 8 9 R.sup.25 = F Cl Br NHAc CF.sub.3 Me Et
OMe CO.sub.2Et
[0720] Variable R.sup.23 is selected from rune different
substitutents assigned the following numbers: TABLE-US-00053 TABLE
R.sup.23 1 2 3 4 5 R.sup.23 = ##STR146## ##STR147## ##STR148##
##STR149## ##STR150## 6 7 8 9 R.sup.23 = ##STR151## ##STR152##
##STR153## ##STR154##
[0721] Variable Ar is selected from six different substitutents
assigned the following numbers: TABLE-US-00054 TABLE Ar 1 2 3 4 5 6
Ar = ##STR155## ##STR156## ##STR157## ##STR158## ##STR159##
##STR160##
[0722] The numbers designated in Table 6 also represented preferred
prodrugs of compounds of formula X as shown in the following
formula (xxi): ##STR161##
[0723] In the above formula (xxi), Ar stands for aryl including
heteroaryl, and is substituted by R.sup.25. The preferred compounds
of formula (xxi) are listed in Table 6 by designated numbers
assigned to Ar'.R.sup.25, and Ar according to the following
convention: Ar.sup.1, R.sup.25, Ar. For each moiety, structures are
assigned to a number in the following tables for A', R.sup.25, and
Ar.
[0724] Variable Ar' is selected from seven different substitutents
assigned the following numbers: TABLE-US-00055 TABLE Ar' 1 2 3 4
Ar' ##STR162## ##STR163## ##STR164## ##STR165## 5 6 7 ##STR166##
##STR167## ##STR168##
[0725] Variable R.sup.25 is selected from nine different
substitutents assigned the following numbers: TABLE-US-00056 TABLE
R.sup.25 1 2 3 4 5 6 7 8 9 R.sup.25 = F Cl Br NHAc CF.sub.3 Me Et
OMe CN
[0726] Variable Ar is selected from six different substitutents
assigned the following numbers: TABLE-US-00057 TABLE Ar 1 2 3 4 5 6
Ar = ##STR169## ##STR170## ##STR171## ##STR172## ##STR173##
##STR174## 1 2 3 4 P' = ##STR175## ##STR176## ##STR177## ##STR178##
5 6 7 P' = ##STR179## ##STR180## ##STR181##
[0727] The numbers designated in Table 6 also represent preferred
prodrugs of compounds of formula X as shown in the following
formula (xxii): ##STR182##
[0728] The preferred compounds of formula (xxii) are listed in
Table 6 by designated numbers assigned to P', R' and R'' according
to the following convention, P'.R'.R''. For each moiety, structures
are assigned to a number in the following tables for P', R' and
R''.
[0729] Variable P' is divided into two Groups each listing seven
different substitutents. The Group 1 substitutents for variable P'
are assigned the following numbers:
Table P'.
[0730] The Group 2 substitutents for variable P' are assigned the
following numbers: TABLE-US-00058 1 2 P' = ##STR183## ##STR184## 3
4 P' = ##STR185## ##STR186## 5 P' = ##STR187## 6 7 P' = ##STR188##
##STR189##
[0731] Variable R' is selected from nine different substitutents
assigned the following numbers: TABLE-US-00059 TABLE R' 1 2 3 4 5 6
7 8 9 R' = H Me Et OMe Br Cl CO.sub.2Et Pr-i Pr-c
[0732] Variable R'' is selected from six different substitutents
assigned the following numbers: TABLE-US-00060 TABLE R'' 1 2 3 4 5
6 R'' = H Br Cl SCN Me OMe
Section 1. Synthesis of Compounds of Formula I
[0733] Synthesis of compounds encompassed by the present invention
typically includes some or all of the following general steps: (1)
preparation of a phosphonate prodrug; (2) deprotection of a
phosphonate ester; (3) modification of a heterocycle; (4) coupling
of a heterocycle with a phosphonate component; (5) construction of
a heterocycle; (6) ring closure to construct a heterocycle with a
phosphonate moiety present and (7) preparation of useful
intermediates. These steps are illustrated in the following scheme
for compounds of formula I wherein R.sup.5 is a 5-membered
heteroaromatic ring. Compounds of formula I wherein R.sup.5 is a
6-member heteroaromatic ring or other heteroaromatic rings are
prepared in an analogous manner. The procedures are also generally
applicable to compounds of formula I where both Y groups are not
--O. ##STR190## (1) Preparation of a Phosphonate Prodrug
[0734] 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 liability. Advantageously,
these prodrugs can be introduced at an earlier stage, provided that
it can withstand the reaction conditions of the subsequent
steps.
[0735] 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 suitable base (e.g.
N,N'-dicyclohexyl-4-morpholinecarboxamidine, triethylamine, Hunig's
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 acetats can also be used to alkylate phosphonic acids
(Alexander, P., et al Collect. Czech. Chem. Commun., 1994, 59,
1853). Compounds of formula I wherein R1 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).
[0736] 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
I 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. Dichlorophosphonates are also useful for the
preparation of various phosphoramides as prodrugs. For example,
treatment of a dichlorophosphonate with ammonia gives both a
monophosphonamide and a diphosphonamide; treatment of a
dichlorophosphonate with a 1-amino-3-propanol gives a cyclic
1,3-propylphosphonamide; treatment of a chlorophosphonate
monophenyl ester with an aminoacid ester in the presence of a
suitable base gives a substituted monophenyl
monophosphonamidate.
[0737] 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).
[0738] Chlorophosphonate monophenyl esters can be prepared from
monophenyl phosphonate esters using the above described methods for
dichlorophosphonate synthesis, and monophenyl phosphonate esters
are easily made from their corresponding diphenyl phosphonate
esters via base (e.g. sodium hydroxide) hydrolysis. Alternatively,
treatment of a dichlorophosphonate with one equivalent of a phenol
following by addition of an amine (e.g. alanine ethyl ester) in the
presence of a suitable base (e.g. pyridine or triethylamine) will
also give a monophenyl monophosphonamidate. When substituted
phenols or other aryl-OH are used in place of phenol, then these
methods are useful for the synthesis of various monoaryl
monophosphonamidates as prodrugs for compounds of formula I.
[0739] 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).
[0740] 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.
[0741] It is envisioned that compounds of formula I 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.
[0742] Cyclic propyl phosphonate esters can be synthesized by
either reactions of the corresponding dichlorophosphonate with a
substituted 1,3-propanediol or coupling reactions using suitable
coupling reagents (e.g. DCC, EDCI, pyBOP: Hoffman, Synthesis, 1988,
62). Some of these methods useful for the preparation of
1,3-propanediols are discussed below.
Synthesis of a 1,3-Propanediol
[0743] Various methods can be used to prepare 1,3-propanediols such
as (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. substitutents on the
1,3-propanediol moiety) can be introduced or modified either during
the synthesis of these diols or after the synthesis of compounds of
formula 2.
(i) 1-Substituted 1,3-Propanediols.
[0744] 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-hydroxy-propan-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-oxidation reactions
(path b). ##STR191## Aldol reactions between an enolate (e.g.
lithium, boron, tin enolates) of a carboxylic acid derivative (e.g.
tert-butyl acetate) and an aldehyde, and these reactions (e.g. the
Evans's aldol reactions) are specially useful for the asymmetric
synthesis of chiral 1,3-propanediols. For example, reaction of a
metal enolate of t-butyl acetate with an aromatic aldehyde followed
by reduction of the ester (path e) gives a 1,3-propanediol
(Turner., J. Org. Chem., 1990, 55 4744). Alternatively, epoxidation
of cinnamyl alcohols using known methods (e.g. Sharpless
epoxidations and other asymmetric epoxidation reactions) followed
by reduction reactions (e.g. using Red-Al) give various
1,3-propanediols (path c). Enantiomerically pure 1,3-propanediols
can be obtained via asymmetric reduction reactions (e.g. chiral
borane reductions) of 3-hydroxy-ketones (Ramachandran et. al.,
Tetrahedron Lett., 1997, 38 761). Alternatively, resolution of
racemic 1,3-propanediols using various methods (e.g. enzymatic or
chemical methods) can also give enantiomerically pure
1,3-propanediol. Propan-3-ols with a 1-heteroaryl substitutent
(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). (ii) 2-Substituted 1,3-Propanediols:
[0745] A variety of 2-substituted 1,3-propanediols useful for the
synthesis of compounds of formula I can be prepared from various
other 1,3-propanediols (e.g. 2-(hydroxymethyl)-1,3-propanediols)
using conventional chemistry (Larock, Comprehensive Organic
Transformations, VCH, New York, 1989).
[0746] 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)-1,3propanediol 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). ##STR192## (iii) Annulated
1,3-Propane Diols:
[0747] 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 in section (ii)) to give various
other 1,3,5-cyclohexanetriols which are useful for the preparations
of compounds of formula I wherein R.sup.1 and R.sup.1 together are
##STR193## wherein together V and W are connected via 3 atoms to
form a cyclic group containing 6 carbon atoms substituted with a
hydroxy group. 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).
2-Hydroxymethylcyclohexanols and 2-hydroxymethylcyclopentanols are
useful for the preparations of compounds of formula I wherein
R.sup.1 and R.sup.1 together are ##STR194## wherein together V and
Z are connected via 2 or 3 atoms to form a cyclic group containing
5 or 6 carbon atoms. 1,3-Cyclohexanediol derivatives are also
prepared via other cycloaddition reaction methodologies. For
example, cycloadducts from the cycloadditon reactions of a nitrite
oxide and an olefin can be converted to a 2-ketoethanol derivative
which can be further converted to a 1,3-propanediol (including
1,3-cyclohexanediol, 2-hydroxymethylcyclohexanol and
2-hydroxymethylcyclopentanol) 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
[0748] 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
[0749] 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
substitutents present in these heterocycles before synthesis of
compounds of formula 4, in some cases, the desired substitutents
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 substitutents (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 substitutents such as A, A'', B and
B''. For example, substitution of a 2-chlorothiazole with
methanethiol gives the corresponding 2-methylthiothiazole.
[0750] 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
[0751] 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.
[0752] Transition metal catalyzed coupling reactions such as Stille
or Suzuki reactions are particularly suited for the synthesis of
compounds of formula I. Coupling reactions between a heteroaryl
halide or triflate (e.g. 2-bromopyridine) and a M-PO.sub.3R'
wherein M is a 2-(5-tributylstannyl)furanyl or a
2-(5-boronyl)furanyl group under palladium catalyzed reaction
conditions (Farina et al, Organic Reactions, Vol. 50; Wiley, New
York, 1997; Mitchell, Synthesis, 1992, 808; Suzuki, Pure App.
Chem., 1991, 63, 419) yield compounds of formula I wherein X is a
furan-2,5-diyl group. It is envisioned that the nature of the
coupling partners for these reactions can also be reversed (e.g.
coupling of trialkylstannyl or boronyl heterocycles with a
halo-X--P(O)(O-alkyl).sub.2). Other coupling reactions between
organostannes and an alkenyl halide or an alkenyl triflate are also
reported which may be used to prepared compounds of formula I
wherein X is an alkenyl group. The Heck reaction may be used to
prepare compounds of formula I wherein X is an 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.
[0753] Substitution reactions are useful for the coupling of a
heterocycle with a phosphonate diester component. For example,
cyanuric chloride can be substituted with dialkyl
mercaptoalkylphosphonates or dialkyl aminoalkylphosphonates to give
compounds of formula I wherein R.sup.5 is a 1,3,5-triazine, X is an
alkylthio or an alkylamino group. Alkylation reactions are also
used for the coupling of a heterocycle with a phosphonate diester
component. For example, a heteroaromatic thiol (e.g. a
1,3,4-thiadiazole-2-thiol) can be alkylated with a dialkyl
methylphosphonate derivative (e.g. ICH.sub.2P(O)(OEt).sub.2,
TsOCH.sub.2P(O)(OEt).sub.2, TfOCH.sub.2P(O)(OEt).sub.2) to lead to
compounds of formula I wherein X is an alkylthio group. In another
aspect, alkylation reactions of a heteroaromatic carboxylic acid
(e.g. a thiazole-4-carboxylic acid) with a dialkyl
methylphosphonate derivative (e.g. ICH.sub.2P(O)(OEt).sub.2,
TsOCH.sub.2P(O)(OEt).sub.2, TfOCH.sub.2P(O)(OEt).sub.2) lead to
compounds of formula I wherein X is an alkoxycarbonyl group, while
alkylation reactions of a heteroaromatic thiocarboxylic acid (e.g.
a thiazole-4-thiocarboxylic acid) with a dialkyl methylphosphonate
derivative (e.g. ICH.sub.2P(O)(OEt).sub.2,
TsOCH.sub.2P(O)(OEt).sub.2, TfOCH.sub.2P(O)(OEt).sub.2) lead to
compounds of formula I wherein X is an alkylthiocarbonyl group.
Substitutions of haloalkyl heterocycles (e.g. 4-haloalkylthiazole)
with nucleophiles containing the phosphonate group (diethyl
hydroxymethylphosphonate) are useful for the preparation of
compounds of formula I wherein X is an alkoxyalkyl or an
alkylthioalkyl group. For example, compounds of formula I where X
is a --CH.sub.2OCH.sub.2-- group can be prepared from
2-chloromethylpyridine or 4-chloromethylthiazole using dialkyl
hydroxymethylphosphonates and a suitable base (e.g. sodium
hydride). It is possible to reverse the nature of the nucleophiles
and electrophiles for the substitution reactions, i.e. haloalkyl-
and/or sulfonylalkylphosphonate esters can be substituted with
heterocycles containing a nucleophile (e.g. a
2-hydroxyalkylpyridine, a 2-mercaptoalkylpyridine, or a
4-hydroxyalkyloxazole).
[0754] Known amide bond formation reactions (e.g. the acyl halide
method, the mixed anhydride method, the carbodiimide method) can
also be used to couple a heteroaromatic carboxylic acid with a
phosphonate diester component leading to compounds of formula I
wherein X is an alkylaminocarbonyl or an alkoxycarbonyl group. For
example, couplings of a thiazole-4-carboxylic acid with a dialkyl
aminoalkylphosphonate or a dialkyl hydroxyalkylphosphonate give
compounds of formula I wherein R.sup.5 is a thiazole, and X is an
alkylaminocarbonyl or an alkoxycarbonyl group. Alternatively, the
nature of the coupling partners can be reversed to give compounds
of formula I wherein X is an alkylcarbonylamino group. For example,
2-aminothiazoles can be coupled with (RO).sub.2P(O)-alkyl-CO.sub.2H
(e.g. diethylphosphonoacetic acid) under these reaction conditions
to give compounds of formula I wherein R.sup.5 is a thiazole and X
is an alkylcarbonylamino group. These reactions are also useful for
parallel synthesis of compound libraries through combinatorial
chemistry on solid phase or in solution phase. For example,
HOCH.sub.2P(O)(OEt)(O-resin), H.sub.2NCH.sub.2P(O)(OEt)(O-resin)
and HOOCCH.sub.2P(O)(OEt)(O-resin) (prepared using known methods)
can be coupled to various heterocycles using the above described
reactions to give libraries of compounds of formula 3 wherein X is
a --C(O)OCH.sub.2--, or a --C(O)NHCH.sub.2--, or a
--NHC(O)CH.sub.2--.
[0755] 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 I wherein X is
an alkylaminocarbonylamino or an alkoxycarbonylamino group. These
reactions can also be adopted for combinatorial synthesis of
various libraries of compounds of formula 3. For example, Curtius'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--.
[0756] For compounds of formula I wherein X is an alkyl group, the
phosphonate group can be introduced using other common phosphonate
formation methods such as Michaelis-Arbuzov reaction (Bhattacharya
et al., Chem. Rev., 1981, 81: 415), Michaelis-Becker reaction
(Blackbum 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).
[0757] Phosphonate component can also be introduced via lithiation
reactions. For example, lithiation of an 2-ethynylpyridine using a
suitable base followed by trapping the thus generated anion with a
dialkyl chlorophosphonate lead to compounds of formula I wherein R5
is a pyridyl, X is a 1-(2-phosphono)ethynyl group.
(5) Construction of a Heterocycle
[0758] Although existing heterocycles are useful for the synthesis
of compounds of formula I, when required, heterocycles can also be
constructed leading to compounds in the current invention, 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: Syntheses,
Reaction and Applications; Wiley, New York, 1982; Syntheses of
Heterocyclic Compounds; Consultants Bureau, New York). Some of the
methods which are useful to prepare compounds in the present
invention are given as examples in the following discussion.
(i) Construction of a Thiazole Ring System
[0759] Thiazoles useful for the present invention can be readily
prepared using a variety of well described ring-forming reactions
(Metzger, Thiazole and its derivatives, part 1 and part 2; Wiley
& Sons, New York, 1979). Cyclization reactions of thioamides
(e.g. thioacetamide, thiourea) and alpha-halocarbonyl compounds
(such as alpha-haloketones, alpha-haloaldehydes) are particularly
useful for the construction of a thiazole ring system. For example,
cyclization reactions between thiourea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is a
thiazole, A is an amino group and X is a furan-2,5-diyl group;
cyclization reaction between thiourea and a bromopyruvate alkyl
ester give a 2-amino-4-alkoxycarbonylthiazole which is useful for
the preparations of compounds of formula I wherein 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
[0760] Oxazoles useful for the present invention can be prepared
using various methods in the literature (Turchi, Oxazoles; Wiley
& Sons, New York, 1986). Reactions between isocyanides (e.g.
tosylmethylisocyanide) and carbonyl compounds (e.g. aldehydes and
acyl chlorides) can be used to construct oxazole ring systems (van
Leusen et al, Tetrahedron Lett., 1972, 2369). Alternatively,
cyclization reactions of amides (e.g. urea, carboxamides) and
alpha-halocarbonyl compounds are commonly used for the construction
of an oxazole ring system. For example, the reactions of urea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is an
oxazole, A is an amino group and X is a furan-2,5-diyl group.
Reactions between amines and imidates are also used to construct
the oxazole ring system (Meyers et at, J. Org. Chem., 1986, 51(26),
5111).
(iii) Construction of a Pyridine Ring System
[0761] 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 Mantich
base (Gill et at, J. Am. Chem. Soc., 1952, 74, 4923)), ozonolysis
of a cyclopentene precursor, or reaction of silyl enol ethers with
3-methoxyallylic alcohols (Duhamel et at, 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 at, Helv. Chim.
Acta, 1955, 38, 1033) or 2-aminopyridines (Vorbruggen et at, 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 at, 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, Marietta, 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
[0762] Pyrimidine ring systems useful for the synthesis of
compounds of formula I are readily available (Brown, The
pyrimidines; Wiley, New York, 1994). One method for pyrimidine
synthesis involves the coupling of a 1,3-dicarbonyl component (or
its equivalent) with an N--C--N fragment. The selection of the
N--C--N component--urea (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 I with various A groups. In
another method, pyrimidines can be prepared via cycloaddition
reactions such as aza-Diels-Alder reactions between a
1,3,5-triazine and an enamine or an ynamine (Boger et al., J. Org.
Chem., 1992, 57, 4331 and references cited therein).
(v) Construction of an Imidazole Ring System
[0763] Imidazoles useful for the synthesis of compounds of formula
I are readily prepared using a variety of different synthetic
methodologies. Various cyclization reactions are generally used to
synthesize imidazoles such as reactions between amidines and
alpha-haloketones (Mallick et al, J. Am. Chem. Soc., 1984, 106(23),
7252) or alpha-hydroxyketones (Shi et al, Synthetic Comm., 1993,
23(18), 2623), reactions between urea and alpha-haloketones, and
reactions between aldehydes and 1,2-dicarbonyl compounds in the
presence of amines.
(vi) Construction of an Isoxazole Ring System
[0764] Isoxazoles useful for the synthesis of compounds of formula
I are readily synthesized using various methodologies (such as
cycloaddition reactions between nitrile oxides and alkynes or
active methylene compounds, oximation of 1,3-dicarbonyl compounds
or alpha, beta-acetylenic carbonyl compounds or
alpha,beta-dihalocarbonyl compounds, etc.) can be used to
synthesize an isoxazole ring system (Grunanger et al., Isoxazoles;
Wiley & Sons, New York, 1991). For example, reactions between
alkynes and 5-diethylphosphono-2-chlorooximidofuran in the presence
of base (e.g. triethylamine, Hunig's base, pyridine) are useful for
the synthesis of compounds of formula I wherein R.sup.5 is an
isoxazole and X is a furan-2,5-diyl group.
(vii) Construction of a Pyrazole Ring System
[0765] Pyrazoles useful for the synthesis of compounds of formula I
are readily prepared using a variety of methods (Wiley, Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings;
Interscience Publishers, New York, 1967) such as reactions between
hydrazines and 1,3-dicarbonyl compounds or 1,3-dicarbonyl
equivalents (e.g. one of the carbonyl group is masked as an enamine
or ketal or acetal), and additions of hydrazines to acrylonitriles
followed by cyclization reactions (Dorn et al, Org. Synth., 1973,
Coll. Vol. V, 39). Reaction of
2-(2-alkyl-3-N,N-dimethylamino)acryloyl-5-diethylphosphono furans
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
[0766] 1,2,4-Triazoles useful for the synthesis of compounds of
formula I are readily available via various methodologies
(Montgomery, 1,2,4-Triazoles; Wiley, New York, 1981). For example,
reactions between hydrazides and imidates or thioimidates (Sui et
al, Bioorg. Med. Chem. Lett., 1998, 8, 1929; Catarzi et al, J. Med.
Chem., 1995, 38(2), 2196), reactions between 1,3,5-triazine and
hydrazines (Grundmann et al, J. Org. Chem., 1956, 21, 1037), and
reactions between aminoguanidine and carboxylic esters (Ried et al,
Chem. Ber., 1968, 101, 2117) are used to synthesize
1,2,4-triazoles.
(6) Ring Closure to Construct a Heterocycle with a Phosphonate
[0767] Compounds of formula 4 can also be prepared using a ring
closure reaction to construct the heterocycle from precursors that
contain the phosphonate component. For example, cyclization
reactions between thiourea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is a
thiazole, A is an amino group and X is a furan-2,5-diyl group.
Oxazoles of the present invention can also be prepared using a ring
closure reaction. In this case, reactions of urea and
5-diethylphosphono-2-[(-2-bromo-1-oxo)alkyl]furans are useful for
the synthesis of compounds of formula I wherein R.sup.5 is an
oxazole, A is an amino group and X is a furan-2,5-diyl group.
Reactions between 5-diethylphosphono-2-furaldehyde, an alkyl amine,
a 1,2-diketone and ammonium acetate are useful to synthesize
compounds of formula I wherein R.sup.5 is an imidazole and X is a
furan-2,5-diyl group. These types of ring closure reactions can
also be used for the synthesis of pyridines or pyrimidines useful
in the present invention. For example, reaction of
5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and
cyanoacetamide in the presence of base gives
5-alkyl-3-cyano-6-[2-(5-diethylphosphono)furanyl]-2-pyridones (Jain
et al., Tetrahedron Lett., 1995, 36, 3307). Subsequent conversion
of these 2-pyridones to the corresponding 2-halopyridines (see
references cited in section 3 for the modifications of
heterocycles) will lead to compounds of formula I wherein R.sup.5
is a pyridine, A is a halo group, X is a furan-2,5-diyl group, and
B is an alkyl group. Reactions of
5-diethylphosphono-2-[3-dimethylamino-2-alkyl)acryloyl]furans and
amidines in the presence of base give
5-alkyl-6-[2-(5-diethylphosphono)-furanyl]pyrimidines which will
lead to compounds of formula I wherein R.sup.5 is a pyrimidine, X
is a furan-2,5-diyl group and B is an alkyl group.
(7) Preparation of Various Precursors Useful for Cyclization
Reactions
[0768] 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.
[0769] Various aryl phosphonate dialkyl esters are particularly
useful for the synthesis of compounds of formula I. For example,
compounds of formula I wherein X is a furan-2,5-diyl group can be
prepared from a variety of furanyl precursors. It is envisioned
that synthesis of other precursors may follow some or all of these
reaction steps, and some modifications of these reactions may be
required for different precursors.
5-Dialkylphosphono-2-furancarbonyl compounds (e.g.
5-diethylphosphono-2-furaldehyde, 5-diethylphosphono-2-acetylfuran)
are well suited for the synthesis of compounds of formula I wherein
X is a furan-2,5-diyl group. These intermediates are prepared from
furan or furan derivatives using conventional chemistry such as
lithiation reactions, protection of carbonyl groups and
deprotection of carbonyl groups. For example, lithiation of furan
using known methods (Gschwend Org. React. 1979, 26: 1) followed by
addition of phosphorylating agents (e.g. ClPO.sub.3R.sub.2) gives
2-dialkylphosphono-furans (e.g. 2-diethylphosphonofuran). This
method can also be applied to a 2-substituted furan (e.g. 2 -furoic
acid) to give a 5-dialkylphosphono-2-substituted furan (e.g.
5-diethylphosphono-2-furoic acid). It is envisioned that other aryl
phosphonate esters can also be prepared using this approach or a
modification of this approach. Alternatively, other methods such as
transition metal catalyzed reactions of aryl halides or triflates
(Balthazar et al. J. Org. Chem., 1980, 45: 5425; Petrakis et al. J.
Am. Chem. Soc., 1987, 109: 2831; Lu et al. Synthesis, 1987, 726)
are used to prepare aryl phosphonates. Aryl phosphonate esters can
also be prepared from aryl phosphates under anionic rearrangement
conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel et
al. Synthesis, 1991, 691). N-Alkoxy aryl salts with alkali metal
derivatives of dialkyl phosphonate provide another general
synthesis for heteroaryl-2-phosphonate esters (Redmore J. Org.
Chem., 1970, 35: 4114).
[0770] 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, animals; protection of ketones
as ketals). The protected functional group is then unmasked after
phosphorylation. (Protective groups in Organic Synthesis, Greene,
T. W., 1991, Wiley, New York). For example, protection of
2-furaldehyde as 1,3-propanediol acetal followed by a lithiation
step (using for example LDA) and trapping the anion with a dialkyl
chlorophosphate (e.g. diethyl chlorophosphate), and subsequent
deprotection of the acetal functionality under normal deprotection
conditions produces the 5-dialkylphosphono-2-furaldehyde (e.g.
5-diethylphosphono-2-furaldehyde). Another example is the
preparation of 5-keto-2-dialkylphosphonofurans which encompass the
following steps: acylations of furan under Friedel-Crafts reaction
conditions give 2-ketofuran, subsequent protection of the ketone as
ketals (e.g. 1,3-propanediol cyclic ketal) followed by a lithiation
step as described above gives the 5-dialkylphosphono-2-furanketone
with the ketone being protected as a 1,3-propanediol cyclic ketal,
and final deprotection of the ketal under, for example, acidic
conditions gives 2-keto-5-dialkylphosphonofurans (e.g.
2-acetyl-5-diethylphosphonofuran). Alternatively, 2-ketofurans can
be synthesized via a palladium catalyzed reaction between
2-trialkylstannylfurans (e.g. 2-tributylstannylfuran) and an acyl
chloride (e.g. acetyl chloride, isobutyryl chloride). 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.
[0771] Some of the above described intermediates can also be used
for the synthesis of other useful intermediates. For example, a
2-keto-5-dialkylphosphonofuran can be further converted to a
1,3-dicarbonyl derivative which is useful for the preparation of
pyrazoles, pyridines or pyrimidines. Reaction of a
2-keto-5-dialkylphosphonofuran (e.g.
2-acetyl-5-diethylphosphonofuran) with a dialkylformamide dialkyl
acetal (e.g. dimethylformamide dimethyl acetal) gives a
1,3-dicarbonyl equivalent as a
2-(3-dialkylamino-2-alkyl-acryloyl)-5-dialkylphosphono furan (e.g.
2-(3-dimethylaminoacryloyl)-5-diethylphosphonofuran).
[0772] 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).
[0773] 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
[0774] 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, where both Y groups are not --O--. ##STR195## (3)
Construction of a Heterocycle i. Benzothiazole Ring System:
[0775] 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.dbd.CH.sub.2O, and R'=Et can be prepared from the
commercially available 4-methoxy-2-amino thiazole via a two-step
sequence: conversion 4-methoxy-2-aminobenzothiazole to
4-hydroxy-2-aminobenzothiazole with reagents such as BBr.sub.3
(Node, M.; et al. J. Org. Chem. 45, 2243-2246, 1980) or AlCl.sub.3
in presence of a thiol (e.g. EtSH) (McOmie, J. F. W.; et al. Org.
Synth., Collect. Vol. V, 412, 1973) followed alkylation of the
phenol group with diethylphosphonomethyl trifluoromethylsulfonate
(Phillion, D. P.; et al. Tetrahedron Lett. 27, 1477-1484, 1986) in
presence of a suitable base (e.g. NaH) in polar aprotic solvents
(e.g. DMF) provide the required compound.
[0776] 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).
[0777] 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''.dbd.S, A=--NH.sub.2, L.sup.2,
E.sup.2, J.sup.2=H, X.sup.2.dbd.CH.sub.2O and R'=Et with bromine in
polar solvents such as AcOH gave compound of formula 3 wherein
E.sup.2=Br.
[0778] 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:
[0779] 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:
[0780] Compounds of formula 4 (wherein X.sup.2.dbd.CH.sub.2O and
R'=alkyl) can made in different ways (e.g. using alkylation and
nucleophilic substitution reactions). Typically, compounds of
formula 5 wherein M'=OH is treated with a suitable base (e.g. NaH)
in polar aprotic solvent (e.g. DMF, DMSO) and the resulting
phenoxide anion can be alkylated with a suitable electrophile
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.dbd.CH.sub.2O and R'=Et) can be
prepared from a 2-chloro-1-nitrobenzene derivative by treatment
with NaOCH.sub.2P(O)(OEt).sub.2 in DMF. Similarly, compounds of
formula 4 where X.sup.2=-alkyl-S-- or -alkyl-N-- can also be
made.
(5) Synthesis of an Aniline Derivative:
[0781] Numerous synthetic methods have been reported for the
synthesis of aniline derivatives, these methods can be applied to
the synthesis of useful intermediates which can lead to compounds
of formula X. For example, various alkenyl or aryl groups can be
introduced on to a benzene ring via transition metal catalyzed
reactions (Kasibhatla, S. R., et al. WO 98/39343 and the references
cited in); anilines can be prepared from their corresponding nitro
derivatives via reduction reactions (e.g. hydrogenation reactions
in presence of 10% Pd/C, or reduction reactions using SnCl.sub.2 in
HCl (Patil, D. G.; Chedekel, M. R. J. Org. Chem. 49, 997-1000,
1984)).
Section 3.
Synthesis of Substituted 1,3-Hydroxyamines and 1,3-Diamines:
[0782] A large number of synthetic methods are available for the
preparation of substituted 1,3-hydroxyamines and 1,3-diamines due
to the ubiquitous nature of these functionalities in naturally
occurring compounds. Following are some of these methods organised
into: 1. synthesis of substituted 1,3-hydroxy amines; 2. synthesis
of substituted 1,3-diamines and 3. Synthesis of chiral substituted
1,3-hydroxyamines and 1,3-diamines.
[0783] i. Synthesis of Substituted 1,3-Hydroxy Amines:
[0784] 1,3-Diols described in the earlier section can be converted
selectively to either hydroxy amines or to corresponding diamines
by converting hydroxy functionally to a leaving group and treating
with anhydrous ammonia or required primary or secondary amines
(Corey, et al., Tetrahedron Lett., 1989, 30, 5207: Gao, et al., J.
Org. Chem., 1988, 53, 4081). A similar transformation may also be
achieved directly from alcohols in Mitsunobu type of reaction
conditions (Hughes, D. L., Org. React., 1992, 42). A general
synthetic procedure for 3-aryl-3-hydroxy-propan-1-amine type of
prodrug moiety involves aldol type condensation of aryl esters with
alkyl nitriles followed by reduction of resulting substituted
benzoylacetonitrile (Shih et al., Heterocycles, 1986, 24, 1599).
The procedure can also be adapted for formation 2-substituted amino
propanols by using substituted alkylnitrile. In another approach,
3-aryl-3-amino-propan-1-ol type of prodrug groups are synthesized
from aryl aldehydes by condensation of malonic acid in presence of
ammonium acetate followed by reduction of resulting substituted
aminoacids. Both these methods enable to introduce wide variety of
substitution of aryl group (Shih, et al., Heterocycles., 1978, 9,
1277). In an alternate approach, -substituted organolithium
compounds of 1-amino-1-aryl ethyl dianion generated from styrene
type of compounds undergo addition with carbonyl compounds to give
variety of W, W' substitution by variation of the carbonyl
compounds (Barluenga, et al., J. Org, Chem., 1979, 44, 4798).
[0785] ii. Synthesis of Substituted 1,3-Diamines:
[0786] Substituted 1,3-diamines are synthesized starting from
variety of substrates, Arylglutaronitriles can be transformed to
1-substituted diamines by hydrolysis to amide and Hoffman
rearrangement conditions (Bertochio, et al., Bull. Soc. Chim. Fr,
1962, 1809). Whereas, malononitrile substitution will enable
variety of Z substitution by electrophile introduction followed by
hydride reduction to corresponding diamines. In another approach,
cinnamaldehydes react with hydrazines or substituted hydrazines to
give corresponding pyrazolines which upon catalytic hydrogenation
result in substituted 1,3-diamines (Weinhardt, et al., J. Med.
Chem., 1985, 28, 694). High trans-diastereoselectivity of
1,3-substitution is also attainable by aryl Grignard addition on to
pyrazolines followed by reduction (Alexakis, et al., J. Org. Chem.,
1992, 576, 4563). 1-Aryl-1,3-diaminopropanes are also prepared by
diborane reduction of 3-amino-3-arylacrylonitriles which inturn are
made from nitrile substituted aromatic compounds (Dornow, et al.,
Chem Ber., 1949, 82, 254). Reduction of 1,3-diimines obtained from
corresponding 1,3-carbonyl compounds are another source of
1,3-diamine prodrug moiety which allows a wide variety of
activating groups V and/or Z (Barluenga, et al., J. Org. Chem.,
1983, 48, 2255).
[0787] iii. Synthesis of Chiral Substituted 1,3-Hydroxyamines and
1,3-Diamines.
[0788] Enantiomerically pure 3-aryl-3-hydroxypropan-1-amines are
synthesized by CBS enantioselective catalytic reaction of
-chloropropiophenone followed by displacement of halo group to make
secondary or primary amines as required (Corey, et al., Tetrahedron
Lett., 1989, 30, 5207). Chiral 3-aryl-3-amino propan-1-ol type of
prodrug moiety may be obtained by 1,3-dipolar addition of chirally
pure olefin and substituted nitrone of arylaldehyde followed by
reduction of resulting isoxazolidine (Koizumi, et al., J. Org.
Chem., 1982, 47, 4005). Chiral induction in 1,3-polar additions to
form substituted isoxazolidines is also attained by chiral
phosphine palladium complexes resulting in enatioselective
formation of amino alcohols (Hori, et al., J. Org. Chem., 1999, 64,
5017). Alternatively, optically pure 1-aryl substituted amino
alcohols are obtained by selective ring opening of corresponding
chiral epoxy alcohols with desired amines (Canas et al.,
Tetrahedron Lett., 1991, 32, 6931).
[0789] Several methods are known for diastereoselective synthesis
of 1,3-disubstituted aminoalcohols. For example, treatment of
(E)-N-cinnamyltrichloroacetamide with hypochlorus acid results in
trans-dihydrooxazine which is readily hydrolysed to
erythro-chloro-hydroxy-phenylpropanamine in high
diastereoselectivity (Commercon et al., Tetrahedron Lett., 1990,
31, 3871). Diastereoselective formation of 1,3-aminoalcohols is
also achieved by reductive amination of optically pure 3-hydroxy
ketones (Haddad et al., Tetrahedron Lett., 1997, 38, 5981). In an
alternate approach, 3-aminoketones are transformed to
1,3-disubstituted aminoalcohols in high stereoslectivity by a
selective hydride reduction (Barluenga et al., J. Org. Chem., 1992,
57, 1219).
[0790] All the above mentioned methods may also be applied to
prepare corresponding V-Z or V--W annulated chiral aminoalcohols.
Furthermore, such optically pure amino alcohols are also a source
to obtain optically pure diamines by the procedures described
earlier in the section.
Formulations
[0791] Compounds of the invention are administered orally in a
total daily dose of about 0.01 mg/kg/dose to about 100 mg/kg/dose,
preferably from about 0.1 mg/kg/dose to about 10 mg/kg/dose. The
use of time-release preparations to control the rate of release of
the active ingredient may be preferred. The dose may be
administered in as many divided doses as is convenient. When other
methods are used (e.g. intravenous administration), compounds are
administered to the affected tissue at a rate from 0.05 to 10
mg/kg/hour, preferably from 0.1 to 1 mg/kg/hour. Such rates are
easily maintained when these compounds are intravenously
administered as discussed below.
[0792] For the purposes of this invention, the compounds may be
administered by a variety of means including orally, parenterally,
by inhalation spray, topically, or rectally in formulations
containing pharmaceutically acceptable carriers, adjuvants and
vehicles. The term parenteral as used here includes subcutaneous,
intravenous, intramuscular, and intraarterial injections with a
variety of infusion techniques. Intraarterial and intravenous
injection as used herein includes administration through catheters.
Oral administration is generally preferred.
[0793] 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.
[0794] 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.
[0795] 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.
[0796] 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.
[0797] 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.
[0798] 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.
[0799] 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.
[0800] 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.
[0801] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions. It is preferred that the
pharmaceutical composition be prepared which provides easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion should contain from
about 3 to 330 .mu.g of the active ingredient per milliliter of
solution in order that infusion of a suitable volume at a rate of
about 30 mL/hr can occur.
[0802] As noted above, formulations of the present invention
suitable for oral administration may be presented as discrete units
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient; as a powder or
granules; as a solution or a suspension in an aqueous or
non-aqueous liquid; or as an oil-in-water liquid emulsion or a
water-in-oil liquid emulsion. The active ingredient may also be
administered as a bolus, electuary or paste.
[0803] 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. This is particularly advantageous with the compounds of
formulae I and X when such compounds are susceptible to acid
hydrolysis.
[0804] 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.
[0805] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0806] 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.
[0807] Formulations suitable for parenteral administration include
aqueous and non-aqueous isotonic sterile injection solutions which
may contain antioxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents. The
formulations may be presented in unit-dose or multi-dose sealed
containers, for example, ampoules and vials, and may be stored in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for injections,
immediately prior to use. Injection solutions and suspensions may
be prepared from sterile powders, granules and tablets of the kind
previously described.
[0808] Preferred unit dosage formulations are those containing a
daily dose or unit, daily sub-dose, or an appropriate fraction
thereof, of a fructose 1,6-bisphosphatase inhibitor compound.
[0809] 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 adcministration; the rate of
excretion; other drugs which have previously been administered; and
the severity of the particular disease undergoing therapy, as is
well understood by those skilled in the art.
Utility
[0810] FBPase inhibitors may be used to treat diabetes mellitus,
lower blood glucose levels, and inhibit gluconeogenesis.
[0811] FBPase inhibitors may also be used to treat excess glycogen
storage diseases. Excessive hepatic glycogen stores are found in
patients with some glycogen storage diseases. Since the indirect
pathway contributes significantly to glycogen synthesis (Shulman,
G. I. Phys. Rev. 72:1019-1035 (1992)), inhibition of the indirect
pathway (gluconeogenesis flux) decreases glycogen
overproduction.
[0812] FBPase inhibitors may also be used to treat or prevent
diseases associated with increased insulin levels. Increased
insulin levels are associated with an increased risk of
cardiovascular complications and atherosclerosis (Folsom, et al.,
Stroke, 25:66-73 (1994); Howard, G. et al., Circulation
93:1809-1817 (1996)). FBPase inhibitors are expected to decrease
postprandial glucose levels by enhancing hepatic glucose uptake.
This effect is postulated to occur in individuals that are
non-diabetic (or pre-diabetic, i.e. without elevated hepatic
glucose output "hereinafter HGO" or fasting blood glucose levels).
Increased hepatic glucose uptake will decrease insulin secretion
and thereby decrease the risk of diseases or complications that
arise from elevated insulin levels.
[0813] One aspect of the invention is directed to the use of new
cyclic 1,3-propanyl ester methodology which results in efficient
conversion of the cyclic phosph(oramid)ate. The phosphonate
containing compounds by p450 enzymes found in large amounts in the
liver and other tissues containing these specific enzymes.
[0814] In another aspect of the invention, this prodrug methodology
can also be used to prolong the pharmacodynamic half-life because
the cyclic phosph(oramid)ates of the invention can prevent the
action of enzymes which degrade the parent drug.
[0815] In another aspect of the invention, this prodrug methodology
can be used to achieve sustained delivery of the parent drug
because various novel prodrugs are slowly oxidized in the liver at
different rates.
[0816] The novel cyclic 1,3-propanylester methodology of the
present invention may also be used to increase the distribution of
a particular drug to the liver which contains abundant amounts of
the p450 isozymes responsible for oxidizing the cylic
1,3-propanylester of the present invention so that the free
phosph(oramid)ate is produced.
[0817] In another aspect of the invention, the cyclic
phosph(oramid)ate prodrugs can increase the oral bioavailability of
the drugs.
[0818] Theses aspects are described in greater detail below.
[0819] Evidence of the liver specificity can also be shown in vivo
after both oral and i.v. administration of the prodrugs as
described in Example E.
[0820] Drug is also detected in the liver following administration
of drugs of formulae VI-VIII, shown below: ##STR196##
[0821] Prodrugs of formulae VI, VII, and VIII are particularly
preferred.
[0822] The mechanism of cleavage could proceed by the following
mechanisms. Further evidence for these mechanisms is indicated by
analysis of the by-products of cleavage. Prodrugs of formula VI
where Y is --O-- generate phenyl vinyl ketone whereas prodrugs of
formula VIII were shown to generate phenol (Example H).
##STR197##
[0823] Although the esters in the invention are not limited by the
above mechanisms, in general, each ester contains a group or atom
susceptible to microsomal oxidation (e.g. alchohol, benzylic
methine proton), which in turn generates an intermediate that
breaks down to the parent compound in aqueous solution via
.beta.-elimination of the phosph(oramid)ate diacid.
EXAMPLES
1. Synthesis of Compounds of Formula I
Example 1
Preparation of 5-diethylphosphono-2-furaldehyde (1)
[0824] Step A. A solution of 2-furaldehyde diethyl acetal (1 mmole)
in THF (tetrahydrofuran) was treated with nBuLi (1 mmole) at
-78.degree. C. After 1 h, diethyl chlorophosphate (1.2 mmole) was
added and the reaction was stirred for 40 min. Extraction and
evaporation gave a brown oil.
Step B. The resulting brown oil was treated with 80% acetic acid at
90.degree. C. for 4 h. Extraction and chromatography gave compound
1 as a clear yellow oil. Alternatively this aldehyde can be
prepared from furan as described below.
[0825] 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=role) was added to the reaction mixture and
stirred for another hour. Extraction and distillation gave diethyl
2-furanphosphonate as a clear oil.
[0826] 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.
[0827] 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).
[0828] Step F. A solution of furan-2-(N,N'-dimethylimidazolidine)
(1 mmole) and TMEDA (1 mmole) in THF was treated with nBuLi (1.3
mmole) at -40 to -48.degree. C. The reaction was stirred at
0.degree. C. for 1.5 h and then cooled to -55.degree. C. and
treated with a solution of diethylchlorophosphate (1.1 mmole) in
THF. After stirring at 25.degree. C. for 12 h the reaction mixture
was evaporated and subjected to extraction to give
5-diethylphosphono-furan-2-(N,N'-dimethylimidazolidine) as a brown
oil.
Step G. A solution of
5-diethylphosphonofuran-2-(N,N'-dimethyl-imidazolidine) (1 mmole)
in water was treated with concentrated sulfuric acid until pH=1.
Extraction and chromatography gave compound 1 as a clear yellow
oil.
Example 2
Preparation of 5-diethylphosphono-2-[(1-oxo)alkyl]furans and
6-diethylphosphono-2-[(1-oxo)alkyl]pyridines
[0829] 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).
[0830] 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.
[0831] 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 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.
[0832] 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).
[0833] The following compounds were prepared according to this
procedure: [0834] (2.2) 5-diethylphosphono-2-acetylfuran: bp
125-136.degree. C., 0.1 mmHg. [0835] (2.3)
5-diethylphosphono-2-[(1-oxo)butyl]furan: bp 130-145.degree. C.,
0.08 mmHg.
[0836] Alternatively these compounds can be prepared using the
following procedures:
[0837] 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.
[0838] 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-di-methyl
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.
[0839] Some of 5-diethylphosphono-2-[(1-oxo)alkyl]furans are
prepared using the following procedures:
[0840] 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.
[0841] 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.
[0842] 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.
[0843] The following compounds were prepared according to this
procedure: [0844] (2.4)
5-Diethylphosphono-2-(2-ethoxycarbonylacetyl)furan [0845] (2.5)
5-Diethylphosphono-2-(2-methylthioacetyl)furan [0846] (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
[0847] 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.
[0848] 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.
[0849] 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.
[0850] According to the above procedures or in some cases with
minor modifications of these procedures using conventional
chemistry the following compounds were prepared: [0851] (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. [0852]
(3.3) 4-[2-(5-Phosphono)furanyl]thiazole. Anal. calcd. for
C.sub.7H.sub.6NO.sub.4PS+0.65HBr: C, 29.63; H, 2.36; N, 4.94.
Found: C, 29.92; H, 2.66; N, 4.57. [0853] (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. [0854] (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. [0855] (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. [0856] (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. [0857] (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. [0858] (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. [0859] (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. [0860] (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. [0861] (3.12)
2-Acetamido-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp
179-181.degree. C. Anal. calcd. for
C.sub.13H.sub.17N.sub.2O.sub.5PS+0.25H.sub.2O: C, 44.76; H, 5.06;
N, 8.03. Found: C, 44.73; H, 5.07; N, 7.89. [0862] (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. [0863] (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. [0864] (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. [0865] (3.16)
2-Amino-5-methyl-4-[2-(5-phosphono)furanyl]thiazole. mp
200-220.degree. C. Anal. calcd. for
C.sub.8H.sub.9N.sub.2O.sub.4PS+0.65HBr: C, 30.72; H, 3.11; N, 8.96.
Found: C, 30.86; H, 3.33; N, 8.85. [0866] (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. [0867]
(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. [0868] (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. [0869] (3.20)
2-Amino-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd. for C.sub.10H.sub.13N.sub.2O.sub.4PS+1HBr: C, 32.53; H,
3.82; N, 7.59. Found: C, 32.90; H, 3.78; N, 7.65. [0870] (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. [0871] (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.
[0872] (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+0.2 hexane+0.3HBr: C, 39.35;
H, 4.78; N, 10.43. Found: C, 39.61; H, 4.48; N, 10.24. [0873]
(3.24) 2-Amino-5-propyl-4-[2-(5-phosphono)furanyl]thiazole. mp
235-237.degree. C. Anal. calcd. for
C.sub.11H.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. [0874] (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. [0875] (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. [0876] (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, [0877]
(3.28)
2-Amino-5-methanesulfinyl-4-[2-(5-phosphono)furanyl]thiazole.
mp>250.degree. C. [0878] 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. [0879] (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. [0880]
(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. [0881] (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. [0882] (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. [0883]
(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. [0884] (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. [0885] (3.35)
2-Amino-5-propyloxycarbonyl-4-[2-(5-phosphono)furanyl]thiazole. Mp
245.degree. C. (decomp). Anal. calcd for
C.sub.11H.sub.13N.sub.2O.sub.6PS: C, 39.76; H, 3.94; N, 8.43.
Found: C, 39.77; H, 3.72; N, 8.19. [0886] (3.36)
2-Amino-5-benzyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.14H.sub.11N.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. [0887] (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. [0888] (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. [0889]
(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. [0890]
(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, [0891] (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. [0892] (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. [0893]
(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. [0894] (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. [0895] (3.45)
2-Amino-5-(4-morpholinyl)methyl-4-[2-(5-phosphono)furanyl]thiazole
dihydrobromide. Anal. calcd for
C.sub.12H.sub.13Br.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. [0896] (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. [0897] (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+1.15C.sub.12H.sub.23N: C,
52.28; H, 7.13; N, 8.81. Found: C, 52.12; H, 7.17; N, 8.81. [0898]
(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. [0899]
(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. [0900] (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. [0901] (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.
[0902] (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. [0903] (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. [0904] (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. [0905] (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. [0906] (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. [0907] (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. [0908]
(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. [0909] (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. [0910] (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. [0911]
(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. [0912] (3.62)
2-Hydroxyl-5-ethyl-4-[2-(5-phosphono)furanyl]thiazole. Anal. calcd
for C.sub.9H.sub.11NO.sub.5PS: C, 39.28; H, 3.66; N, 5.09. Found:
C, 39.04; H, 3.44; N, 4.93. [0913] (3.63)
2-Hydroxyl-5-isopropyl-4-[2-(5-phosphono)furanyl]thiazole. Anal.
calcd for C.sub.10H.sub.2NO.sub.5PS+0.1HBr: C, 40.39; H, 4.10; N,
4.71. Found: C, 40.44; H, 4.11; N, 4.68. [0914] (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. [0915] (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. [0916] (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. [0917] (3.67)
2-Amino-4-[2-(6-phosphono)pyridyl]thiazole hydrobromide. [0918]
(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. [0919] (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. [0920] (3.70)
2-Amino-5-isobutyl-4-[2-(5-phosphono)furanyl]selenazole. Anal.
calcd for C.sub.11H.sub.15N.sub.2O.sub.4PSe+0.14HBr+0.6EtOAc: C,
38.93; H, 4.86; N, 6.78. Found: C, 39.18; H, 4.53; N, 6.61. [0921]
(3.71) 2-Amino-5-methylthio-4-[2-(5-phosphono)furanyl]selenazole.
Anal. calcd for C.sub.8H.sub.9N.sub.2O.sub.4PSSe+0.7HBr+0.2EtOAc:
C, 25.57; H, 2.75; N, 6.78. Found: C, 25.46; H, 2.49; N, 6.74.
[0922] (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
[0923] 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.
[0924] 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.
[0925] The following compounds were prepared according to this
procedure: [0926] (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. [0927] (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. [0928] (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
[0929] 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.
[0930] 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.
[0931] The following compound was prepared according to this
procedure: [0932] (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. [0933] (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
[0934] 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.
[0935] Step B.
2-Vinyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole was
subjected to Step C of Example 3 to give
2-vinyl-5-isobutyl-4-[2-(5-phosphono)-furanyl]thiazole (6.1) as a
yellow solid. Anal. calcd. for
C.sub.13H.sub.16NO.sub.4PS+1HBr+0.1H.sub.2O: C, 39.43; H, 4.38; N,
3.54. Found: C, 39.18; H, 4.38; N, 3.56.
[0936] This method can also be used to prepare various
5-substituted 4-[2-(5-phosphono)furanyl]thiazoles from their
corresponding halides.
Step C. 2-Amino-5-bromo-4-[2-(5-diethylphosphono)furanyl]thiazole
was subjected to Step A using 2-tributylstannylfuran as the
coupling partner to give
2-amino-5-(2-furanyl)-4-[2-(5-diethylphosphono)furanyl]thiazole.
[0937] 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.
[0938] The following compound was prepared according to this
procedure: [0939] (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+0.1HBr: 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
[0940] 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.
[0941] 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
[0942] 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 (I mmole) at 0.degree. C. and
stirred at 25.degree. C. for 12 h. Extraction and chromatography
gave 2-methyl-4-(diethylphosphonomethoxymethyl)thiazole.
[0943] 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.
[0944] 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.
[0945] 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.
[0946] Step E. A solution of
2-[(N-Boc)amino]-4-hydroxymethylthiazole (1 mmole) in DMF (10 mL)
was cooled to 0.degree. C., and treated with NaH (1.1 mmole). The
mixture was stirred at room temperature for 30 min, then
phosphonomethyl trifluoromethanesulfonate (1.1 mmole) was added.
After stirring at room temperature for 4 h, the reaction was
evaporated to dryness. Chromatography of the residue gave
2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole as a
solid.
[0947] Step F.
2-[(N-Boc)amino]-4-diethylphosphonomethoxylmethylthiazole was
subjected to Step C of Example 3 to give
2-amino-4-phosphonomethoxymethylthiazole (8.3) as a solid. Anal.
calcd. for C.sub.5H.sub.9N.sub.2O.sub.4PS+0.16HBr+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
[0948] 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.
[0949] 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.
[0950] The following compound was prepared according to this
procedure: [0951] (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.
[0952] 2-Ethoxycarbonyl-4-[2-(5-diethylphosphono)furanyl]thiazoles
can also be converted to other 2-substituted
4-[2-(5-phosphono)furanyl]thiazoles.
[0953] 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.
[0954] 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.
[0955] The following compound was prepared according to this
procedure: [0956] (9.4)
2-Hydroxymethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole. mp
160-170.degree. C. Anal. calcd. for
C.sub.12H.sub.16NO.sub.5PS+0.75HBr: C, 38.13; H, 4.47; N, 3.71.
Found: C, 37.90; H, 4.08; N, 3.60. Step E A solution of
2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in methylene chloride was treated with phosphorus
tribromide (1.2 mmole) at 25.degree. C. for 2 h. Extraction and
chromatography gave 2-bromo
methyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole. Step
F.
2-Bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazo-
le 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.
[0957] The following compound was prepared according to this
procedure: [0958] (9.6)
2-Bromomethyl-4-[2-(5-phosphono)furanyl]thiazole. mp>250.degree.
C. Anal. calcd. for C.sub.8H.sub.7BrNO.sub.4PS: C, 29.65; H, 2.18;
N, 4.32. Found: C, 29.47; H, 1.99; N, 4.16. Step G. A solution of
2-hydroxymethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in methylene chloride was treated with thionyl chloride
(1.2 mmole) at 25.degree. C. for 2 h. Extraction and chromatography
gave
2-chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step H.
2-Chloromethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiaz-
ole was subjected to Step C of Example 3 to give
2-chloromethyl-5-isobutyl-4-[2-(5-phosphono)furanyl]thiazole (9.7).
mp 160-162.degree. C. Anal. calcd. for
C.sub.12H.sub.15ClNO.sub.4PS+0.45HBr: C, 38.73; H, 4.18; N, 3.76.
Found: C, 38.78; H, 4.14; N, 3.73. Step I. A solution of
2-bromomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole
(1 mmole) in DMF was treated with potassium phthalimide (1.2 mmole)
at 25.degree. C. for 12 h. Extraction and chromatography gave
2-phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step J.
2-Phthalimidomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl-
]-thiazole (1 mmole) in ethanol was treated with hydrazine (1.5
mmole) at 25.degree. C. for 12 h. Filtration, evaporation and
chromatography gave
2-aminomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]thiazole.
Step K.
2-Aminomethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-thiazo-
le 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.
[0959] According to the above procedures or in some cases with some
minor modifications of the above procedures, the following
compounds were prepared: [0960] (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. [0961] (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
[0962] 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 r=role) 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.
[0963] 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.
[0964] 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.
[0965] Alternatively 4-[2-(5-phosphono)furanyl]oxazoles and
4-[2-(5-phosphono)furanyl]imidazoles can be prepared as
following:
[0966] 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.
[0967] 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:
[0968] (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. [0969] (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. [0970] (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.
[0971] Alternatively 4-[2-(5-phosphono)furanyl]imidazoles can be
prepared as following:
[0972] 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.
[0973] 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.
[0974] Alternatively
4,5-dimethyl-1-isobutyl-2-[2-(5-phosphono)furanyl]-imidazole can be
prepared as following:
[0975] 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.
[0976] 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.
[0977] According to the above procedures or in some cases with some
minor modifications of the above procedures, the following
compounds were prepared: [0978] (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. [0979]
(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. [0980] (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. [0981] (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. [0982] (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. [0983] (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. [0984] (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. [0985] (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. [0986] (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. [0987] (10.11)
5-Isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal. Calcd. for
C.sub.11H.sub.14NO.sub.5P: C, 48.72; H, 5.20; N, 5.16. Found: C,
48.67; H, 5.02; N, 5.10. [0988] (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. [0989] (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. [0990] (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. [0991] (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. [0992] (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. [0993] (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. [0994] (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. [0995] (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 [0996] (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. [0997] (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 [0998] (10.28)
2-Methylamino-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole hydrogen
bromide. Anal. Calcd for
C.sub.12H.sub.18BrN.sub.2O.sub.5P+0.7H.sub.2O: C, 36.60; H, 4.97;
N, 7.11. Found: C, 36.50; H, 5.09; N, 7.04. [0999] (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. [1000] (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. [1001]
(10.31) 2-Vinyl-5-isobutyl-4-[2-(5-phosphono)furanyl]oxazole. Anal.
Calcd for C.sub.13H.sub.16NO.sub.5P+0.5HBr: C, 49.18; H, 5.16; N,
4.41. Found: C, 48.94; H, 5.15; N, 4.40. [1002] (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. [1003] (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. [1004] (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. [1005] (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. [1006] (10.36)
2-Amino-5-isopropyloxycarbonyl-4-[2-(5-phosphono)furanyl]oxazole.
mp 221.degree. C. (decomp). Anal. calcd for
C.sub.11H.sub.13N.sub.2O.sub.7P+0.9H.sub.2O: C, 39.75; H, 4.49; N,
8.43. Found: C, 39.72; H, 4.25; N, 8.20. [1007] (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. [1008] (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. [1009] (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. [1010] (10.40)
2-Amino-5-isopropylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal.
calcd for C.sub.11H.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. [1011] (10.41)
2-Amino-5-phenylthio-4-[2-(5-phosphono)furanyl]oxazole. Anal. calcd
for C.sub.13H.sub.11N.sub.2O.sub.5PS+0.25HBr: C, 43.55; H, 3.16; N,
7.81. Found: C, 43.82; H, 3.28; N, 7.59. [1012] (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. [1013] (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. [1014] (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, [1015] (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
[1016] 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.
Step B.
1,2-Dimethyl-4-isobutyl-5-[2-(5-diethylphosphono)furanyl]-imidaz-
ole and
1,2-dimethyl-5-isobutyl-4-[2-(5-diethylphosphono)furanyl]-imidazol-
e were subjected to Step C of Example 3 to give the following
compounds:
[1017] (11.1) 1,2-Dimethyl-5-isobutyl-4-[2-(5-phosphono)
furanyl]imidazole hydrogen bromide. Anal. Calcd. for
C.sub.13H.sub.20N.sub.2O.sub.4PBr+0.8H.sub.2O: C, 39.67; H, 5.53;
N, 7.12. Found: C, 39.63; H, 5.48; N, 7.16.
Example 12
Preparation of 2-[2-(6-phosphono)pyridyl]pyridine
[1017] 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.
[1018] 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.
[1019] 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
[1020] 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.
[1021] 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.
[1022] Step C. 2-Diethylphosphonomethyl-4,6-dimethylpyridine was
subjected to Step C of Example 3 to give
4,6-dimethyl-2-(phosphonomethoxymethyl)pyridine (13.1). mp
109-112.degree. C. Anal. Calcd. for
C.sub.9H.sub.14NO.sub.4P+1.0H.sub.2O+0.5HBr: C, 37.32; H, 5.74; N,
4.84. Found: C, 37.18; H, 5.38; N, 4.67.
[1023] The following compound was prepared similarly: [1024] (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)
[1025] 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 THE 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
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.
[1026] 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.
[1027] 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.
[1028] Step D. A solution of
2-amino-6-[2-(5-diethylphosphono)furanyl]pyridine (1 mmole) in
acetic acid was treated with a solution of bromine in acetic acid
(1N, 1 mmole) at 25.degree. C. for 0.5 h. Evaporation and
chromatography gave
2-amino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine and
2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine.
Step E. 2-Amino-5-bromo-6-[2-(5-diethylphosphono)furanyl]pyridine
and 2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)furanyl]pyridine
were subjected to Step C of Example 3 to give the following
compounds:
[1029] (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.
[1030] (15.3)
6-Amino-3,5-dibromo-2-[2-(5-phosphono)furanyl]pyridine, mp
233-235.degree. C. Anal. Calcd. for
C.sub.9H.sub.7Br.sub.2N.sub.2O.sub.4P+1.2HBr: C, 21.84; H, 1.67; N,
5.66. Found: C, 21.90; H, 1.52; N, 5.30. Step F. A solution of
2-amino-3,5-dibromo-6-[2-(5-diethylphosphono)-furanyl]pyridine (1
mmole) in DMF was treated with tributyl(vinyl)tin (1.2 mmole) and
tetrakis(triphenylphosphine) palladium (0.2 mmole) at 85.degree. C.
for 4 h. Evaporation and chromatography gave
2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)furanyl]pyridine.
Step G. A solution of
2-amino-3,5-bis(vinyl)-6-[2-(5-diethylphosphono)-furanyl]pyridine
(1 mmole) in ethyl acetate was treated with palladium on carbon
(10%) at 25.degree. C. under 1 atmosphere of hydrogen for 12 h.
Filtration, evaporation and chromatography gave
2-amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine. Step
H. 2-Amino-3,5-diethyl-6-[2-(5-diethylphosphono)furanyl]pyridine
was subjected to Step C of Example 3 to give
2-amino-3,5-diethyl-6-[2-(5-phosphono)furanyl]pyridine (15.4). mp
217-218.degree. C. Anal. Calcd. for
C.sub.13H.sub.17N.sub.2O.sub.4P+0.7H.sub.2O+1.0HBr: C, 40.06; H,
5.02; N, 7.19. Found: C, 40.14; H, 4.70; N, 6.87. Step 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. 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.
[1031] Following compounds were prepared according to the above
described procedures or with some minor modifications of these
procedures using conventional chemistry. [1032] (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. [1033] (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. [1034] (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. [1035] (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. [1036] (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. [1037]
(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. [1038] (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. [1039] (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. [1040] (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.
[1041] (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. [1042] (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. [1043] (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. [1044] (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. [1045]
(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. [1046] (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. [1047] (15.22)
2-Methyl-5-cyano-6-[2-(5-phosphono)furanyl]pyridine. Anal. Calcd.
for C.sub.11H.sub.9N.sub.2O.sub.4P+0.75HBr+0.5H.sub.2O+0.5MePh: C,
45.84; H, 3.91; N, 7.37. Found: C, 45.93; H, 3.56; N, 7.36. [1048]
(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.
[1049] (15.24) 2-Chloro-4-cyano-6-[2-(5-phosphono)furanyl]pyridine.
Anal. Calcd. for C.sub.10H.sub.6N.sub.2O.sub.4PCl: C, 42.20; H,
2.13; N, 9.84. Found: C, 41.95; H, 2.10; N, 9.47.
Example 16
Preparation of 2-[2-(5-phosphono)furanyl]pyrimidines and
4-[2-(5-phosphono)furanyl]pyrimidines
[1049] 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.
[1050] 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.
[1051] 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 CC for 12 h. Evaporation and chromatography gave
2-amino-5-propyl-4-[2-(5-diethylphosphono)furanyl]pyrimidine.
[1052] 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.
[1053] The following compound was prepared according to this
procedure: [1054] (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.
[1055] Alternatively other 4-[2-(5-phosphono)furanyl]pyrimidines
can be prepared according to the following procedures:
Step E. Compound 2.2 was subjected to Step A of Example 16 to give
diethyl 5-(3-N,N-dimethylamino)acryloyl-2-furanphosphonate as an
orange solid.
[1056] 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.
[1057] Step G. 2-Amino-4-[2-(5-diethylphosphono)furanyl]pyrimidine
was subjected to Step C of Example 3 to give
2-amino-4-[2-(5-phosphono)furanyl]-pyrimidine (16.3).
mp>230.degree. C. Anal. Calcd. for
C.sub.8H.sub.8N.sub.3O.sub.4P+0.75H.sub.2O+0.2HBr: C, 35.48; H,
3.61; N, 15.51. Found: C, 35.42; H, 3.80; N, 15.30.
[1058] 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.
[1059] Step 1.
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.
[1060] The following compounds were prepared according to the above
described procedures or with some minor modifications using,
conventional chemistry: [1061] (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. [1062]
(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. [1063] (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. [1064] (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. [1065] (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. [1066] (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. [1067] (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. [1068] (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+0.8HBr+0.2MePh:
C, 27.80; H, 2.56; N, 9.35. Found: C, 27.74; H, 2.40; N, 8.94.
[1069] (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+0.05MePh: C, 36.02; H, 4.01; N,
13.61. Found: C, 35.98; H, 4.04; N, 13.33. [1070] (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
[1071] 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: [1072] (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. [1073]
(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. [1074] (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. [1075] (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.
[1076] (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. [1077] (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. [1078] (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+1.7HBr+0.25MePh: C,
27.19; H, 3.54; N, 8.85. Found: C, 27.10; H, 3.85; N, 8.49. [1079]
(17.8) 6-Amino-5-methylthio-2-[2-(5-phosphono)furanyl]pyrazine.
Anal. calcd. for C.sub.9H.sub.10N.sub.3O.sub.4PS+1.1HBr+0.05MePh:
C, 29.49; H, 3.04; N, 11.03. Found: C, 29.23; H, 2.79: N, 10.87.
[1080] (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+0.3HBr+0.04MePh:
C, 34.15; H, 2.68; N, 11.62. Found: C, 34.20; H, 2.90; N, 11.21.
[1081] (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+0.8HBr: C,
29.30; H, 3.77; N, 15.18. Found: C, 29.03; H, 3.88; N, 15.08.
[1082] (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+0.1EtOAc: 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
[1083] 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.
[1084] Step B. A solution of
2-[N-Boc(amino)]-4-ethoxycarbonylthiazole (1 mmole) in a 2:1
mixture of EtOH:H.sub.2O (10 mL) was treated with NaOH (3N, 3
mmole) and the reaction was stirred at 60.degree. C. for 4 h. The
reaction was cooled to 0.degree. C. and neutralized to pH 5 with 3
N HCl, and the resulting solid was collected via filtration to give
2-[N-Boc(amino)]-4-carboxylthiazole as a white solid.
[1085] 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.
[1086] Alternatively the ester linkage can be formed using a mixed
anhydride method as exemplified in the following procedures:
[1087] 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.
[1088] 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.
[1089] 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.
[1090] 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.
[1091] 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.
[1092] Step H. A suspension of
2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonyl thiazole
(1 mmole) and 10% Pd/C (0.5 mmole) in MeOH (5 mL) was stirred under
an atmosphere of H.sub.2 (balloon) at room temperature for 15 h.
Filtration and evaporation gave
2-[N-Boc(amino)]-5-ethyl-4-diethylphosphonomethoxycarbonylthiazole
as a yellow solid, which was subjected to Step D of Example 18
followed by Step C of Example 3 to give
2-amino-5-ethyl-4-phosphonomethoxycarbonylthiazole (18.3) as a
solid. Mp>230.degree. C. (decomp). Anal. Calcd. for
C.sub.7H.sub.11N.sub.2O.sub.5PS: 31.58; H, 4.16; N, 10.52. Found:
C, 31.80; H, 4.04; N, 10.18.
[1093] 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+0.1HBr: C, 29.99; H, 4.12; N,
8.74. Found: C, 29.71; H, 4.10; N, 8.60.
II. Preparation of 4-phosphonomethylthiocarbonylthiazole
[1094] 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 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.
[1095] 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
[1096] 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+1.05HBr: 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
[1097] 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.
[1098] 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: [1099]
(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. [1100] (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. [1101] (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. [1102] (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. [1103] (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+0.1EtOAc: C, 27.60; H,
2.91; N, 10.27. Found: C, 27.20; H, 2.67; N, 9.98. [1104] (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. [1105] (18.14)
2-Amino-5-bromo-4-{[N-(1-phosphono-1-phenyl)methyl]carbarnoyl}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. [1106] (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. [1107] (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. [1108] (18.17)
2-Methylthio-5-methylamino-4-phosphonomethoxycarbonylthiazole.
Anal. Calcd. for C.sub.7H.sub.11N.sub.2O.sub.5PS.sub.2+0.2HBr: C,
26.74; H, 3.59; N, 8.91. Found: C, 26.79; H, 3.89; N, 8.89. [1109]
(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. [1110]
(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. [1111] (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. [1112] (18.21)
2-Amino-5-phenyl-4-phosphonomethoxycarbonylthiazole.
Mp>230.degree. C. Anal. Calcd. for
C.sub.11H.sub.11N.sub.2O.sub.5PS: C, 42.04; H, 3.53; N, 8.91.
Found: C, 42.04; H, 3.40; N, 8.72. [1113] (18.22)
2-Amino-4-phosphonomethoxycarbonyloxazole. Anal. Calcd. for
C.sub.5H.sub.7N.sub.2O.sub.6P+0.09HBr: C, 26.18; H, 3.12; N, 12.21.
Found: C, 26.29; H, 3.04; N, 11.90. [1114] (18.23)
2-Amino-6-[(N-phosphonoacetyl)amino]pyridine. Anal. Calcd. for
C.sub.7H.sub.10N.sub.3O.sub.4P+1.1HBr+0.25 MeOH: C, 26.54; H, 3.72;
N, 12.80. Found: C, 26.79; H, 3.63; N, 12.44. [1115] (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+0.06EtOAc: C, 29.22; H, 4.12; N,
16.38. Found: C, 29.03; H, 3.84; N, 16.01. [1116] (18.25)
2-Amino-3-bromo-6-[(N-phosphonoacetyl)amino]pyridine. Anal. Caicd.
for C.sub.7H.sub.9N.sub.3O.sub.4PBr+1.25HBr+0.8EtOAc: C, 25.43; H,
3.48; N, 8.72. Found: C, 25.58; H, 3.71; N, 8.56. [1117] (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+0.5EtOAc: C,
21.03; H, 2.55; N, 8.18. Found: C, 21.28; H, 2.55; N, 7.91. [1118]
(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, 11.1. Found:
C, 28.38; H, 3.49; N, 11.10. [1119] (18.28)
2-Amino-3,5-diethyl-6-[(N-phosphonoacetyl)amino]pyridine. MS calcd.
for C.sub.11H.sub.13N.sub.3O.sub.4P+H, 288, found 288. [1120]
(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+0.5HBr+EtOAc: C, 19.56; H,
2.16; N, 6.22. Found: C, 19.26; H, 2.29; N, 5.91. [1121] (18.30)
2-Amino-5-isopropyl-4-phosphonomethoxycarbonyloxazole. Anal. Calcd.
for C.sub.8H.sub.13N.sub.2O.sub.6P+0.2HBr: C, 34.27; H, 4.75; N,
9.99. Found: C, 34.47; H, 4.84; N, 9.83. [1122] (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+0.1HBr: C, 45.89; H, 5.25; N,
7.64. Found: C, 45.85; H, 4.96; N, 7.44. [1123] (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+0.25HBr: C, 35.80; H, 3.08; N,
12.53. Found: C, 35.92; H, 2.99; N, 12.20. [1124] (18.33)
2-Amino-5-methyl-4-phosphonomethoxycarbonyloxazole. Anal. Calcd.
for C.sub.6H.sub.9N.sub.2O.sub.6P+0.15HBr: C, 29.03; H, 3.71; N,
11.28. Found: C, 28.98; H, 3.66; N, 11.21, [1125] (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. [1126] (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. [1127] (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. [1128] (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. [1129] (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. [1130] (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. [1131] (18.40)
2-Amino-5-propyl-4-phosphonomethoxycarbonyloxazole. Anal. Calcd.
for C.sub.8H.sub.13N.sub.2O.sub.6P+0.35EtOAc+0.05HBr: C, 37.75; H,
5.34; N, 9.37. Found: C, 37.69; H, 5.21; N, 9.03. [1132] (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. [1133]
(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. [1134] (18.43)
2-Amino-5-bromo-4-phosphonomethylthiocarbonylthiazole. Mp
230.degree. C. (decomp).
[1135] 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. [1136]
(18.44) 2-Amino-5-(2-furanyl)-4-phosphonomethoxycarbonylthiazole.
MD 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. [1137] (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.
[1138] (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
[1139] 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: [1140] (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. [1141]
(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. [1142]
(19.3)
2-Methyl-5-isobutyl-4-{2-[5-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. [1143]
(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. [1144] (19.5)
2-Amino-5-isobutyl-4-{2-[5-bis(3,4-diacetoxybenzyl)phosphono]furanyl)}thi-
azole. 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. [1145]
(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.
[1146] This method is also useful for the preparation of phenyl
phosphonate esters as prodrugs, and the following compound was
prepared: [1147] (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. [1148] (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. [1149] (19.64)
2-Amino-5-isobutyl-4-[2-(5-phenylphosphono)furanyl]thiazole.
Mp>250 0.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. [1150] (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. [1151] (19.67)
2-Amino-5-isobutyl-4-[2-(5-bis(4-methoxyphenyl)phosphono)furanyl]-
thiazole. Anal. Calcd. 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.
[1152] This method is also useful for the preparation of some
thio-containing phosphonate esters as prodrugs, and the following
compounds were prepared: [1153] (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. [1154]
(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.
[1155] 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 phosphonic 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: [1156]
(19.10)
5-Isobutyl-2-methyl-4-{2-[5-(1-hydroxy-3,5-cyclohexyl)phosphono]f-
uranyl}thiazole (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. [1157] (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. [1158] (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. [1159]
(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. [1160] (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. [1161] (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. [1162] (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. [1163] (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+0.4+CH.sub.2Cl.sub.2: C,
50.16; H, 5.74; N, 5.74. Found: C, 50.36; H, 5.36; N, 5.80. [1164]
(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. [1165] (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. [1166] (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. [1167] (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. [1168] (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. [1169] (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. [1170] (19.25)
2-Methyl-4-{2-[5-(2-acetoxymethylpropan-1,3-diyl)phosphono]furany-
l}thiazole. 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. [1171] (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. [1172] (19.27)
2-Amino-5-methylthio-4-(2-{5-[1-(4-pyridyl)propan-1,3-diyl]phosph-
ono}furanyl)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. [1173] (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. [1174] (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. [1175]
(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.2NO.sub.4PSBr+0.25HCl: C, 47.43; H, 4.43; N,
5.53. Found: C, 47.58; H, 4.16; N, 5.31. [1176] (19.31)
2-Amino-5-isobutyl-4-{2-[5-(2-benzyl-1,3-propyl)phosphono]furanyl}thiazol-
e. Anal. Calcd. for C.sub.2H.sub.2N.sub.2O.sub.4PS: C, 58.32; H,
5.83; N, 6.48. Found: C, 57.98; H, 5.65; N. 6.47. [1177] (19.32)
2-Amino-5-cycloproyl-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. [1178] (19.33)
2-Methyl-5-isobutyl-4-{2-[5-(1-(S)-phenyl-1,3-propyl)phosphono]fu-
ranyl}thiazole, 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. [1179] (19.34)
2-Methyl-5-isobutyl-4-{2-[5-(1-(S)-phenyl-1,3-propyl)phosphono]fu-
ranyl}thiazole, 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. [1180] (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. [1181] (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. [1182] (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. [1183]
(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. [1184] (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. [1185] (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. [1186] (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. [1187] (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. [1188] (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. [1189] (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. [1190] (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. [1191] (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. [1192] (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. [1193] (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.
[1194] (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. [1195] (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. [1196] (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. [1197] (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. [1198] (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. [1199] (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. [1200] (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. [1201] (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. [1202] (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. [1203] (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. [1204] (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+0.3EtOAc:
C, 51.98; H, 5.02; N, 5.72. Found: C, 51.67; H, 4.77; N, 5.42.
[1205] (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. [1206] (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, +0.3EtOAc: C, 42.25; H,
3.91; N, 4.65. Found: C, 42.52; H, 3.91; N, 4.96. [1207] (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. [1208] (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. [1209] (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.3PS+0.75H.sub.2O: C, 52.59; H, 5.23:
N, 6.46. Found: C, 52.38; H, 4.85; N, 6.08.
[1210] Preferably the cyclic 1,3-propanediol phosphonate esters
were prepared using 1,3-dicyclohexylcarbodiimide (DCC) coupling
reaction conditions as following.
[1211] 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 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-5-isobutyl-4-{2-[5-(1-(3,5-dichlorophenyl)-1,3-propyl)phosphono]f-
uranyl}thiazole, major isomer. (19.48) as a solid.
[1212] 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. [1213] (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.
[1214] 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.
[1215]
2-Amino-5-isobutyl-4-{2-[5-bis(3-phthalidyl-2-ethyl)phosphono]}fur-
anyl-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 Acryloxyalkyl and Alkyloxycarbonyloxyalkyl
Phosphonate Diesters as Prodrugs
[1216] 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.
[1217] The following compounds were prepared according to this
procedure: [1218] (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,
53.81; H, 6.83; N, 2.60. [1219] (20.3)
2-Methyl-5-isobutyl-4-{2-[5-(dipivaloyloxymethyl)phosphono]furanyl-
}thiazole. 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. [1220] (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. [1221] (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.
[1222] 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). [1223]
(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. [1224] (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.
[1225] Alkyloxycarbonyloxyalkyl phosphonate esters were also
prepared according to the above procedures with slight
modifications described below:
[1226] 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.
[1227] The following compounds were prepared according to this
procedure: [1228] (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. [1229]
(20.8)
2-Amino-5-isobutyl-4-{-2-[5-bis(phenoxycarbonyloxy-methyl)phosphono]-fura-
nyl}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.
[1230] (20.9)
2-Amino-5-isobutyl-4-{-2-[5-bis(ethoxycarbonyloxymethyl)phosphono]-
-furanyl}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. [1231] (20.10)
2-Methyl-5-isobutyl-4-{-2-[5-bis(isopropylthiocarbonyloxymethyl)--
phosphono]furanyl}thiazole. Anal. Calcd. for
C.sub.22H.sub.32NO.sub.8PS.sub.3+0.2EtOAc: C, 46.95; H, 5.81; N,
2.40. Found: C, 47.06; H, 5.86; N, 2.73. [1232] (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.10PS:
C, 47.19; H, 5.85; N, 5.24. Found: C, 47.33; H, 5.66; N, 5.57.
[1233] (20.12)
2-Methyl-5-isobutyl-4-{2-[5-bis(benzoyloxymethyl)phosphono]furany-
l}thiazole. 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. [1234] (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.
[1235]
2-Amino-5-isobutyl-4-{2-[5-bis(3-(5,6,7-trimethoxy)phthalidyl)-pho-
sphono]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
[1236] 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.
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
[1237] A solution of phthalide-3-acetic acid (1 mmole) in THT 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
[1238] 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.
[1239] 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.
[1240] A solution of
5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene (I
rrimole) 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-dioxoiene.
[1241] A solution of
5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxotlene
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
[1242] 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
[1243] 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.
[1244] 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,
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.
[1245] 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
Step A. A solution of 5-diethylphosphono-2-furaldehyde (1 mmole) in
ethanol was treated with hydroxylamine (1.1 mmole) and sodium
acetate (2.2 mmole) at 25.degree. C. for 12 h. Extraction and
chromatography gave 5-diethylphosphono-2-furaldehyde oxime.
Step B. A solution of 5-diethylphosphono-2-furaldehyde oxime (1
mmole) in DMF was treated with N-chlorosuccinimide (1.1 mmole) at
25.degree. C. for 12 h. Extraction gave
5-diethylphosphono-2-chlorooximidofuran.
[1246] 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.
[1247] 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.
[1248] The following compound was prepared according to this
procedure: [1249] (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. [1250] (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. [1251] (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. [1252] (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.
[1253] (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. [1254] (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. [1255] (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 T 0.2HBr: C, 35.18;
H, 2.36; N, 15.39. Found: C, 35.34; H, 2.50; N, 15.08. [1256]
(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
[1256] 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.
[1257] 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
[1258] 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.
[1259] Step B. A solution of LDA (1.06 mmole) in THF was treated
with a solution of diethyl difluoromethylphosphonate (1 mmole) at
-78.degree. C. for 45 min. The reaction was then treated with a THF
solution of 3-(tert-butyldiphenylsilyloxy)-1-propanal (1.07 mmole)
and the resulting solution was stirred at -78.degree. C. for
another 4 h. The reaction was quenched with phenyl
chlorothioformate (2.14 mmole), and the reaction mixture was
subjected to extraction and chromatography to give diethyl
4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutyl-
phosphonate as a clear oil.
[1260] Step C. A solution of diethyl
4-(tert-butyldiphenylsilyloxy)-3-phenoxythiocarbonyloxy-2,2-difluorobutyl-
phosphonate (1 mmole) in toluene (11 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.
[1261] 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.
[1262] 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.
[1263] 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.
[1264] The following compound was prepared in a similar manner:
2-Amino-5-methylthio-4-[1-(3-phosphono-3,3-difluoro)propyl]thiazole
(28.2). MS m/e 305 (M+H).
Example 29
Preparation of 2-methylthio-5-phosphonomethylthio-1,3,4-thiadiazole
and 2-phosphonomethylthiopyridine
[1265] 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.
[1266] 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+0.2HBr: C, 17.50; H, 2.64; N,
10.21. Found: C, 17.64; H, 2.56; N, 10.00.
[1267] Alternatively, phosphonomethylthio substituted
heteroaromatics are made using the following method as exemplified
by the synthesis of 2-phosphonomethylthiopyridine:
[1268] Step C. A solution of 2,2'-dipyridyl disulfide (1 mmole) in
THF was treated with tri-n-butylphosphine (1 mmole) and diethyl
hydroxymethylphosphonate at 0.degree. C. The resulting reaction
solution was stirred at room temperature for 18 h. Extraction and
chromatography gave 2-diethylphosphonomethylthiopyridine as a
yellow oil.
Step D. 2-Diethylphosphonomethylthiopyridine was subjected to Step
C of Example 3 to give 2-phosphonomethylthiopyridine (29.2) as a
yellow solid. Anal. Calcd. for C.sub.6H.sub.8NO.sub.3PS+0.62HBr: 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
[1269] Step A. A solution of 2-ethynylpyridine (1 mmole) in THE (5
mL) was treated with LDA (1.2 mmole) at 0.degree. C. for 40 min.
Diethyl chlorophosphate (1.2 mmole) was added to the reaction and
the resulting reaction solution was stirred at room temperature for
16 h. The reaction was quenched with saturated ammonium chloride
followed by extraction and chromatography to give
2-[(2-diethylphosphono)ethynyl]pyridine as a yellow oil.
Step B. 2-[(2-Diethylphosphono)ethynyl]pyridine was subjected to
Step C of Example 3 to give 2-[1-(2-phosphono)ethynyl]pyridine
(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
[1270] 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. [1271] (31.1)
2-Methyl-5-isopropyl-4-[2-(5-phosphonomonoamido)furanyl]thiazole:
MS m/e 299 (M-H). [1272] (31.2)
2-Methyl-5-isopropyl-4-[2-(5-phosphorodiamido)furanyl]thiazole: MS
m/e 298 (M-H).
[1273] Alternatively, a different method was used to prepare other
phosphoramides as exemplified in the following procedure:
[1274] 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.
[1275] The following compounds were prepared according to the above
described procedures or in some cases with minor modifications of
these procedures: [1276] (31.4)
2-Amino-5-isobutyl-4-[2-(5-phosphonomonoamido)furanyl]thiazole. Mp
77-81.degree. C.
[1277] 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. [1278]
(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.
[1279] (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. [1280] (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.10PS: C, 51.78: H, 6.74; N, 8.33.
Found: C, 51.70; H, 6.64; N, 8.15. [1281] (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. [1282] (31.31)
2-Amino-5-isobutyl-4-{2-[5-bis(2-methoxycarbonyl-1-azirdinyl)phos-
phorodiamido]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. [1283] (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.
[1284] The monophenyl-monophosphonamide derivatives of compounds of
formula I can also be prepared according to the above described
procedures:
[1285] 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 mL) 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),
[1286] 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.
[1287] The following compounds were prepared according to the above
described procedures: [1288] (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. [1289] (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. [1290] (31.9)
2-amino-5-isobutyl-4-{2-[5-(O-phenyl-N-isobutyl)phosphonamido]fura-
nyl}thiazole. 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. [1291] (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. [1292] (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. [1293] (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. [1294] (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. [1295] (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. [1296] (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 [1297] (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. [1298]
(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. [1299] (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. [1300] (31.36)
2-amino-5-isobutyl-4-{2-[5-(O-(4-methyoxyphenyl)-N-(1-(1-methoxyc-
arbonyl)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. [1301] (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. [1302] (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.
[1303] 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: [1304] (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. [1305] (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.25N.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. [1306] (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.
[1307] (31.13)
2-Amino-5-isobutyl-4-{2-[5-(1-phenyl-1,3-propyl)phosphonamido]fur-
anyl}thiazole 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. [1308] (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. [1309] (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. [1310] (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. [1311] (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. [1312] (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.30O.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.
[1313] (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. [1314] (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. [1315] (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
[1316] 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.
[1317] 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.
[1318] 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.
[1319] 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.
Step E.
[1320] 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.
[1321] 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.
[1322] 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.
[1323] 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. [1324] (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
[1325] 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.
[1326] 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)furnayl]pyridine.
[1327] 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.
[1328] 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
12-100 formate resin was added. After stirring this mixture 30 min
it was filtered and the resin washed with DMF (210 min), CH.sub.3CN
(210 min) and then 9:1 CH.sub.3CN:water (110 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.
[1329] 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 n 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 12-100
formate resin was added and after stirring 30 min it was filtered
and the resin washed with DMF (210 min), CH.sub.3CN (210 min) and
then 9:1 CH.sub.3CN:water (110 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)furnayl]pyrazine.
[1330] 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=mole) and CuI (0.002 mole) 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
[1331] 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.
[1332] Step H. Hydroxymethylpolystyrene (2.35 mmol) was prepared
for coupling by combining with anhyrous THF (40 mL), gently skaking
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.
[1333] Step I. To coupled phosphonate resin (2.41 mmol) in THF (100
mL) was added IM 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
[1334] 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
[1335] Step K. To a solution of dimethyl
phthalimidomethylphosphonate (37 mmole) in 2-butanone (150 mL) was
added LiI (38.9 mmol). After refluxing overnight under N.sub.2, the
solution was diluted with EtOAc, washed with 1N HCl, dried over
MgSO.sub.4 and concentrated under vacuum to afford monomethyl
phthalimidomethylphosphonate as a white solid.
Step L. As described above in Step H, monomethyl
phthalimidomethyl-phosphonate was coupled to
hydroxymethylpolystyrene to give the resin-coupled
phthalimidomethylphosphonate monomethyl ester.
[1336] 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.
[1337] 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.
[1338] 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.
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.
[1339] HPLC Elution Program: 1.5 mL/min flow rate TABLE-US-00061
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
[1340] TABLE-US-00062 TABLE 33.1 ##STR198## synthetic HPLC example
Rt number X Y' (min.) M-1 found A B 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 A* B* 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-dichloro) null NHC(O)CH2 O 34.163 Br
null furan-2,5-diyl NH 4.46 292/294 34.164 Br null furan-2,5-diyl S
5.96 309/311 *when A or B is null, then the corresponding G is
N.
[1341] TABLE-US-00063 TABLE 33.2 ##STR199## 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-,5-diy 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 OEt 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-amino- furan-2,5-diyl H H 8.91
398 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--CH(OH)Me
H furan-2,5-diyl CH3 null 4.65 312 33.83 NH2 null furan-2,S-diyl
NHCH2--CH(OH)Me H 4.63 313 33.84 NHCH2--CH(OH)Me H furan-2,5-diyl
NH2 null 4.63 313 33.85 NHCH2--CH(OH)Me H furan-2,5-diyl CH2OH H
4.52 327 33.86 NH2 H furan-2,5-diyl NHCH2--CH(OH)Me null 4.65 313
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--(CH2)3OH 4.76 414 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-morpholinyl) 7.47 438
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
[1342] 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.
[1343] 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.
[1344] 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.
[1345] 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.
[1346] Similarly, the following compounds were prepared according
to the above described procedures: [1347] (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
[1348] 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.
[1349] Similarly, the following compounds were prepared according
to the above described procedures: [1350] (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. [1351] (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. [1352] (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-5,67,8-tetrahydronaphtho[1,2-d]thiazole
[1352] 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-tetrahydronaphthlene.
[1353] 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.
[1354] 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.
[1355] The following compounds were also prepared according to
above procedures: [1356] (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. [1357] (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-phosphonomethoxy-benzothiazole
[1357] Step A. 2-Hydroxy-5-methoxynitrobenzene was subjected to
Step B of Example 34 to give
2-diethylphosphonomethyloxy-5-methoxynitrobenzene.
[1358] 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.
[1359] 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.
[1360] Similarly, the following compounds were prepared according
to above procedures: [1361] (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. [1362] (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. [1363] (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
[1364] 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.
[1365] 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.2Br: C, 27.29; H, 1.78; N,
10.61. Found: C, 26.90; H, 1.58; N, 10.54.
[1366] Similarly, the following compound was prepared according to
above procedures: [1367] (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.4PFS.sub.2+0.3HBr: C, 30.07; H, 2.05; N,
11.69. Found: C, 30.27; H, 2.01; N, 11.38.
Preparation of
2-Amino-7-hydroxymethyl-6-thiocyano-4-phosphonomethoxy
benzothiazole
[1367] Step A. 2-Chloro-5-formylnitrobenzene was subjected to Step
A of Example 38 to give
2-diethylphosphonomethyloxy-5-formylnitrobenzene.
[1368] 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, 161.
Example 40
Preparation of
2-Amino-6-bromo-7-fluoro-4-phosphonomethoxybenzothiazole
[1369] 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
[1370] 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
[1371] 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
[1372] 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+0.4HBr: C,
31.20; H, 3.20; N, 8.09. Found: C, 31.37; H, 2.87; N, 7.89.
[1373] Similarly, the following compounds were prepared according
to above procedures: [1374] (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,
[1375] 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.
[1376] 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
[1377] 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
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.
[1378] Step B. 2-Amino-4-diethylphosphonomethylhiobenzothiazole 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
[1379] 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, 50.511; H, 4.24; N,
5.61. Found: C, 50.83; H, 4.34; N, 5.25.
[1380] 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.
[1381] Alternatively, a different method is used to prepare other
phosphoramides as exemplified in the following procedure:
[1382] 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.
[1383] The monophenyl-monophosphonamide derivatives of compounds of
formula X can also be prepared according to the above described
procedures:
[1384] 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.
[1385] 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.
[1386] 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.
[1387]
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.
[1388] Examples of use of the method of the invention includes the
following. It will be understood that these examples are exemplary
and that the method of the invention is not limited solely to these
examples.
[1389] For the purposes of clarity and brevity, chemical compounds
are referred to by synthetic Example number in the biological
examples below.
[1390] Besides the following Examples, assays that may be useful
for identifying compounds which inhibit gluconeogenesis include the
following animal models of diabetes:
[1391] i. Animals with pancreatic b-cells destroyed by specific
chemical cytotoxins such as Alloxan or Streptozotocin (e.g. the
Streptozotocin-treated mouse, rat, dog, and monkey). Kodama, H.,
Fujita, M., Yamaguchi, I., Japanese Journal of Pharmacology 66,
331-336 (1994) (mouse); Youn, J. H., Kim, J. K., Buchanan, T. A.,
Diabetes 43, 564-571 (1994) (rat); Le Marchand, Y., Loten, E. G.,
Assimacopoulos-Jannet, F., et al., Diabetes 27, 1182-88 (1978)
(dog); and Pitkin, R. M., Reynolds, W. A., Diabetes 19, 70-85
(1970) (monkey).
[1392] ii. Mutant mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob,
and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and
others such as Yellow Obese, T-KK, and New Zealand Obese. Coleman,
D. L., Hummel, K. P., Diabetologia 3, 238-248 (1967) (C57BL/Ks
db/db); Coleman, D. L., Diabetologia 14, 141-148 (1978) (C57BL/6J
ob/ob); Wolff, G. L., Pitot, H. C., Genetics 73, 109-123 (1973)
(Yellow Obese); Dulin, W. E., Wyse, B. M., Diabetologia 6, 317-323
(1970) (T-KK); and Bielschowsky, M., Bielschowsky, F. Proceedings
of the University of Otago Medical School 31, 29-31 (1953) (New
Zealand Obese).
[1393] iii. Mutant rats such as the Zucker fa/fa Rat rendered
diabetic with Streptozotocin or Dexamethasone, the Zucker Diabetic
Fatty Rat, and the Wistar Kyoto Fatty Rat. Stolz, K. J., Martin, R.
J. Journal of Nutrition 112, 997-1002 (1982) (Streptozotocin);
Ogawa, A., Johnson, J. H., Ohnbeda, M., McAllister, C. T., Inman,
L., Alam, T., Unger, R. H., The Journal of Clinical Investigation
90, 497-504 (1992) (Dexamethasone); Clark, J. B., Palmer, C. J.,
Shaw, W. N., Proceedings of the Society for Experimental Biology
and Medicine 173, 68-75 (1983) (Zucker Diabetic Fatty Rat); and
Idida, H., Shino, A., Matsuo, T., et al., Diabetes 30, 1045-1050
(1981) (Wistar Kyoto Fatty Rat).
[1394] iv. Animals with spontaneous diabetes such as the Chinese
Hamster, the Guinea Pig, the New Zealand White Rabbit, and
non-human primates such as the Rhesus monkey and Squirrel monkey.
Gerritsen, G. C., Connel, M. A., Blanks, M. C., Proceedings of the
Nutrition Society 40, 237 245 (1981) (Chinese Hamster); Lang, C.
M., Munger, B. L., Diabetes 25, 434-443 (1976) (Guinea Pig);
Conaway, H. H., Brown, C. J., Sanders, L. L. et al., Journal of
Heredity 71, 179-186 (1980) (New Zealand White Rabbit); Hansen, B.
C., Bodkin, M. L., Diabetologia 29, 713-719 (1986) (Rhesus monkey);
and Davidson, I. W., Lang, C. M., Blackwell, W. L., Diabetes 16,
395-401 (1967) (Squirrel monkey).
[1395] v. Animals with nutritionally induced diabetes such as the
Sand Rat, the Spiny Mouse, the Mongolian Gerbil, and the Cohen
Sucrose-Induced Diabetic Rat. Schmidt-Nielsen, K., Hainess, H. B.,
Hackel, D. B., Science 143, 689-690 (1964) (Sand Rat); Gonet, A.
E., Stauffacher, W., Pictet, R., et al., Diabetologia 1, 162-171
(1965) (Spiny Mouse); Boquist, L., Diabetologia 8, 274-282 (1972)
(Mongolian Gerbil); and Cohen, A. M., Teitebaum, A., Saliternik,
R., Metabolism 21, 235-240 (1972) (Cohen Sucrose-Induced Diabetic
Rat).
[1396] vi. Any other animal with one of the following or a
combination of the following characteristics resulting from a
genetic predisposition, genetic engineering, selective breeding, or
chemical or nutritional induction: impaired glucose tolerance,
insulin resistance, hyperglycemia, obesity, accelerated
gluconeogenesis, increased hepatic glucose output.
BIOLOGICAL EXAMPLES
Example A
Inhibition of Human Liver FBPase
[1397] E. coli strain BL21 transformed with a human liver
FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at
the State University of New York at Stony Brook. The enzyme was
typically purified from 10 liters of recombinant E. coli culture as
described (M. Gidh-Jain et al. 1994, The Journal of Biological
Chemistry 269, pp 27732-27738). Enzymatic activity was measured
spectrophotometrically in reactions that coupled the formation of
product (fructose 6-phosphate) to the reduction of
dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP.sup.+ and
phenazine methosulfate (PMS), using phosphoglucose isomerase and
glucose 6-phosphate dehydrogenase as the coupling enzymes. Reaction
mixtures (200 .mu.l) were made up in 96-well microtitre plates, and
consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM
MgCl.sub.2, 0.2 mM NADP, 1 mg/ml BSA, 1 mM MTT, 0.6 mM PMS, 1
unit/ml phosphoglucose isomerase, 2 units/ml glucose 6-phosphate
dehydrogenase, and 0.150 mM substrate (fructose 1,6-bisphosphate).
Inhibitor concentrations were varied from 0.01 .mu.M to 10 .mu.M.
Reactions were started by the addition of 0.002 units of pure
hlFBPase, and were monitored for 7 minutes at 590 nm in a Molecular
Devices Plate Reader (37.degree. C.).
[1398] The table below provides the IC.sub.50 values for several
compounds prepared. The IC.sub.50 for AMP is 1 .mu.M.
TABLE-US-00064 Compound # IC.sub.50 (hlFBPase), .mu.M 3.1 0.025 3.2
0.1 3.25 0.014 3.26 0.015 3.58 82 3.67 2 3.69 1 3.70 0.04 6.3 0.044
10.1 0.12 10.27 0.038 10.43 0.07 15.20 0.04 15.14 0.032 16.1 0.06
17.6 0.62 17.11 0.78 18.3 0.05 18.11 0.33 18.20 0.039 18.25 2 25.2
0.4 28.2 2.8 41.1 0.022
Inhibition of Rat Liver FBPase
[1399] E. coli strain BL21 transformed with a rat liver
FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at
the State University of New York at Stony Brook. Recombinant FBPase
was purified as described (El-Maghrabi, M. R., and Pilkis, S. J.
(1991) Biochem. Biophys. Res. Commun. 176, 137-144) The enzyme
assay was identical to that described above for human liver
FBPase.
[1400] The table below provides the IC.sub.50 values for several
compounds prepared. The IC.sub.50 for AMP is 20 .mu.M.
TABLE-US-00065 Compound # IC.sub.50 (rlFBPase), .mu.M 3.1 0.18 3.2
2.5 3.25 0.5 3.26 0.25 3.70 0.15 6.3 0.5 10.1 2 10.2 2.5 10.27 2.9
10.43 0.8 15.2 1.3 15.4 4.1 15.6 7 15.20 0.6 15.14 0.68 16.1 1.8
18.20 0.28 18.3 0.49 41.1 0.16
Example B
AMP Site Binding
[1401] To assess whether compounds bind to the allosteric AMP
binding site of hlFBPase, the enzyme is incubated with radiolabeled
AMP in the presence of a range of test compound concentrations. The
reaction mixtures consist of 25 mM .sup.3H-AMP (54 mCi/mmole) and
0-1000 mM test compound in 25 mM Tris-HCl, pH 7.4, 100 mM KCl and 1
mM MgCl.sub.2. 1.45 mg of homogeneous FBPase (+1 mmole) is added
last. After a 1 minute incubation, AMP bound to FBPase is separated
from unbound AMP by means of a centrifugal ultrafiltration unit
("Ultrafree-MC", Millipore) used according to the instructions of
the manufacturer. The radioactivity in aliquots (100 .mu.l) of the
upper compartment of the unit (the retentate, which contains enzyme
and label) and the lower compartment (the filtrate, which contains
unbound label) is quantified using a Beckman liquid scintillation
counter. The amount of AMP bound to the enzyme is estimated by
comparing the counts in the filtrate (the unbound label) to the
total counts in the retentate.
Example C
AMP Site/Enzyme Selectivity
[1402] To determine the selectivity of compounds towards FBPase,
effects of FBPase inhibitors on 5 key AMP binding enzymes were
measured using the assays described below:
[1403] Adenosine Kinase. Human adenosine kinase was purified from
an E. coli expression system as described by Spychala et al.
(Spychala, J., Datta, N. S., Takabayashi, K., Datta, M., Fox, I.
H., Gribbin, T., and Mitchell; B. S. (1996) Proc. Natl. Acad. Sci.
USA 93, 1232-1237). Activity was measured essentially as described
by Yamada et al. (Yamada, Y., Goto, H., Ogasawara, N. (1988)
Biochim. Biophys. Acta 660, 36-43.) with a few minor modifications.
Assay mixtures contained 50 mM TRIS-maleate buffer, pH 7.0, 0.1%
BSA, 1 mM ATP 1 mM MgCl.sub.2, 1.0 .mu.M [U-.sup.14C] adenosine
(400-600 mCi/mmol) and varying duplicate concentrations of
inhibitor. .sup.14C-AMP was separated from unreacted
.sup.14C-adenosine by absorption to anion exchange paper (Whatman)
and quantified by scintillation counting.
[1404] Adenosine Monophosphate Deaminase. Porcine heart AMPDA was
purified essentially as described by Smiley et al. (Smiley, K. L.,
Jr, Berry, A. J., and Suelter, C. H. (1967) J. Biol. Chem. 242,
2502-2506) through the phosphocellulose step. Inhibition of AMPDA
activity was determined at 37.degree. C. in a 0.1 ml assay mixture
containing inhibitor, .about.0.005 U AMPDA, 0.1% bovine serum
albumin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The
concentration of the substrate AMP was varied from 0.125-10.0 mM.
Catalysis was initiated by the addition of enzyme to the otherwise
complete reaction mixture, and terminated after 5 minutes by
injection into an HPLC system. Activities were determined from the
amount of IMP formed during 5 minutes. IMP was separated from AMP
by HPLC using a Beckman Ultrasil-SAX anion exchange column (4.6
mm.times.25 cm) with an isocratic buffer system (12.5 mM potassium
phosphate, 30 mM KCl, pH 3.5) and detected spectrophotometrically
by absorbance at 254 nm.
[1405] Phosphofructokinase. Enzyme (rabbit liver) was purchased
from Sigma. Activity was measured at 30.degree. C. in reactions in
which the formation of fructose 1,6-bisphosphate was coupled to the
oxidation of NADH via the action of aldolase, triosephosphate
isomerase, and a-glycerophosphate dehydrogenase. Reaction mixtures
(200 .mu.l) were made up in 96-well microtitre plates and were read
at 340 nm in a Molecular Devices Microplate Reader. The mixtures
consisted of 200 mM Tris-HCl pH 7.0, 2 mM DTT, 2 mM MgCl.sub.2, 0.2
mM NADH, 0.2 MM ATP, 0.5 mM Fructose 6-phosphate, 1 unit
aldolase/ml, 3 units/ml triosephosphate isomerase, and 4 units/ml
a-glycerophosphate dehydrogenase. Test compound concentrations
ranged from 1 to 500 .mu.M. Reactions were started by the addition
of 0.0025 units of phosphofructokinase and were monitored for 15
minutes.
[1406] Glycogen Phosphorylase. Enzyme (rabbit muscle) was purchased
from Sigma. Activity was measured at 37.degree. C. in reactions in
which the formation of glucose 1-phosphate was coupled to the
reduction of NADP via phosphoglucomutase and glucose 6-phosphate
dehydrogenase. Assays were performed on 96-well microtitre plates
and were read at 340 nm on a Molecular Devices Microplate Reader.
Reaction mixtures consisted of 20 mM imidazole, pH 7.4, 20 mM
MgCl.sub.2, 150 mM potassium acetate, 5 mM: potassium phosphate, 1
mM DTT, 1 mg/ml BSA, 0.1 mM NADP, 1 unit/ml phosphoglucomutase,
unit/ml glucose 6-phosphate dehydrogenase, 0.5% glycogen. Test
compound concentrations ranged from 1 to 500 .mu.M. Reactions were
started by the addition of 17 .mu.g enzyme and were monitored for
20 minutes.
[1407] Adenylate Kinase Enzyme (rabbit muscle) was purchase from
Sigma. Activity was measured at 37.degree. C. in reaction mixtures
(100 .mu.l) containing 100 mM Hepes, pH 7.4, 45 mM MgCl.sub.2, 1 mM
EGTA, 100 mM KCl, 2 mg/ml BSA, 1 mM AMP and 2 mM ATP. Reactions
were started by addition of 4.4 ng enzyme and terminated after 5
minutes by addition of 17 .mu.l perchloric acid. Precipitated
protein was removed by centrifugation and the supernatant
neutralized by addition of 33 .mu.l 3 M KOH/3 M KHCO.sub.3. The
neutralized solution was clarified by centrifugation and filtration
and analyzed for ADP content (enzyme activity) by HPLC using a YMC
ODS AQ column (25.times.4.6 cm). A gradient was run from 0.1 M
K.sub.2PO.sub.4, pH 6, 8 mM tetrabutyl ammonium hydrogen sulfate to
75% acetonitrile. Absorbance was monitored at 254 nM.
[1408] The table below gives the selectivity data for compounds
10.1 and 3.1. TABLE-US-00066 10.1 3.1 (.mu.M) (.mu.M) FBPase (inh.)
0.1 0.025 Adenosine Kinase (inh.) >>10 >>10 AMP
Deaminase (inh.) >>10 >>10 Adenylate Kinase (inh.)
>500 >500 Glycogen Phosphorylase (act.) >100 >100
Phosphofructokinase (act.) >500 >500
Example D
Inhibition of Gluconeogenesis in Rat Hepatocytes
[1409] Hepatocytes were prepared from overnight fasted
Sprague-Dawley rats (250-300 g) according to the procedure of Berry
and Friend (Berry, M. N., Friend, D. S., 1969, J. Cell. Biol. 43,
506-520) as modified by Groen (Groen, A. K., Sips, H. J., Vervoom,
R. C., Tager, J. M., 1982, Eur. J. Biochem. 122, 87-93).
Hepatocytes (75 mg wet weight/ml) were incubated in 1 ml
Krebs-bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1
mg/ml BSA, and test compound concentrations from 1 to 500 .mu.M.
Incubations were carried out in a 95% oxygen, 5% carbon dioxide
atmosphere in closed, 50-ml Falcon tubes submerged in a rapidly
shaking water bath (37.degree. C.). After 1 hour, an aliquot (0.25
ml) was removed, transferred to an Eppendorf tube and centrifuged.
50 .mu.l of supernatant was then assayed for glucose content using
a Sigma Glucose Oxidase kit as per the manufacturer's
instructions.
[1410] IC.sub.50's for select compounds in this assay are shown in
the table below. TABLE-US-00067 Compound IC.sub.50 Glucose
Production, .mu.M 3.1 2.5 3.2 26 3.26 10 3.58 1.2 10.1 15 10.2 16
16.1 10 19.18 10 19.48 6.5 20.9 2.2 31.6 2.3 31.8 3
Example E
Glucose Production Inhibition and Fructose 1,6-Bisphosphate
Accumulation in Rat Hepatocytes
[1411] Isolated rat hepatocytes are prepared as described in
Example D and incubated under the identical conditions described.
Reactions are terminated by removing an aliquot (250 .mu.l) of cell
suspension and spinning it through a layer of oil (0.8 ml
silicone/mineral oil, 4/1) into a 10% perchloric acid layer (100
.mu.l). After removal of the oil layer, the acidic cell extract
layer is neutralized by addition of 1/3rd volume of 3 M KOH/3 M
KHCO.sub.3. After thorough mixing and centrifugation, the
supernatant is analyzed for glucose content as described in Example
D, and also for fructose 1,6-bisphosphate. Fructose
1,6-bisphosphate is assayed spectrophotometrically by coupling its
enzymatic conversion to glycerol 3-phosphate to the oxidation of
NADH, which is monitored at 340 nm. Reaction mixtures (1 ml)
consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/ml
glycerol 3-phosphate dehydrogenase, 2 units/ml triosephosphate
isomerase, and 50-100 .mu.l cell extract. After a 30 minute
preincubation at 37.degree. C., 1 unit/ml of aldolase is added and
the change in absorbance measured until a stable value is obtained.
2 moles of NADH are oxidized in this reaction per mole of fructose
1,6-bisphosphate present in the cell extract.
[1412] A dose-dependent inhibition of glucose production
accompanied by a dose-dependent accumulation of fructose 1,6
bisphosphate (the substrate of FBPase) is an indication that the
target enzyme in the gluconeogenic pathway, FBPase, is
inhibited.
Example F
Blood Glucose Lowering Following Intravenous Administration to
Fasted Rats
[1413] Sprague Dawley rats (250-300 g) were fasted for 18 hours and
then dosed intravenously either with saline or 10 mg/kg of an
FBPase inhibitor. Inhibitors were dissolved in water and the
solution adjusted to neutrality with NaOH. Blood samples were
obtained from the tail vein of conscious animals just prior to
injection and after 1 hour. Blood glucose was measured using a
HemoCue Inc. glucose analyzer according to the instructions of the
manufacturer.
[1414] The table below shows the % glucose lowering elicited by the
compounds relative to saline-treated control animals.
TABLE-US-00068 Compound # i.v. Glucose Lowering, % 3.1 65 3.2 55
(30 mg/kg) 3.25 76 3.26 73 3.58 82 3.71 72 6.3 24 10.1 51 10.43 61
15.20 24 18.2 80 18.3 75 35.3 65 41.1 80
[1415] Several compounds were also tested at doses <10 mg/kg.
Compound 3.26, for instance, was tested at 3 mg/kg and found to
lower blood glucose by 52%.
Example G
Analysis of Drug Levels and Liver Accumulation in Rats
[1416] Sprague-Dawley rats (250-300 g) were fasted for 18 hours and
then dosed intravenously either with saline (n=3) or 10 mgs/kg of
either 10.1 or 3.1 (n=3/group). The compound was dissolved in water
and the solution adjusted to neutrality with NaOH. One hour post
injection 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 were 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
KHCO.sub.3. Following centrifugation and filtration, 50 .mu.l of
the neutralized extract was analyzed for 10.1 content by HPLC. A
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 310-325 nm. Plasma was prepared from
the blood sample 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. Results are shown in the table below.
TABLE-US-00069 Compound # Plasma Conc. .mu.M Liver Conc., nmoles/g
10.1 18 .+-. 2.8 35.6 .+-. 4.2 10.2 22 .+-. 1.5 5.1 100 .+-. 5.7
6.7 .+-. 0.7 3.21 25 .+-. 1 15.20 66.3 .+-. 3.9 13.1 .+-. 2.3 3.26
56 .+-. 2
Example H
Glucose Lowering Following Oral Administration to the Fasted
Rat
[1417] Compounds were administered by oral gavage to 18-hour
fasted, Sprague Dawley rats (250-300 g, n=3/4/group). Phosphonic
acids were prepared in deionized water, and the solution adjusted
to neutrality with solidum hydroxide. Prodrugs were dissolved in
polyethylene glycol (mw 400). Blood glucose was measured
immediately prior to dosing and at 1 hour intervals thereafter by
means of a HemoCue glucose analyzer (HemoCue Inc., Mission Viejo,
Calif.). The table below indicates the maximum glucose lowering
achieved relative to control animals dosed with saline.
TABLE-US-00070 Compound # % Glucose Lowering Dose, mg/kg Time
point, h 3.26 70 30 2 3.27 61 60 3 10.1 55 90 3 10.2 36 90 3 19.42
26 30 3 19.48 63 30 2 19.46 53 30 2 20.9 67 90 3 31.6 60 10 3
Example I
Estimation of the Oral Bioavailability of Phosphonic Acids and
their Prodrugs
[1418] Phosphonic acids were dissolved in water, and the solution
adjusted to neutrality with sodium hydroxide. Prodrugs were
dissolved in 10% ethanol/90% polyethlene glycol (mw 400). Compound
was administered by oral gavage to 18-hour fasted Sprague-Dawley
rats (220-250 g) at doses ranging from 10-50 mg/kg. The rats were
subsequently placed in metabolic cages and urine was collected for
24 hours. The quantity of phosphonic acid excreted into urine was
determined by HPLC analysis as described in Example G. In a
separate study, urinary recovery was determined following
intravenous (tail vein) administration of compound (in the case of
the prodrugs, the appropriate parent phosphonic acid was
administered i.v.). The percentage oral bioavailability was
estimated by comparison of the recovery of compound in urine 24
hours following oral administration, to that recovered in urine 24
hours after intravenous administration. The oral bioavailabilities
of select phosphonic acids, and prodrugs of phosphonic acids are
shown in the table below. TABLE-US-00071 Compound # % Oral
bioavailability 3.1 4 3.26 18 3.27 32 10.1 21 10.2 22 19.42 10 19.9
18.5 19.17 16.2 19.48 12 20.1 46 20.3 17.5 20.4 11 20.9 17.4 31.6
19 31.8 14
Example J
Blood Glucose Lowering in Zucker Diabetic Fatty Rats, Oral
[1419] Zucker Diabetic Fatty rats were purchased from Genetics
Models Inc. (Indiannapolis, Ind.) at 8 weeks of age and fed the
recommended Purina 5008 diet. At the age of 12 weeks, 16 animals
with fed blood glucose levels between 500 and 700 mg/dl were
selected and divided into two groups (n=8) with statistically
equivalent average blood glucose levels. Compound 3.26 was
administered at a dose of 100 mg/kg by oral gavage to one group of
animals at 1 pm. The drug solution for this treatment was prepared
at 25 mg/ml in deionized water and adjusted to neutrality by
dropwise addition of 5 N NaOH. A second group of rats (n=8) was
dosed orally with saline, in parallel. Blood glucose was measured
in each rat just prior to drug or saline administration and 6 hours
post administration. A HemoCue blood glucose analyzer (HemoCue
Inc., Mission Viejo, Calif.) was used for these measurements
according to the manufacturer's instructions. As shown in the table
below, compound 3.26 treatment resulted in a 15.4% lowering of
blood glucose relative to saline treated controls (p=0.01).
TABLE-US-00072 Blood Glucose, mg/dl Treatment Group 1 pm 7 pm
Saline 575 .+-. 28 587 .+-. 26 3.26 573 .+-. 26 497 .+-. 14
The data indicate that Compound 3.26 is an effective oral glucose
lowering agent in the Zucker Diabetic Fatty rat model of type II
diabetes.
Example K
Blood Glucose Lowering in Zucker Diabetic Fatty Rats,
Intravenous
[1420] 12-week old Zucker Diabetic Fatty rats (Genetics Models
Inc., Indiannapolis, Ind.) maintained on Purina 5008 diet were
instrumented with tail artery and tail vein catethers at 8 am on
the day of the study. Food was removed for the remainder of the
day. Starting at 12 pm, animals were infused for 6 hours via the
tail vein catheter either with saline or compound 3.26 at 1, 3 or
30 mg/kg/h. Blood samples were obtained from the tail artery
catheter at the start of the infusions, and at hourly intervals
thereafter. Glucose was measured in the samples by means of a
HemoCue analyzer (HemoCue Inc., Mission Viejo, Calif.) according to
the manufacturer's instructions.
[1421] At the six hour time point, infusion of 3.26 at 3 and 30
mg/kg/h resulted in significant decreases in blood glucose of 29%
and 39% respectively, relative to saline-infused controls. The
study shows that 3.26 is an effective glucose lowering agent when
administered intravenously to the Zucker Diabetic Fatty rat, a key
rodent model of type II diabetes.
Example L
Inhibition of Gluconeogenesis by FBPase Inhibitor in Zucker
Diabetic Fatty Rats
[1422] Following a 6-hour infusion of 3.26 at 3 mg/kg/h or saline
to Zucker Diabetic Fatty rats (n=3/group) as described in Example
K, a bolus of .sup.14C-bicarbonate (40 .mu.Ci/100 g body weight)
was administered via the tail vein catheter. 20 minutes later, a
blood sample (0.6 mL) was taken via the tail artery. Blood (0.5 ml)
was diluted into 6 mL deionized water and protein precipitated by
addition of 1 mL zinc sulfate (0.3 N) and 1 mL barium hydroxide
(0.3 N). The mixture was centrifuged (20 minutes, 1000.times.g) and
5 mL of the resulting supernatant was then combined with 1 g of a
mixed bed ion exchange resin (I part AG 50W-X8, 100-200 mesh,
hydrogen form, and 2 parts AG 1-X8, 100-200 mesh, acetate form) to
separate .sup.14-C-bicarbonate from .sup.14C-glucose. The slurry
was shaken at room temperature for four hours and then allowed to
settle. An aliquot of the supernatant (0.5 mL) was then counted in
5 mL scintillation cocktail. The percentage inhibition of
gluconeogenesis in drug-treated rats was calculated by dividing the
average cpm of .sup.14C-glucose in samples from drug-treated
animals by those from saline-injected animals.
[1423] .sup.14C-Glucose production was found to be inhibited by 75%
in the 3.26-infused rats. This result provides evidence that the
glucose lowering activity of 3.26 in the Zucker Diabetic Fatty rat
(Example K) is due to the inhibition of gluconeogenesis.
Example M
Blood Glucose Lowering in the Streptozotocin-Treated Rat
[1424] Diabetes is induced in male Sprague-Dawley rats (250-300 g)
by intraperitoneal injection of 55 mg/kg streptozotocin (Sigma
Chemical Co.). Six days later, blood glucose is measured as
described in Example F. Animals are selected with fed blood glucose
values (8 am) between 350 and 600 mg/dl, and divided into two
groups. One group is dosed orally with compound (10-100 mg/kg) and
the second with an equivalent volume of saline. Food is removed
from the animals. Blood glucose is measured again after 2 and 4
hours of drug/saline administration.
Example N
Oral Absorption Determinations of Prodrugs in the Rat
[1425] Prodrugs 19.42, 19.48, 31.6, and 31.8 were administered to
normal, fed rats at 30 mg/kg both by intraperitoneal injection and
by oral gavage (n=3 rats/compound/route of administration). Rats
were subsequently placed in metabolic cages and urine collected for
24 hours. Parent compound, 3.1, was quantitated in urine by reverse
phase HPLC as described in Example G. By comparison of the amount
of parent compound excreted in urine following oral administration
to that following intraperitoneal administration, the % oral
absorption was calculated for each prodrug. Results are shown
below: TABLE-US-00073 % % % Compound excreted p.o. excreted i.p.
absorption 19.42 8.1 15.4 52 19.48 11.6 11.3 100 31.6 16.5 38.9 43
31.8 12.3 28.4 43
All four prodrugs tested were readily absorbed (43-100%) following
oral administration
Example O
Treatment with an FBPase Inhibitor Results in the Normalization of
Hepatic Glycogen Levels in the db/db Mouse
[1426] Db/db mice and their nondiabetic db/+ littermates were
obtained at 8 weeks of age (Jackson Labs., Bar Harbor, Me.) and
enrolled in the study at 11 weeks of age. Db/db mice were treated
orally either with saline or compound 3.26 (100 mg/kg) at 8 am and
at 2 pm on the day of the study. Db/- mice were treated with saline
according to the same schedule. At 6 pm, mice were anesthetized
with halothane and a small section of liver (0.5 g) was removed by
the freeze-clamping technique. The liver samples were fully frozen
by subsequent immersion in liquid nitrogen and then homogenized in
5 volumes of cold 0.6 N perchloric acid. Glycogen content was
determined enzymatically in the homogenates by the method of
Keppler and Decker (Keppler D and Decker K in Methods of Enzymatic
Analysis, Bergmeyer, HET, Ed., Verlag Chemie International,
Deerfield Beach, Fla., 1974). Results relative to pretreatment (8
am) values determined in separate groups of mice, are shown in the
table below: TABLE-US-00074 Liver Glycogen, .mu.mol glucose/g
Treatment Group Morning, 8 am Evening, 6 pm db/db, control 102.9
.+-. 1.9 (n = 3) 83.2 .+-. 22.5 (n = 7) db/db, 3.26 -- 34.4 .+-.
7.1 (n = 3) db/+, control 120.2 .+-. 6.7 (n = 3) 15.7 .+-. 7.2 (n =
3)
The data indicate that liver glycogen stores were not significantly
reduced during the day in control (saline-treated) diabetic db/db
mice, whereas there was significant glycogen mobilization in
control, nondiabetic db/+ mice. Acute treatment of db/db mice with
3.26 resulted in the reduction of glycogen stores to levels that
approached those of nondiabetic db/+ mice.
* * * * *