U.S. patent application number 11/825377 was filed with the patent office on 2008-01-10 for modulators of toll-like receptor 7.
Invention is credited to Lee S. Chong, Manoj C. Desai, Brian Gallagher, Michael Graupe, Randall L. Halcomb, Hong Yang, Jennifer R. Zhang.
Application Number | 20080008682 11/825377 |
Document ID | / |
Family ID | 38599366 |
Filed Date | 2008-01-10 |
United States Patent
Application |
20080008682 |
Kind Code |
A1 |
Chong; Lee S. ; et
al. |
January 10, 2008 |
Modulators of toll-like receptor 7
Abstract
The present application provides for a compound of Formula I or
II: ##STR1## or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, compositions containing such compounds, therapeutic
methods that include the administration of such compounds, and
therapeutic methods that include the administration of such
compounds with at least one additional active agent.
Inventors: |
Chong; Lee S.; (Newark,
CA) ; Desai; Manoj C.; (Pleasant Hill, CA) ;
Gallagher; Brian; (Goleta, CA) ; Graupe; Michael;
(Pacifica, CA) ; Halcomb; Randall L.; (Foster
City, CA) ; Yang; Hong; (Fremont, CA) ; Zhang;
Jennifer R.; (Foster City, CA) |
Correspondence
Address: |
GILEAD SCIENCES INC
333 LAKESIDE DR
FOSTER CITY
CA
94404
US
|
Family ID: |
38599366 |
Appl. No.: |
11/825377 |
Filed: |
July 6, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60832851 |
Jul 24, 2006 |
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60819490 |
Jul 7, 2006 |
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Current U.S.
Class: |
424/85.6 ;
424/133.1; 424/85.4; 424/85.7; 435/375; 514/223.5; 514/371;
514/383; 514/394; 514/567; 514/81; 544/118; 544/244 |
Current CPC
Class: |
A61P 31/12 20180101;
A61P 31/00 20180101; C07F 9/65616 20130101; A61P 31/14 20180101;
A61P 43/00 20180101; A61P 31/20 20180101 |
Class at
Publication: |
424/085.6 ;
424/133.1; 424/085.4; 424/085.7; 435/375; 514/223.5; 514/371;
514/383; 514/394; 514/567; 514/081; 544/118; 544/244 |
International
Class: |
A61K 38/21 20060101
A61K038/21; A61K 31/192 20060101 A61K031/192; A61K 31/4184 20060101
A61K031/4184; A61K 31/4196 20060101 A61K031/4196; A61K 39/395
20060101 A61K039/395; C07D 239/70 20060101 C07D239/70; C12N 5/00
20060101 C12N005/00; C07D 295/00 20060101 C07D295/00; A61P 31/12
20060101 A61P031/12; A61K 31/426 20060101 A61K031/426; A61K 31/5415
20060101 A61K031/5415; A61K 31/675 20060101 A61K031/675 |
Claims
1. A compound of Formula I or II: ##STR399## wherein: Z is
--NH.sub.2 or --OH; X.sup.1 is alkylene, substituted alkylene,
alkenylene, substituted alkenylene, alkynylene, substituted
alkynylene, carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; L.sup.1 is a
covalent bond, arylene, substituted arylene, heterocyclylene,
substituted heterocyclylene, carbocyclylene, substituted
carbocyclylene, --S--, --S(O)--, S(O).sub.2, --NR.sup.5--, or
--O--; X.sup.2 is a covalent bond, alkylene, or substituted
alkylene; L.sup.2 is --NR.sup.5--, --N(R.sup.5)C(O)--, --O--,
--S--, --S(O)--, S(O).sub.2, or a covalent bond; R.sup.3 is H,
alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl,
alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl,
substituted arylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; Y.sup.1 and
Y.sup.2 are each independently a covalent bond, --O-- or
--NR.sup.5--; or --Y.sup.1--R.sup.1 and --Y.sup.2--R.sup.2 are each
independently --O--N.dbd.C(R.sup.6R.sup.7); R.sup.1 and R.sup.2 are
each independently H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, substituted heterocyclyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5; R.sup.4 is H, halogen, --OH,
--O-alkyl, --O-alkylene-O--C(O)--O--R.sup.5, --O--C(O)--O--R.sup.5,
--SH, or --NH(R.sup.5); each R.sup.5, R.sup.6, and R.sup.7 are
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, substituted heterocyclyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; and with the following provisos: (a) when
R.sup.4 is --OH, and X.sup.1 is C.sub.1-C.sub.2 alkylene, and
L.sup.1 is phenylene or heterocyclylene, and X.sup.2 is a covalent
bond or a C.sub.1-C.sub.2 alkylene, and L.sup.2 is a covalent bond,
--NH--, --O--, or --S--, and R.sup.3 is alkyl or substituted alkyl,
and Y.sup.1 and Y.sup.2 are both --O--; then: neither R.sup.1 nor
R.sup.2 are alkyl, substituted alkyl or cycloalkyl; (b) when
-L.sup.2-R.sup.3 is alkyl, amino, aminoalkyl, amidoalkyl, or
thioalkyl, and R.sup.4 is H, and X.sup.1 is alkylene or substituted
alkylene, and L.sup.1 is --O--, and X.sup.2 is --CH.sub.2--, and
Y.sup.1 and Y.sup.2 are both --O--; then: R.sup.1 and R.sup.2 are
not both H or both alkyl; (c) when L.sup.2 is a covalent bond; then
R.sup.3 is not H; (d) when Y.sup.1 is a covalent bond; then R.sup.1
is not H; (e) when Y.sup.2 is a covalent bond, then R.sup.2 is not
H; and (f) R.sup.6 and R.sup.7 are not both H.
2. The compound of claim 1, wherein: L.sup.2 is --NR.sup.5 or
--O--; and R.sup.3 is heteroalkyl or substituted heteroalkyl.
3. The compound of claim 1, wherein: X.sup.1 is alkylene or
substituted alkylene; L.sup.1 is arylene, substituted arylene,
heterocyclylene, substituted heterocyclylene, carbocyclylene, or
substituted carbocyclylene; and X.sup.2 is alkylene or substituted
alkylene.
4. The compound of claim 1, wherein: X.sup.1 is alkylene or
substituted alkylene; L.sup.1 is --S--, --NR.sup.5--, or --O--; and
X.sup.2 is alkylene or substituted alkylene.
5. The compound of claim 1, wherein: Y.sup.1 is --O-- or
--NR.sup.5--; Y.sup.2 is a covalent bond; R.sup.1 is H, alkyl, or
substituted alkyl; and R.sup.2 is alkyl or substituted alkyl.
6. The compound of claim 1, wherein: Y.sup.1 and Y.sup.2 are each
independently --O-- or --NR.sup.5--; and R.sup.1 and R.sup.2 are
each independently H, alkyl, or substituted alkyl.
7. The compound of claim 1, wherein: Y.sup.1 and Y.sup.2 are each
independently --O-- or --NR.sup.5--; and R.sup.1 and R.sup.2 are
each independently -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.1.
8. The compound of claim 1, wherein: Y.sup.1 is --O-- or
--NR.sup.5--; Y.sup.2 is a covalent bond; and R.sup.2 is
carbocyclyl, substituted carbocyclyl heterocyclyl, or substituted
heterocyclyl.
9. The compound of claim 1, wherein Formula I is represented by
Formula Ia: ##STR400## wherein: X.sup.1 is alkylene, substituted
alkylene, alkenylene, substituted alkenylene, alkynylene,
substituted alkynylene, carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; X.sup.2 is a
covalent bond, alkylene, or substituted alkylene; Y.sup.1 and
Y.sup.2 are each independently a covalent bond, --O-- or
--NR.sup.5--; or --Y.sup.1--R.sup.1 and --Y.sup.2--R.sup.2 are each
independently --O--N.dbd.C(R.sup.6R.sup.7); L.sup.1 is a covalent
bond, arylene, substituted arylene, heterocyclylene, substituted
heterocyclylene, carbocyclylene, substituted carbocyclylene, --S--,
--S(O)--, S(O).sub.2, --NR.sup.5--, or --O--; L.sup.2 is
--NR.sup.5--, --N(R.sup.5)C(O)--, --O--, --S--, --S(O)--,
S(O).sub.2, or a covalent bond; R.sup.1 and R.sup.2 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, substituted heterocyclyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5; R.sup.3 is H, alkyl, substituted
alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted
alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or
substituted heterocyclylalkyl; R.sup.4 is H, halogen, --OH,
--O-alkyl, --O-alkylene-O--C(O)--O--R.sup.5, --O--C(O)--O--R.sup.5,
--SH, or --NH(R.sup.5); R.sup.5 is H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted
heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or
substituted heterocyclylalkyl; and with the following provisos: (a)
when R.sup.4 is --OH, and X.sup.1 is C.sub.1-C.sub.2 alkylene, and
L.sup.1 is phenylene or heterocyclylene, and X.sup.2 is a covalent
bond or a C.sub.1-C.sub.2 alkylene, and L.sup.2 is a covalent bond,
--NH--, --O--, or --S--, and R.sup.3 is alkyl or substituted alkyl,
and Y.sup.1 and Y.sup.2 are both --O--; then: neither R.sup.1 nor
R.sup.2 are alkyl, substituted alkyl or cycloalkyl; (b) when
-L.sup.2-R.sup.3 is alkyl amino, aminoalkyl, amidoalkyl, or
thioalkyl, and R.sup.4 is H, and X.sup.1 is alkylene or substituted
alkylene, and L.sup.1 is --O--, and X.sup.2 is --CH.sub.2--, and
Y.sup.1 and Y.sup.2 are both --O--; then: R.sup.1 and R.sup.2 are
not both H or both alkyl; (c) when L.sup.2 is a covalent bond; then
R.sup.3 is not H; (d) when Y.sup.1 is a covalent bond; then R.sup.1
is not H; (e) when Y.sup.2 is a covalent bond, then R.sup.2 is not
H; and (f) R.sup.6 and R.sup.7 are not both H.
10. The compound of claim 9, wherein: --Y.sup.1--R.sup.1 is
--OH.
11. The compound of claim 9, wherein: --Y.sup.1--R.sup.1 and
--Y.sup.2--R.sup.2 are both --OH.
12. The compound of claim 9, wherein: L.sup.2 is --,
--N(R.sup.5)--, or --S--.
13. The compound of claim 9, wherein: R.sup.3 is alkyl, arylalkyl,
or heteroalkyl.
14. The compound of claim 13, wherein: R.sup.3 is
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
15. The compound of claim 9, wherein: R.sup.3 is
-alkylene-O-alkyl.
16. The compound of claim 15, wherein: R.sup.3 is
--CH.sub.2CH.sub.2--O--CH.sub.3.
17. The compound of claim 9, wherein: R.sup.3 is benzyl.
18. The compound of claim 9, wherein: X.sup.1 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH(CH.sub.2)--.
19. The compound of claim 9, wherein: --X.sup.1-L.sup.1- is
--CH.sub.2-phenylene-.
20. The compound of claim 9, wherein: --X.sup.1-L.sup.1- is
--CH.sub.2CH.sub.2--O-- or --CH.sub.2CH(CH.sub.3)--O--.
21. The compound of claim 9, wherein: X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-CH.sub.2--.
22. The compound of claim 9, wherein: X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-.
23. The compound of claim 9, wherein: X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
24. The compound of claim 9, wherein: Y.sup.1 and Y.sup.2 are each
independently --O-- or --NR.sup.5--.
25. The compound of claim 9, wherein: Y.sup.1 and Y.sup.2 are both
--O--.
26. The compound of claim 9, wherein: Y.sup.1 and Y.sup.2 are each
independently --O-- or a covalent bond.
27. The compound of claim 9, wherein: R.sup.1 and R.sup.2 are each
independently H, alkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, -(substituted
alkylene)-O--C(O)--O--R.sup.5, aryl, or substituted aryl.
28. The compound of claim 9, wherein: R.sup.1 and R.sup.2 are each
independently H, alkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, -(substituted
alkylene)-O--C(O)--O--R.sup.5, aryl, or substituted aryl.
29. The compound of claim 9, wherein: Y.sup.1 is --NR.sup.5--;
Y.sup.2 is --O--; R.sup.1 is alkyl, -alkylene-C(O)--O--R.sup.5,
-(substituted alkylene)-C(O)--O--R.sup.5,
-alkylene-O--C(O)--R.sup.5, -(substituted
alkylene)-O--C(O)--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; and R.sup.2 is aryl or
substituted aryl.
30. The compound of claim 9, wherein: Y.sup.1 is --O-- or
--NR.sup.5--; Y.sup.2 is a covalent bond; and R.sup.2 is
carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted
heterocyclyl.
31. The compound of claim 9, wherein: R.sup.2 is aryl, substituted
aryl, substituted or unsubstituted 5- to 7-membered non-aromatic
heterocyclyl containing one to 4 hetero atoms selected from a group
consisting of N, O, S, and a combination thereof.
32. The compound of claim 9, wherein: R.sup.4 is --OH,
--O--C(O)--O--CH.sub.2CH.sub.3,
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2,
--NH--CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--NH.sub.2--CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.2).sub.2O, or
--SH.
33. The compound of claim 9, wherein: X.sup.1 is alkylene; Y.sup.1
is --O-- or --NR.sup.5--; Y.sup.2 is --O-- or a covalent bond;
L.sup.1 is a covalent bond or arylene; L.sup.2 is --; R.sup.1 is H,
alkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.1; R.sup.2 is H, alkyl or aryl; R.sup.3
is heteroalkyl; and R.sup.4 is --OH.
34. The compound of claim 9, wherein: X.sup.1 and X.sup.2 are
alkylene; Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is --O-- or
--NR.sup.5--; L.sup.1 is arylene; L.sup.2 is --O--; R.sup.1 is H,
alkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5; R.sup.2 is H, alkyl, or aryl;
R.sup.3 is alkyl or heteroalkyl; and R.sup.4 is --NH(R.sup.5).
35. The compound of claim 9, wherein: X.sup.1 and X.sup.2 are
alkylene or substituted alkylene; Y.sup.1 is --O-- or --NR.sup.5--;
Y.sup.2 is a covalent bond; and L.sup.1 is arylene or --O--;
L.sup.2 is --O--; R.sup.1 is H, alkyl, or substituted alkyl; and
R.sup.2 is carbocyclyl, substituted carbocyclyl, heterocyclyl or
substituted heterocyclyl.
36. The compound of claim 9, wherein: X.sup.1 and X.sup.2 are
alkylene or substituted alkylene; Y.sup.1 and Y.sup.2 are each
independently --O-- or --NR.sup.5--; L.sup.1 is arylene or --O--;
L.sup.2 is --O--; R.sup.1 is -alkylene-C(O)--O--R.sup.5,
-(substituted alkylene)-C(O)--O--R.sup.5,
-alkylene-O--C(O)--R.sup.5, -(substituted
alkylene)-O--C(O)--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; and R.sup.2 is
carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted
heterocyclyl.
37. The compound of claim 9, wherein: X.sup.1 and X.sup.2 are
alkylene or substituted alkylene; Y.sup.1--R.sup.1 is
--O--N.dbd.C(R.sup.6R.sup.7); Y.sup.2 is --O-- or --NR.sup.5--;
L.sup.1 is arylene or --O--; L.sup.2 is --O--; and R.sup.2 is
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5.
38. The compound of claim 9, wherein
--X.sup.1-L.sup.1-X.sup.2--P(O)(Y.sup.1R.sup.1)(Y.sup.2R.sup.2) is:
##STR401## wherein Z.sup.2 is selected from the group consisting of
halo, alkyl haloalkyl, and alkoxy.
39. The compound of claim 9 selected from the group consisting of:
##STR402## ##STR403## ##STR404## ##STR405## ##STR406## ##STR407##
##STR408## ##STR409## ##STR410## ##STR411## ##STR412## or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
40. The compound of claim 1, wherein Formula II is represented by
Formula IIa: ##STR413## or a pharmaceutically acceptable tautomer,
salt, solvate, and/or ester thereof, wherein: X.sup.1 is alkylene,
substituted alkylene, alkenylene, substituted alkenylene,
alkynylene, substituted alkynylene, carbocyclylene, substituted
carbocyclylene, heterocyclylene, or substituted heterocyclylene;
X.sup.2 is a covalent bond, alkylene, or substituted alkylene;
L.sup.1 is a covalent bond, arylene, substituted arylene,
heterocyclylene, substituted heterocyclylene, carbocyclylene,
substituted carbocyclylene, --S--, --S(O)--, S(O).sub.2,
--NR.sup.3--, or --O--; Y.sup.1 and Y.sup.2 are each independently
a covalent bond, --O--, or --NR.sup.4--; R.sup.1 and R.sup.2 are
each independently H, alkyl, substituted alkyl, carbocyclyl,
substituted carbocyclyl, heterocyclyl, substituted heterocyclyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; and R.sup.3, R.sup.4,
and R.sup.5 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted
heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or
substituted heterocyclylalkyl; with the following provisos: (a)
Y.sup.1 and Y.sup.2 are not both covalent bonds; (b) when Y.sup.1
is a covalent bond, then R.sup.1 is not H; and (c) when Y.sup.2 is
a covalent bond, then R.sup.2 is not H.
41. The compound of claim 40, wherein: X.sup.1 is --CH.sub.2-- or
--CH.sub.2CH.sub.2--.
42. The compound of claim 40, wherein: X.sup.1 is ##STR414##
wherein Z is O, NR.sup.7, or S; each R.sup.6 is independently halo,
hydroxyl, amino, cyano, alkyl, substituted alkyl, alkoxy, N-alkyl
amino, N,N-dialkyl amino, carbocyclyl, substituted carbocyclyl,
heterocyclyl, substituted heterocyclyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
R.sup.7 is H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, substituted heterocyclyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; n is 1, 2, 3, 4, or 5; and when n is 1, then m
is 0, 1, or 2; when n is 2, then m is 0, 1, 2, or 3; when n is 3,
then m is 0, 1, 2, 3, or 4; when n is 4, then m is 0, 1, 2, 3, 4,
or 5; and when n is 5, then m is 0, 1, 2, 3, 4, 5, or 6.
43. The compound of claim 40, wherein: L.sup.1 is a covalent
bond.
44. The compound of claim 40, wherein: L.sup.1 is --NR.sup.3-- or
--O--.
45. The compound of claim 40, wherein: Y.sup.1 and Y.sup.2 are both
--O--.
46. The compound of claim 40, wherein: R.sup.1 and R.sup.2 are each
independently H, alkyl, or substituted alkyl.
47. The compound of claim 40, wherein: X.sup.1 is alkylene or
substituted alkylene; L.sup.1 is a covalent bond; and X.sup.2 is a
covalent bond, alkylene, or substituted alkylene.
48. The compound of claim 40, wherein: --X.sup.1-L.sup.1-X.sup.2--
is --CH.sub.2CH.sub.2--.
49. The compound of claim 40, wherein: X.sup.1 is alkylene or
substituted alkylene; L.sup.1 is --NR.sup.3-- or --O--; and X.sup.2
is a covalent bond, alkylene, or substituted alkylene.
50. The compound of claim 49, wherein: --X.sup.1-L.sup.1-X.sup.2--
is --CH.sub.2CH.sub.2--CH.sub.2--.
51. The compound of claim 40, wherein: X.sup.1 is carbocyclylene,
substituted carbocyclylene, heterocyclylene, or substituted
heterocyclylene; L.sup.1 is a covalent bond; and X.sup.2 is a
covalent bond, alkylene, or substituted alkylene.
52. The compound of claim 51, wherein: --X.sup.1-L.sup.1-X.sup.2--
is ##STR415##
53. The compound of claim 42 selected from the group consisting of:
##STR416## or a pharmaceutically acceptable tautomer, salt,
solvate, and/or ester thereof.
54. A pharmaceutical composition comprising: at least one compound
of claim 1, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof; and a pharmaceutically acceptable carrier or
excipient.
55. A pharmaceutical composition comprising: at least one compound
of claim 9, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof; and a pharmaceutically acceptable carrier or
excipient.
56. A pharmaceutical composition comprising: at least one compound
of claim 40, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof; and a pharmaceutically acceptable carrier or
excipient.
57. The pharmaceutical composition of claim 54, further comprising:
at least one additional active agent.
58. The pharmaceutical composition of claim 55, further comprising:
at least one additional active agent.
59. The pharmaceutical composition of claim 56, further comprising:
at least one additional active agent.
60. The pharmaceutical composition of claim 57, wherein: the
additional active agent is selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
61. The pharmaceutical composition of claim 58, wherein: the
additional active agent is selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
62. The pharmaceutical composition of claim 59, wherein: the
additional active agent is selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
63. The pharmaceutical composition of claim 60, wherein: (1) said
interferons are selected from the group consisting of pegylated
rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha
2a, consensus IFN alpha (infergen), feron, reaferon, intermax
alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS,
albuferon, locteron, Albuferon, Rebif, Oral interferon alpha,
IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta; (2)
said ribavirin analogs are selected from the group consisting of
rebetol, copegus, and viramidine (taribavirin); (3) said NS5b
polymerase inhibitors are selected from the group consisting of
NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB
1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554,
and GSK625433; (4) said HCV NS3 protease inhibitor are selected
from the group consisting of SCH-503034 (SCH-7), VX-950
(telaprevir), BILN-2065, BMS-605339, and ITMN-191; (5) said
alpha-glucosidase 1 inhibitors are selected from the group
consisting of MX-3253 (celgosivir) and UT-231B; (6) said
hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
64. The pharmaceutical composition of claim 61, wherein: (1) said
interferons are selected from the group consisting of pegylated
rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha
2a, consensus IFN alpha (infergen), feron, reaferon, intermax
alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS,
albuferon, locteron, Albuferon, Rebif, Oral interferon alpha,
IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta; (2)
said ribavirin analogs are selected from the group consisting of
rebetol, copegus, and viramidine (taribavirin); (3) said NS5b
polymerase inhibitors are selected from the group consisting of
NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB
1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554,
and GSK625433; (4) said HCV NS3 protease inhibitor are selected
from the group consisting of SCH-503034 (SCH-7), VX-950
(telaprevir), BILN-2065, BMS-605339, and ITMN-191; (5) said
alpha-glucosidase 1 inhibitors are selected from the group
consisting of MX-3253 (celgosivir) and UT-231B; (6) said
hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
65. The pharmaceutical composition of claim 62, wherein: (1) said
interferons are selected from the group consisting of pegylated
rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha
2a, consensus IFN alpha (infergen), feron, reaferon, intermax
alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS,
albuferon, locteron, Albuferon, Rebif, Oral interferon alpha,
IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta; (2)
said ribavirin analogs are selected from the group consisting of
rebetol, copegus, and viramidine (taribavirin); (3) said NS5b
polymerase inhibitors are selected from the group consisting of
NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB
1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554,
and GSK625433; (4) said HCV NS3 protease inhibitor are selected
from the group consisting of SCH-503034 (SCH-7), VX-950
(telaprevir), BILN-2065, BMS-605339, and ITMN-191; (5) said
alpha-glucosidase 1 inhibitors are selected from the group
consisting of MX-3253 (celgosivir) and UT-231B; (6) said
hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
66. A method for treating or preventing a viral infection
comprising: administering, to a patient in need thereof, a
therapeutically effective amount of at least one compound of claim
1, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof.
67. A method for treating or preventing a viral infection
comprising: administering, to a patient in need thereof, a
therapeutically effective amount of at least one compound of claim
9, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof.
68. A method for treating or preventing a viral infection
comprising: administering, to a patient in need thereof, a
therapeutically effective amount of at least one compound of claim
40, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof.
69. The method of claim 66, wherein said viral infection is an HCV
or HBV viral infection.
70. The method of claim 67, wherein said viral infection is an HCV
or HBV viral infection.
71. The method of claim 68, wherein said viral infection is an HCV
or HBV viral infection.
72. The method of claim 66, further comprising: co-administering at
least one additional active agent selected from the group
consisting of interferons, ribavirin analogs, HCV NS3 protease
inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,
non-nucleoside inhibitors of HCV, and other drugs for treating HCV,
or mixtures thereof.
73. The method of claim 67, further comprising: co-administering at
least one additional active agent selected from the group
consisting of interferons, ribavirin analogs, HCV NS3 protease
inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,
non-nucleoside inhibitors of HCV, and other drugs for treating HCV,
or mixtures thereof.
74. The method of claim 68, further comprising: co-administering at
least one additional active agent selected from the group
consisting of interferons, ribavirin analogs, HCV NS3 protease
inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,
non-nucleoside inhibitors of HCV, and other drugs for treating HCV,
or mixtures thereof.
75. The method of claim 72, wherein: (1) said interferons are
selected from the group consisting of pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; (2) said ribavirin analogs
are selected from the group consisting of rebetol, copegus, and
viramidine (taribavirin); (3) said NS5b polymerase inhibitors are
selected from the group consisting of NM-283, valopicitabine,
R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608,
NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) said
HCV NS3 protease inhibitor are selected from the group consisting
of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339,
and ITMN-191; (5) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (6)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
76. The method of claim 73, wherein: (1) said interferons are
selected from the group consisting of pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; (2) said ribavirin analogs
are selected from the group consisting of rebetol, copegus, and
viramidine (taribavirin); (3) said NS5b polymerase inhibitors are
selected from the group consisting of NM-283, valopicitabine,
R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608,
NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) said
HCV NS3 protease inhibitor are selected from the group consisting
of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339,
and ITMN-191; (5) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (6)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
77. The method of claim 74, wherein: (1) said interferons are
selected from the group consisting of pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; (2) said ribavirin analogs
are selected from the group consisting of rebetol, copegus, and
viramidine (taribavirin); (3) said NS5b polymerase inhibitors are
selected from the group consisting of NM-283, valopicitabine,
R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608,
NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) said
HCV NS3 protease inhibitor are selected from the group consisting
of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339,
and ITMN-191; (5) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (6)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
78. A method of agonizing toll-like receptor 7, comprising:
contacting a cell having a toll-like receptor 7 with an effective
amount of a compound of claim 1, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof.
79. A method of agonizing toll-like receptor 7, comprising:
contacting a cell having a toll-like receptor 7 with an effective
amount of a compound of claim 9, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof.
80. A method of agonizing toll-like receptor 7, comprising:
contacting a cell having a toll-like receptor 7 with an effective
amount of a compound of claim 40, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof.
81. A combination pharmaceutical agent comprising: a) a first
pharmaceutical composition comprising a compound of claim 1, or a
pharmaceutically acceptable salt, solvate, or ester thereof; and b)
a second pharmaceutical composition comprising at least one
additional active agent selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
82. A new compound, substantially as described herein.
83. A compound as described in claim 1, substantially as described
herein and illustrated.
84. A compound as described in claim 9, substantially as described
herein and illustrated.
85. A compound as described in claim 40, substantially as described
herein and illustrated.
86. A new pharmaceutical composition or use for the preparation of
a medicament, substantially as described herein.
87. A compound of claim 1 as a therapeutic substance.
88. A compound of claim 9 as a therapeutic substance.
89. A compound of claim 40 as a therapeutic substance.
90. The use of a compound claim 1 for the manufacture of a
medicament for the treatment of viral infection in a patient.
91. The use of a compound claim 9 for the manufacture of a
medicament for the treatment of viral infection in a patient.
92. The use of a compound claim 40 for the manufacture of a
medicament for the treatment of viral infection in a patient.
93. The use of claim 90, wherein said viral infection is an HCV or
HBV viral infection.
94. The use of claim 91, wherein said viral infection is an HCV or
HBV viral infection.
95. The use of claim 92, wherein said viral infection is an HCV or
HBV viral infection.
96. The use of claim 90, wherein said medicament further comprises
at least one additional active agent.
97. The use of claim 91, wherein said medicament further comprises
at least one additional active agent.
98. The use of claim 92, wherein said medicament further comprises
at least one additional active agent.
99. The use of claim 96, wherein said at least one additional
active agent is selected from the group consisting of: interferons,
ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1
inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV,
and other drugs for treating HCV, or mixtures thereof.
100. The use of claim 97, wherein said at least one additional
active agent is selected from the group consisting of: interferons,
ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1
inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV,
and other drugs for treating HCV, or mixtures thereof.
101. The use of claim 98, wherein said at least one additional
active agent is selected from the group consisting of: interferons,
ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1
inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV,
and other drugs for treating HCV, or mixtures thereof.
102. The use of claim 99, wherein: (1) said interferons are
selected from the group consisting of pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; (2) said ribavirin analogs
are selected from the group consisting of rebetol, copegus, and
viramidine (taribavirin); (3) said NS5b polymerase inhibitors are
selected from the group consisting of NM-283, valopicitabine,
R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608,
NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) said
HCV NS3 protease inhibitor are selected from the group consisting
of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339,
and ITMN-191; (5) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (6)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
103. The use of claim 100, wherein: (1) said interferons are
selected from the group consisting of pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; (2) said ribavirin analogs
are selected from the group consisting of rebetol, copegus, and
viramidine (taribavirin); (3) said NS5b polymerase inhibitors are
selected from the group consisting of NM-283, valopicitabine,
R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608,
NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) said
HCV NS3 protease inhibitor are selected from the group consisting
of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339,
and ITMN-191; (5) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (6)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
104. The use of claim 101, wherein: (1) said interferons are
selected from the group consisting of pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; (2) said ribavirin analogs
are selected from the group consisting of rebetol, copegus, and
viramidine (taribavirin); (3) said NS5b polymerase inhibitors are
selected from the group consisting of NM-283, valopicitabine,
R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608,
NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433; (4) said
HCV NS3 protease inhibitor are selected from the group consisting
of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339,
and ITMN-191; (5) said alpha-glucosidase 1 inhibitors are selected
from the group consisting of MX-3253 (celgosivir) and UT-231B; (6)
said hepatoprotectants are selected from the group consisting of
IDN-6556, ME 3738, LB-84451, and MitoQ; (7) said non-nucleoside
inhibitors of HCV are selected from the group consisting of
benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,
phenylalanine derivatives, GS-9190, A-831, and A-689; and (8) said
other drugs for treating HCV are selected from the group consisting
of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17
(altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir,
GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18,
NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab,
Oglufanide, and VX-497 (merimepodib).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 60/832,851, entitled "Modulators of Toll-like
Receptor 7", filed Jul. 24, 2006 and U.S. Provisional Application
Ser. No. 60/819,490, entitled "TLR-7 Agonist", filed Jul. 7, 2006.
The contents of these provisional applications are herein
incorporated by reference in their entirety for all purposes.
FIELD OF THE INVENTION
[0002] This application relates generally to compounds and
pharmaceutical compositions which selectively activates toll-like
receptor 7 (TLR7), and methods of making and using them.
BACKGROUND OF THE INVENTION
[0003] The innate immune system provides the body with a first line
defense against invading pathogens. In an innate immune response,
an invading pathogen is recognized by a germline-encoded receptor,
the activation of which initiates a signaling cascade that leads to
the induction of cytokine expression. Innate immune system
receptors have broad specificity, recognizing molecular structures
that are highly conserved among different pathogens. One family of
these receptors is known as Toll-like receptors (TLRs), due to
their homology with receptors that were first identified and named
in Drosophila, and are present in cells such as macrophages,
dendritic cells, and epithelial cells.
[0004] There are at least ten different TLRs in mammals. Ligands
and corresponding signaling cascades have been identified for some
of these receptors. For example, TLR2 is activated by the
lipoprotein of bacteria (e.g., E. coli.), TLR3 is activated by
double-stranded RNA, TLR4 is activated by lipopolysaccharide (i.e.,
LPS or endotoxin) of Gram-negative bacteria (e.g., Salmonella and
E. coli O157:H7), TLR5 is activated by flagellin of motile bacteria
(e.g., Listeria), TLR7 recognizes and responds to imiquimod and
TLR9 is activated by unmethylated CpG sequences of pathogen DNA.
The stimulation of each of these receptors leads to activation of
the transcription factor NF-.kappa.B, and other signaling molecules
that are involved in regulating the expression of cytokine genes,
including those encoding tumor necrosis factor-alpha (TNF-.alpha.),
interleukin-1 (IL-1), and certain chemokines.
SUMMARY OF THE INVENTION
[0005] The present invention is based, in part, on the discovery by
the applicants that a number of small molecules can alter
TLR-mediated immunostimulatory signaling. Accordingly, the present
application is directed to compounds and pharmaceutical
compositions, and methods for use in preventing or treating
diseases or conditions characterized by Toll-like receptor 7 (TLR7)
activation in patients. In one embodiment, the invention features a
compound of formula I or II: ##STR2## [0006] wherein: [0007] Z is
--NH.sub.2 or --OH; [0008] X.sup.1 is alkylene, substituted
alkylene, alkenylene, substituted alkenylene, alkynylene,
substituted alkynylene, carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; [0009] L.sup.1 is
a covalent bond, arylene, substituted arylene, heterocyclylene,
substituted heterocyclylene, carbocyclylene, substituted
carbocyclylene, --S--, --S(O)--, S(O).sub.2, --NR.sup.5--, or
--O--; [0010] X.sup.2 is a covalent bond, alkylene, or substituted
alkylene; [0011] L.sup.2 is --NR.sup.5--, --N(R.sup.5)C(O)--,
--O--, --S--, --S(O)--, S(O).sub.2, or a covalent bond; [0012]
R.sup.3 is H, alkyl, substituted alkyl, heteroalkyl, substituted
heteroalkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,
arylalkyl, substituted arylalkyl, heterocyclyl, substituted
heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl;
[0013] Y.sup.1 and Y.sup.2 are each independently a covalent bond,
--O-- or --NR.sup.5--; or --Y.sup.1--R.sup.1 and --Y.sup.2--R.sup.2
are each independently --O--N.dbd.C(R.sup.6R.sup.7); [0014] R.sup.1
and R.sup.2 are each independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted
heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl,
substituted heterocyclylalkyl, -alkylene-C(O)--O--R.sup.5,
-(substituted alkylene)-C(O)--O--R.sup.5,
-alkylene-O--C(O)--R.sup.5, -(substituted
alkylene)-O--C(O)--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; [0015] R.sup.4 is H,
halogen, --OH, --O-alkyl, --O-alkylene-O--C(O)--O--R.sup.5,
--O--C(O)--O--R.sup.5, --SH, or --NH(R.sup.5); [0016] each R.sup.5,
R.sup.6, and R.sup.7 are independently H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted
heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or
substituted heterocyclylalkyl; and [0017] with the following
provisos: [0018] (a) when R.sup.4 is --OH, and [0019] X.sup.1 is
C.sub.1-C.sub.2 alkylene, and [0020] L.sup.1 is phenylene or
heterocyclylene, and [0021] X.sup.2 is a covalent bond or a
C.sub.1-C.sub.2 alkylene, and [0022] L.sup.2 is a covalent bond,
--NH--, --O--, or --S--, and [0023] R.sup.3 is alkyl or substituted
alkyl, and [0024] Y.sup.1 and Y.sup.2 are both --O--; [0025] then:
[0026] neither R.sup.1 nor R.sup.2 are alkyl, substituted alkyl or
cycloalkyl; [0027] (b) when -L.sup.2-R.sup.3 is alkyl, amino,
aminoalkyl, amidoalkyl, or thioalkyl, and [0028] R.sup.4 is H, and
[0029] X.sup.1 is alkylene or substituted alkylene, and [0030]
L.sup.1 is --O--, and [0031] X.sup.2 is --CH.sub.2--, and [0032]
Y.sup.1 and Y.sup.2 are both --O--; [0033] then: [0034] R.sup.1 and
R.sup.2 are not both H or both alkyl; [0035] (c) when L.sup.2 is a
covalent bond; then R.sup.3 is not H; [0036] (d) when Y.sup.1 is a
covalent bond; then R.sup.1 is not H; [0037] (e) when Y.sup.2 is a
covalent bond, then R.sup.2 is not H; and [0038] (f) R.sup.6 and
R.sup.7 are not both H.
[0039] In another embodiment, Formula I can be represented by
Formula Ia: ##STR3## [0040] wherein: [0041] X.sup.1 is alkylene,
substituted alkylene, alkenylene, substituted alkenylene,
alkynylene, substituted alkynylene, carbocyclylene, substituted
carbocyclylene, heterocyclylene, or substituted heterocyclylene;
[0042] X.sup.2 is a covalent bond, alkylene, or substituted
alkylene; [0043] Y.sup.1 and Y.sup.2 are each independently a
covalent bond, --O-- or --NR.sup.5--; or --Y.sup.1--R.sup.1 and
--Y.sup.2--R.sup.2 are each independently
--O--N.dbd.C(R.sup.6R.sup.7); [0044] L.sup.1 is a covalent bond,
arylene, substituted arylene, heterocyclylene, substituted
heterocyclylene, carbocyclylene, substituted carbocyclylene, --S--,
--S(O)--, S(O).sub.2, --NR.sup.5--, or --O--; [0045] L.sup.2 is
--NR.sup.5--, --N(R.sup.5)C(O)--, --O--, --S--, --S(O)--,
S(O).sub.2, or a covalent bond; [0046] R.sup.1 and R.sup.2 are each
independently H, alkyl, substituted alkyl, carbocyclyl, substituted
carbocyclyl, heterocyclyl, substituted heterocyclyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl,
substituted arylalkyl, heterocyclylalkyl, substituted
heterocyclylalkyl, -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5; [0047] R.sup.3 is H, alkyl,
substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl,
substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted
arylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0048] R.sup.4
is H, halogen, --OH, --O-alkyl, --O-alkylene-O--C(O)--O--R.sup.5,
--O--C(O)--O--R.sup.5, --SH, or --NH(R.sup.5); [0049] R.sup.5 is H,
alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl,
heterocyclyl, substituted heterocyclyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl; and
[0050] with the following provisos: [0051] (a) when R.sup.4 is
--OH, and [0052] X.sup.1 is C.sub.1-C.sub.2 alkylene, and [0053]
L.sup.1 is phenylene or heterocyclylene, and [0054] X.sup.2 is a
covalent bond or a C.sub.1-C.sub.2 alkylene, and [0055] L.sup.2 is
a covalent bond, --NH--, --O--, or --S--, and [0056] R.sup.3 is
alkyl or substituted alkyl, and [0057] Y.sup.1 and Y.sup.2 are both
--O--; [0058] then: [0059] neither R.sup.1 nor R.sup.2 are alkyl,
substituted alkyl or cycloalkyl; [0060] (b) when -L.sup.2-R.sup.3
is alkyl, amino, aminoalkyl, amidoalkyl, or thioalkyl, and [0061]
R.sup.4 is H, and [0062] X.sup.1 is alkylene or substituted
alkylene, and [0063] L.sup.1 is --O--, and [0064] X.sup.2 is
--CH.sub.2--, and [0065] Y.sup.1 and Y.sup.2 are both --O--; [0066]
then: [0067] R.sup.1 and R.sup.2 are not both H or both alkyl;
[0068] (c) when L.sup.2 is a covalent bond; then R.sup.3 is not H;
[0069] (d) when Y.sup.1 is a covalent bond; then R.sup.1 is not H;
[0070] (e) when Y.sup.2 is a covalent bond, then R.sup.2 is not H;
and [0071] (f) R.sup.6 and R.sup.7 are not both H.
[0072] In another embodiment, Formula II can be represented by
Formula IIa: ##STR4## [0073] or a pharmaceutically acceptable
tautomer, salt, solvate, and/or ester thereof, wherein: [0074]
X.sup.1 is alkylene, substituted alkylene, alkenylene, substituted
alkenylene, alkynylene, substituted alkynylene, carbocyclylene,
substituted carbocyclylene, heterocyclylene, or substituted
heterocyclylene; [0075] X.sup.2 is a covalent bond, alkylene, or
substituted alkylene; [0076] L.sup.1 is a covalent bond, arylene,
substituted arylene, heterocyclylene, substituted heterocyclylene,
carbocyclylene, substituted carbocyclylene, --S--, --S(O)--,
S(O).sub.2, --NR.sup.3--, or --O--; [0077] Y.sup.1 and Y.sup.2 are
each independently a covalent bond, --O--, or --NR.sup.4--; [0078]
R.sup.1 and R.sup.2 are each independently H, alkyl, substituted
alkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl,
substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, substituted heterocyclylalkyl,
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; and [0079] R.sup.3,
R.sup.4, and R.sup.5 are each independently H, alkyl, substituted
alkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl,
substituted heterocyclyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, arylalkyl, substituted arylalkyl,
heterocyclylalkyl, or substituted heterocyclylalkyl; [0080] with
the following provisos: [0081] (a) Y.sup.1 and Y.sup.2 are not both
covalent bonds; [0082] (b) when Y.sup.1 is a covalent bond, then
R.sup.1 is not H; and [0083] (c) when Y.sup.2 is a covalent bond,
then R.sup.2 is not H.
[0084] In another embodiment, the present application provides for
a pharmaceutical composition comprising a compound of Formula I or
II, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof; and a pharmaceutically acceptable carrier or
excipient.
[0085] In another embodiment, the present application provides for
a pharmaceutical composition comprising a compound of Formula I or
II, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof; at least one additional active agent; and a
pharmaceutically acceptable carrier or excipient.
[0086] In another embodiment, the present application provides for
a method for treating or preventing a viral infection comprising
administering, to a patient in need thereof, a therapeutically
effective amount of at least one compound of Formula I or II, or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0087] In another embodiment, the present application provides for
a combination pharmaceutical agent comprising:
[0088] a) a first pharmaceutical composition comprising a compound
of Formula I or II, or a pharmaceutically acceptable salt, solvate,
and/or ester thereof; and
[0089] b) a second pharmaceutical composition comprising at least
one additional active agent selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HBV/HCV, another drug for treating HBV/HCV, and
combinations thereof.
DETAILED DESCRIPTION
[0090] Reference will now be made in detail to certain claims of
the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated claims, it will be
understood that they are not intended to limit the invention to
those claims. On the contrary, the invention is intended to cover
all alternatives, modifications, and equivalents, which may be
included within the scope of the present invention as defined by
the claims.
Definitions
[0091] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0092] When trade names are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0093] As used herein, "a compound of the invention" or "a compound
of formula I or II" means a compound of formula I or II, or a
pharmaceutically acceptable salt, solvate, or physiologically
functional derivative thereof. Similarly, with respect to
isolatable intermediates such as for example, compounds of formula
(IX), the phrase "a compound of formula (number)" means a compound
of that formula and pharmaceutically acceptable salts, solvates and
physiologically functional derivatives thereof.
[0094] "Alkyl" is hydrocarbon containing normal, secondary,
tertiary or cyclic carbon atoms. For example, an alkyl group can
have 1 to 20 carbon atoms (i.e., C.sub.1-C.sub.20 alkyl), 1 to 10
carbon atoms (i.e., C.sub.1-C.sub.10 alkyl), or 1 to 6 carbon atoms
(i.e., C.sub.1-C.sub.6 alkyl). Examples of suitable alkyl groups
include, but are not limited to, methyl (Me, --CH.sub.3), ethyl
(Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, and octyl
(--(CH.sub.2).sub.7CH.sub.3).
[0095] "Alkoxy" means a group having the formula --O-alkyl, in
which an alkyl group, as defined above, is attached to the parent
molecule via an oxygen atom. The alkyl portion of an alkoxy group
can have 1 to 20 carbon atoms (i.e., C.sub.1-C.sub.20 alkoxy), 1 to
12 carbon atoms (i.e., C.sub.1-C.sub.12 alkoxy), or 1 to 6 carbon
atoms (i.e., C.sub.1-C.sub.6 alkoxy). Examples of suitable alkoxy
groups include, but are not limited to, methoxy (--O--CH.sub.3 or
--OMe), ethoxy (--OCH.sub.2CH.sub.3 or --OEt), t-butoxy
(--O--C(CH.sub.3).sub.3 or --OtBu) and the like.
[0096] "Haloalkyl" is an alkyl group, as defined above, in which
one or more hydrogen atoms of the alkyl group is replaced with a
halogen atom. The alkyl portion of a haloalkyl group can have 1 to
20 carbon atoms (i.e., C.sub.1-C.sub.20 haloalkyl), 1 to 12 carbon
atoms (i.e., C.sub.1-C.sub.2 haloalkyl), or 1 to 6 carbon atoms
(i.e., C.sub.1-C.sub.6 alkyl). Examples of suitable haloalkyl
groups include, but are not limited to, --CF.sub.3, --CHF.sub.2,
--CFH.sub.2, --CH.sub.2CF.sub.3, and the like.
[0097] "Alkenyl" is a hydrocarbon containing normal, secondary,
tertiary or cyclic carbon atoms with at least one site of
unsaturation, i.e. a carbon-carbon, sp.sup.2 double bond. For
example, an alkenyl group can have 2 to 20 carbon atoms (i.e.,
C.sub.2-C.sub.20 alkenyl), 2 to 12 carbon atoms (i.e.,
C.sub.2-C.sub.12 alkenyl), or 2 to 6 carbon atoms (i.e.,
C.sub.2-C.sub.6 alkenyl). Examples of suitable alkenyl groups
include, but are not limited to, ethylene, vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
cyclopentenyl (--C.sub.5H.sub.7), and 5-hexenyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2).
[0098] "Alkynyl" is a hydrocarbon containing normal, secondary,
tertiary or cyclic carbon atoms with at least one site of
unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an
alkynyl group can have 2 to 20 carbon atoms (i.e., C.sub.2-C.sub.20
alkynyl), 2 to 12 carbon atoms (i.e., C.sub.2-C.sub.12 alkyne,), or
2 to 6 carbon atoms (i.e., C.sub.2-C.sub.6 alkynyl). Examples of
suitable alkynyl groups include, but are not limited to, acetylenic
(--C.ident.CH), propargyl (--CH.sub.2C.ident.CH), and the like.
[0099] "Alkylene" refers to a saturated, branched or straight chain
or cyclic hydrocarbon radical having two monovalent radical centers
derived by the removal of two hydrogen atoms from the same or two
different carbon atoms of a parent alkane. For example, an alkylene
group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to
6 carbon atoms. Typical alkylene radicals include, but are not
limited to, methylene (--CH.sub.2--), 1,1-ethyl (--CH(CH.sub.3)--),
1,2-ethyl (--CH.sub.2CH.sub.2--), 1,1-propyl
(--CH(CH.sub.2CH.sub.3)--), 1,2-propyl (--CH.sub.2CH(CH.sub.3)--),
1,3-propyl (--CH.sub.2CH.sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0100] "Alkenylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same
or two different carbon atoms of a parent alkene. For example, and
alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon
atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include,
but are not limited to, 1,2-ethylene (--CH.dbd.CH--).
[0101] "Alkynylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical having two monovalent radical
centers derived by the removal of two hydrogen atoms from the same
or two different carbon atoms of a parent alkyne. For example, an
alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon
atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include,
but are not limited to, acetylene (--C.ident.C--), propargyl
(--CH.sub.2C.ident.C--), and 4-pentynyl
(--CH.sub.2CH.sub.2CH.sub.2C.ident.CH--).
[0102] "Aminoalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an amino radical.
[0103] "Amidoalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with a --NRCOR.sup.a group
where R is hydrogen or alkyl and R.sup.a is alkyl, substituted
alkyl, aryl, or substituted aryl as defined herein, e.g.,
--(CH.sub.2).sub.2--NHC(O)CH.sub.3,
--(CH.sub.2).sub.3--NH--C(O)--CH.sub.3, and the like.
[0104] "Aryl" means a monovalent aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. For example, an aryl group
can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12
carbon atoms. Typical aryl groups include, but are not limited to,
radicals derived from benzene (e.g., phenyl), substituted benzene,
naphthalene, anthracene, biphenyl, and the like.
[0105] "Arylene" refers to an aryl as defined above having two
monovalent radical centers derived by the removal of two hydrogen
atoms from the same or two different carbon atoms of a parent aryl.
Typical arylene radicals include, but are not limited to,
phenylene.
[0106] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The
arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl
moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon
atoms.
[0107] "Arylalkenyl" refers to an acyclic alkenyl radical in which
one of the hydrogen atoms bonded to a carbon atom, typically a
terminal or sp.sup.3 carbon atom, but also an sp.sup.2 carbon atom,
is replaced with an aryl radical. The aryl portion of the
arylalkenyl can include, for example, any of the aryl groups
disclosed herein, and the alkenyl portion of the arylalkenyl can
include, for example, any of the alkenyl groups disclosed herein.
The arylalkenyl group can comprise 6 to 20 carbon atoms, e.g., the
alkenyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to
14 carbon atoms.
[0108] "Arylalkynyl" refers to an acyclic alkynyl radical in which
one of the hydrogen atoms bonded to a carbon atom, typically a
terminal or sp.sup.3 carbon atom, but also an sp carbon atom, is
replaced with an aryl radical. The aryl portion of the arylalkynyl
can include, for example, any of the aryl groups disclosed herein,
and the alkynyl portion of the arylalkynyl can include, for
example, any of the alkynyl groups disclosed herein. The
arylalkynyl group can comprise 6 to 20 carbon atoms, e.g., the
alkynyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to
14 carbon atoms.
[0109] The term "substituted" in reference to alkyl, alkylene,
aryl, arylalkyl, heterocyclyl, etc., for example, "substituted
alkyl", "substituted alkylene", "substituted aryl", "substituted
arylalkyl", "substituted heterocyclyl", and "substituted
carbocyclyl" means alkyl, alkylene, aryl, arylalkyl, heterocyclyl,
carbocyclyl respectively, in which one or more hydrogen atoms are
each independently replaced with a non-hydrogen substituent.
Typical substituents include, but are not limited to, --X, --R,
--O--, .dbd.O, --OR, --SR, --S--, --NR.sub.2, --N+R.sub.3, .dbd.NR,
--CX.sub.3, --CN, --OCN, --SCN, --N.dbd.C.dbd.O, --NCS, --NO,
--NO.sub.2, .dbd.N.sub.2, --N.sub.3, --NHC(.dbd.O)R,
--C(.dbd.O)NRR--S(.dbd.O).sub.2O--; --S(.dbd.O).sub.2OH,
--S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR, --S(.dbd.O).sub.2NR,
--S(.dbd.O)R, --OP(.dbd.O)(OR).sub.2, --P(.dbd.O)(OR).sub.2,
--P(.dbd.O)(O--).sub.2, --P(.dbd.O)(OH).sub.2, --P(O)(OR)(O--),
--C(.dbd.O)R, --C(S)R, --C(O)OR, --C(O)O--, --C(S)OR, --C(O)SR,
--C(S)SR, --C(O)NRR, --C(S)NRR, --C(.dbd.NR)NRR, where each X is
independently a halogen: F, Cl, Br, or I; and each R is
independently H, alkyl, aryl, arylalkyl, a heterocycle, or a
protecting group or prodrug moiety. Alkylene, alkenylene, and
alkynylene groups may also be similarly substituted.
[0110] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e., active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s),
photolysis, and/or metabolic chemical reaction(s). A prodrug is
thus a covalently modified analog or latent form of a
therapeutically active compound.
[0111] One skilled in the art will recognize that substituents and
other moieties of the compounds of Formula I or II should be
selected in order to provide a compound which is sufficiently
stable to provide a pharmaceutically useful compound which can be
formulated into an acceptably stable pharmaceutical composition.
Compounds of Formula I or II which have such stability are
contemplated as falling within the scope of the present
invention.
[0112] "Heteroalkyl" refers to an alkyl group where one or more
carbon atoms have been replaced with a heteroatom, such as, O, N,
or S. For example, if the carbon atom of the alkyl group which is
attached to the parent molecule is replaced with a heteroatom
(e.g., O, N, or S) the resulting heteroalkyl groups are,
respectively, an alkoxy group (e.g., --OCH.sub.3, etc.), an amine
(e.g., --NHCH.sub.3, --N(CH.sub.3).sub.2, etc.), or a thioalkyl
group (e.g., --SCH.sub.3). If a non-terminal carbon atom of the
alkyl group which is not attached to the parent molecule is
replaced with a heteroatom (e.g., O, N, or S) and the resulting
heteroalkyl groups are, respectively, an alkyl ether (e.g.,
--CH.sub.2CH.sub.2--O--CH.sub.3, etc.), an alkyl amine (e.g.,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2, etc.), or a
thioalkyl ether (e.g., --CH.sub.2--S--CH.sub.3). If a terminal
carbon atom of the alkyl group is replaced with a heteroatom (e.g.,
O, N, or S), the resulting heteroalkyl groups are, respectively, a
hydroxyalkyl group (e.g., --CH.sub.2CH.sub.2--OH), an aminoalkyl
group (e.g., --CH.sub.2NH.sub.2), or an alkyl thiol group (e.g.,
--CH.sub.2CH.sub.2--SH). A heteroalkyl group can have, for example,
1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
A C.sub.1-C.sub.6 heteroalkyl group means a heteroalkyl group
having 1 to 6 carbon atoms.
[0113] "Heterocycle" or "heterocyclyl" as used herein includes by
way of example and not limitation those heterocycles described in
Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.
A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7,
and 9; The Chemistry of Heterocyclic Compounds, A Series of
Monographs" (John Wiley & Sons, New York, 1950 to present), in
particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.
(1960) 82:5566. In one specific embodiment of the invention
"heterocycle" includes a "carbocycle" as defined herein, wherein
one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced
with a heteroatom (e.g. O, N, or S). The terms "heterocycle" or
"heterocyclyl" includes saturated rings, partially unsaturated
rings, and aromatic rings (i.e., heteroaromatic rings). Substituted
heterocyclyls include, for example, heterocyclic rings substituted
with any of the substituents disclosed herein including carbonyl
groups. A non-limiting example of a carbonyl substituted
heterocyclyl is: ##STR5##
[0114] Examples of heterocycles include by way of example and not
limitation pyridyl, dihydroypyridyl, tetrahydropyridyl(piperidyl),
thiazolyl, tetrahydrothiophenyl, sulfur oxidized
tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,
indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,
piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl,
pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,
isatinoyl, and bis-tetrahydrofuranyl: ##STR6##
[0115] By way of example and not limitation, carbon bonded
heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine,
position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl.
[0116] By way of example and not limitation, nitrogen bonded
heterocycles are bonded at position 1 of an aziridine, azetidine,
pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,
position 4 of a morpholine, and position 9 of a carbazole, or
.beta.-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,
1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
[0117] "Heterocyclylene" refers to a heterocyclyl, as defined
herein, derived by replacing a hydrogen atom from a carbon atom or
heteroatom of a heterocyclyl, with an open valence. Similarly,
"heteroarylene" refers to an aromatic heterocyclylene.
[0118] "Heterocyclylalkyl" refers to an acyclic alkyl radical in
which one of the hydrogen atoms bonded to a carbon atom, typically
a terminal or Sp.sup.3 carbon atom, is replaced with a heterocyclyl
radical (i.e., a heterocyclyl-alkylene-moiety). Typical
heterocyclyl alkyl groups include, but are not limited to
heterocyclyl-CH.sub.2--, 2-(heterocyclyl)ethan-1-yl, and the like,
wherein the "heterocyclyl" portion includes any of the heterocyclyl
groups described above, including those described in Principles of
Modern Heterocyclic Chemistry. One skilled in the art will also
understand that the heterocyclyl group can be attached to the alkyl
portion of the heterocyclyl alkyl by means of a carbon-carbon bond
or a carbon-heteroatom bond, with the proviso that the resulting
group is chemically stable. The heterocyclyl alkyl group comprises
2 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl
group comprises 1 to 6 carbon atoms and the heterocyclyl moiety
comprises 1 to 14 carbon atoms. Examples of heterocyclylalkyls
include by way of example and not limitation 5-membered sulfur,
oxygen, and/or nitrogen containing heterocycles such as
thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl,
oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur,
oxygen, and/or nitrogen containing heterocycles such as
piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,
pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl,
etc.
[0119] "Heterocyclylalkenyl" refers to an acyclic alkenyl radical
in which one of the hydrogen atoms bonded to a carbon atom,
typically a terminal or sp.sup.3 carbon atom, but also a sp.sup.2
carbon atom, is replaced with a heterocyclyl radical (i.e., a
heterocyclylalkenylene-moiety). The heterocyclyl portion of the
heterocyclyl alkenyl group includes any of the heterocyclyl groups
described herein, including those described in Principles of Modern
Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl
alkenyl group includes any of the alkenyl groups disclosed herein.
One skilled in the art will also understand that the heterocyclyl
group can be attached to the alkenyl portion of the heterocyclyl
alkenyl by means of a carbon-carbon bond or a carbon-heteroatom
bond, with the proviso that the resulting group is chemically
stable. The heterocyclyl alkenyl group comprises 2 to 20 carbon
atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group
comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises
1 to 14 carbon atoms.
[0120] "Heterocyclylalkynyl" refers to an acyclic alkynyl radical
in which one of the hydrogen atoms bonded to a carbon atom,
typically a terminal or Sp.sup.3 carbon atom, but also an sp carbon
atom, is replaced with a heterocyclyl radical (i.e., a
heterocyclyl-alkynylene-moiety). The heterocyclyl portion of the
heterocyclyl alkynyl group includes any of the heterocyclyl groups
described herein, including those described in Principles of Modern
Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl
alkynyl group includes any of the alkynyl groups disclosed herein.
One skilled in the art will also understand that the heterocyclyl
group can be attached to the alkynyl portion of the heterocyclyl
alkynyl by means of a carbon-carbon bond or a carbon-heteroatom
bond, with the proviso that the resulting group is chemically
stable. The heterocyclyl alkynyl group comprises 2 to 20 carbon
atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group
comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises
1 to 14 carbon atoms.
[0121] "Heteroaryl" refers to a monovalent aromatic heterocyclyl
having at least one heteroatom in the ring. Non-limiting examples
of suitable heteroatoms which can be included in the aromatic ring
include oxygen, sulfur, and nitrogen. Non-limiting examples of
heteroaryl rings include all of those listed in the definition of
"heterocyclyl", including pyridinyl, pyrrolyl, oxazolyl, indolyl,
isoindolyl, purinyl, furanyl, thienyl, benzofuranyl,
benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl,
pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl,
pyrimidyl, pyrazyl, etc.
[0122] "Carbocycle" or "carbocyclyl" refers to a saturated,
partially unsaturated or aromatic ring having 3 to 7 carbon atoms
as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about
20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6
ring atoms, still more typically 5 or 6 ring atoms. Bicyclic
carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo
(4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged
as a bicyclo (5,6) or (6,6) system. Examples of monocyclic
carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,
1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,
cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,
1-cyclohex-3-enyl, phenyl.
[0123] "Carbocyclylene" refers to a carbocyclyl or carbocycle as
defined above having two monovalent radical centers derived by the
removal of two hydrogen atoms from the same or two different carbon
atoms of a parent carbocyclyl. Typical carbocyclylene radicals
include, but are not limited to, phenylene.
[0124] "Arylheteroalkyl" refers to a heteroalkyl as defined herein,
in which a hydrogen atom (which may be attached either to a carbon
atom or a heteroatom) has been replaced with an aryl group as
defined herein. The aryl groups may be bonded to a carbon atom of
the heteroalkyl group, or to a heteroatom of the heteroalkyl group,
provided that the resulting arylheteroalkyl group provides a
chemically stable moiety. For example, an arylheteroalkyl group can
have the general formulae -alkylene-O-aryl,
-alkylene-O-alkylene-aryl, -alkylene-NH-aryl,
-alkylene-NH-alkylene-aryl, -alkylene-S-aryl,
-alkylene-S-alkylene-aryl, etc. In addition, any of the alkylene
moieties in the general formulae above can be further substituted
with any of the substituents defined or exemplified herein.
[0125] "Heteroarylalkyl" refers to an alkyl group, as defined
herein, in which a hydrogen atom has been replaced with a
heteroaryl group as defined herein. Non-limiting examples of
heteroaryl alkyl include --CH.sub.2-pyridinyl, --CH.sub.2-pyrrolyl,
--CH.sub.2-oxazolyl, --CH.sub.2-indolyl, --CH.sub.2-isoindolyl,
--CH.sub.2-purinyl, --CH.sub.2-furanyl, --CH.sub.2-thienyl,
--CH.sub.2-benzofuranyl, --CH.sub.2-benzothiophenyl,
--CH.sub.2-carbazolyl, --CH.sub.2-imidazolyl, --CH.sub.2-thiazolyl,
--CH.sub.2-isoxazolyl, --CH.sub.2-pyrazolyl,
--CH.sub.2-isothiazolyl, --CH.sub.2-quinolyl,
--CH.sub.2-isoquinolyl, --CH.sub.2-pyridazyl, --CH.sub.2-pyrimidyl,
--CH.sub.2-pyrazyl, --CH(CH.sub.3)-pyridinyl,
--CH(CH.sub.3)-pyrrolyl, --CH(CH.sub.3)-oxazolyl,
--CH(CH.sub.3)-indolyl, --CH(CH.sub.3)-isoindolyl,
--CH(CH.sub.3)-purinyl, --CH(CH.sub.3)-furanyl,
--CH(CH.sub.3)-thienyl, --CH(CH.sub.3)-benzofuranyl,
--CH(CH.sub.3)-benzothiophenyl, --CH(CH.sub.3)-carbazolyl,
--CH(CH.sub.3)-imidazolyl, --CH(CH.sub.3)-thiazolyl,
--CH(CH.sub.3)-isoxazolyl, --CH(CH.sub.3)-pyrazolyl,
--CH(CH.sub.3)-isothiazolyl, --CH(CH.sub.3)-quinolyl,
--CH(CH.sub.3)-isoquinolyl, --CH(CH.sub.3)-pyridazyl,
--CH(CH.sub.3)-pyrimidyl, --CH(CH.sub.3)-pyrazyl, etc.
[0126] The term "optionally substituted" in reference to a
particular moiety of the compound of Formula I (e.g., an optionally
substituted aryl group) refers to a moiety having 0, 1, 2, or more
substituents.
[0127] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0128] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0129] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties,
e.g., melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0130] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0131] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and l or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or 1 meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory. For a given
chemical structure, these stereoisomers are identical except that
they are mirror images of one another. A specific stereoisomer may
also be referred to as an enantiomer, and a mixture of such isomers
is often called an enantiomeric mixture. A 50:50 mixture of
enantiomers is referred to as a racemic mixture or a racemate,
which may occur where there has been no stereoselection or
stereospecificity in a chemical reaction or process. The terms
"racemic mixture" and "racemate" refer to an equimolar mixture of
two enantiomeric species, devoid of optical activity.
Protecting Groups
[0132] In the context of the present invention, protecting groups
include prodrug moieties and chemical protecting groups.
[0133] Protecting groups are available, commonly known and used,
and are optionally used to prevent side reactions with the
protected group during synthetic procedures, i.e. routes or methods
to prepare the compounds of the invention. For the most part the
decision as to which groups to protect, when to do so, and the
nature of the chemical protecting group "PG" will be dependent upon
the chemistry of the reaction to be protected against (e.g.,
acidic, basic, oxidative, reductive or other conditions) and the
intended direction of the synthesis. The PG groups do not need to
be, and generally are not, the same if the compound is substituted
with multiple PG. In general PG will be used to protect functional
groups such as carboxyl, hydroxyl, thio, or amino groups and to
thus prevent side reactions or to otherwise facilitate the
synthetic efficiency. The order of deprotection to yield free,
deprotected groups is dependent upon the intended direction of the
synthesis and the reaction conditions to be encountered, and may
occur in any order as determined by the artisan.
[0134] Various functional groups of the compounds of the invention
may be protected. For example, protecting groups for --OH groups
(whether hydroxyl, carboxylic acid, phosphonic acid, or other
functions) include "ether- or ester-forming groups". Ether- or
ester-forming groups are capable of functioning as chemical
protecting groups in the synthetic schemes set forth herein.
However, some hydroxyl and thio protecting groups are neither
ether-nor ester-forming groups, as will be understood by those
skilled in the art, and are included with amides, discussed
below.
[0135] A very large number of hydroxyl protecting groups and
amide-forming groups and corresponding chemical cleavage reactions
are described in Protective Groups in Organic Synthesis, Theodora
W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New
York, 1999, ISBN 0-471-16019-9) ("Greene"). See also Kocienski,
Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New
York, 1994), which is incorporated by reference in its entirety
herein. In particular Chapter 1, Protecting Groups: An Overview,
pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94,
Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4,
Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl
Protecting Groups, pages 155-184. For protecting groups for
carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and
other protecting groups for acids see Greene as set forth below.
Such groups include by way of example and not limitation, esters,
amides, hydrazides, and the like.
Ether- and Ester-Forming Protecting Groups
[0136] Ester-forming groups include: (1) phosphonate ester-forming
groups, such as phosphonamidate esters, phosphorothioate esters,
phosphonate esters, and phosphon-bis-amidates; (2) carboxyl
ester-forming groups, and (3) sulphur ester-forming groups, such as
sulphonate, sulfate, and sulfinate.
Metabolites of the Compounds of the Invention
[0137] Also falling within the scope of this invention are the in
vivo metabolic products of the compounds described herein. Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising contacting a compound of this invention with a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products typically are identified by preparing a
radiolabelled (e.g., C.sup.14 or H.sup.3) compound of the
invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS or
NMR analysis. In general, analysis of metabolites is done in the
same way as conventional drug metabolism studies well-known to
those skilled in the art. The conversion products, so long as they
are not otherwise found in vivo, are useful in diagnostic assays
for therapeutic dosing of the compounds of the invention even if
they possess no anti-infective activity of their own.
Compounds of Formula I or II
[0138] In one embodiment, the present application provides
compounds according to Formula I or II, as described herein.
[0139] In another embodiment of the compounds of formula I or II,
-L.sup.2-R.sup.3 is --NH.sub.2.
[0140] In another embodiment of the compounds of formula I or II,
L.sup.2 is --NR.sup.5 or --O--; and R.sup.3 is heteroalkyl or
substituted heteroalkyl.
[0141] In another embodiment of the compounds of formula I or II,
L.sup.2 is --NR.sup.5 or --O--; and R.sup.3 is alkyl or substituted
alkyl.
[0142] In another embodiment of the compounds of formula I or II,
L.sup.2 is --NR.sup.5 or --O--; and R.sup.3 is arylalkyl,
substituted arylalkyl, heterocyclylalkyl, or substituted
heterocyclylalkyl.
[0143] In another embodiment of the compounds of formula I or II,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is arylene,
substituted arylene, heterocyclylene, substituted heterocyclylene,
carbocyclylene, or substituted carbocyclylene; and X.sup.2 is
alkylene or substituted alkylene.
[0144] In another embodiment of the compounds of formula I or II,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is --S--,
--NR.sup.5--, or --O--; and X.sup.2 is alkylene or substituted
alkylene.
[0145] In another embodiment of the compounds of formula I or II,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is a covalent
bond; and X.sup.2 is a covalent bond, alkylene or substituted
alkylene.
[0146] In another embodiment of the compounds of formula I or II,
X.sup.1 is carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; L.sup.1 is a
covalent bond; and X.sup.2 is alkylene or substituted alkylene.
[0147] In another embodiment of the compounds of formula I or II,
Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is a covalent bond;
R.sup.1 is H, alkyl, or substituted alkyl; and R.sup.2 is alkyl or
substituted alkyl.
[0148] In another embodiment of the compounds of formula I or II,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.1 and R.sup.2 are each independently H, alkyl, or
substituted alkyl.
[0149] In another embodiment of the compounds of formula I or II,
Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is a covalent bond;
R.sup.1 is -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5; and R.sup.2 is alkyl or substituted
alkyl.
[0150] In another embodiment of the compounds of formula I or II,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.1 and R.sup.2 are each independently
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5.
[0151] In another embodiment of the compounds of formula I or II,
Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is a covalent bond; and
R.sup.2 is carbocyclyl, substituted carbocyclyl, heterocyclyl, or
substituted heterocyclyl.
[0152] In another embodiment of the compounds of formula I or II,
Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is a covalent bond; and
R.sup.2 is aryl, substituted aryl, substituted or unsubstituted 5-
to 7-membered non-aromatic heterocyclyl containing one to 4 hetero
atoms selected from a group consisting of N, O, S, and a
combination thereof.
[0153] In another embodiment of the compounds of formula I or II,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.2 is carbocyclyl, substituted carbocyclyl, heterocyclyl,
or substituted heterocyclyl.
[0154] In another embodiment of the compounds of formula I or II,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
R.sup.2 is aryl, substituted aryl, heteroaryl, or substituted
heteroaryl.
[0155] In another embodiment of the compounds of formula I or II,
--Y.sup.1--R.sup.1 is --O--N.dbd.C(R.sup.6R.sup.7).
[0156] In another embodiment of the compounds of formula I or II,
--Y.sup.1--R.sup.1 is --O--N.dbd.C(R.sup.6R.sup.7); Y.sup.2 is
--O-- or --NR.sup.5--.
[0157] In the above embodiments of the compounds of formula I or
II, each R.sup.5, R.sup.6, and R.sup.7 are independently H, alkyl,
substituted alkyl, carbocyclyl, substituted carbocyclyl,
heterocyclyl, substituted heterocyclyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.
Compounds of Formula Ia
[0158] In one embodiment, the present application provides
compounds according to Formula Ia, as described herein.
[0159] In another embodiment of the compounds of formula Ia,
--Y.sup.1--R.sup.1 is --OH.
[0160] In another embodiment of the compounds of formula Ia,
--Y.sup.2--R.sup.2 is --OH.
[0161] In another embodiment of the compounds of formula Ia,
--Y.sup.1--R.sup.1 and --Y.sup.2--R.sup.2 are both --OH.
[0162] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.1 and R.sup.2 are each independently
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5.
[0163] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--.
[0164] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; and R.sup.3 is alkyl,
arylalkyl, or heteroalkyl.
[0165] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; and R.sup.3 is
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0166] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; and R.sup.3 is
-alkylene-O-alkyl.
[0167] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; and R.sup.3 is
--CH.sub.2CH.sub.2--O--CH.sub.3.
[0168] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; and R.sup.3 is
benzyl.
[0169] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; and X.sup.1 is
alkylene.
[0170] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--; X.sup.1 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
or --CH.sub.2CH(CH.sub.2)--.
[0171] In another embodiment of the compounds of formula Ia,
R.sup.4 is --OH.
[0172] In another embodiment of the compounds of formula Ia,
L.sup.1 is arylene or substituted arylene.
[0173] In another embodiment of the compounds of formula Ia,
--X.sup.1-L.sup.1- is --CH.sub.2-phenylene-.
[0174] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; L.sup.1 is --O--.
[0175] In another embodiment of the compounds of formula Ia,
--X.sup.1-L.sup.1- is --CH.sub.2CH.sub.2--O-- or
--CH.sub.2CH(CH.sub.3)--O--.
[0176] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; L.sup.1 is a covalent bond.
[0177] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is alkylene.
[0178] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-CH.sub.2--.
[0179] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)-CH.sub.2--.
[0180] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; L.sup.1 is arylene or substituted arylene;
X.sup.2 is a covalent bond.
[0181] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-.
[0182] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-(1,3-phenylene)- or
--CH.sub.2-(1,4-phenylene)-.
[0183] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; L.sup.1 is --O--; X.sup.2 is alkylene.
[0184] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; L.sup.1 is --O--; X.sup.2 is --CH.sub.2--.
[0185] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
[0186] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or
--NR.sup.5--.
[0187] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are both --O--.
[0188] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or a covalent
bond.
[0189] In another embodiment of the compounds of formula Ia,
R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, -(substituted
alkylene)-O--C(O)--O--R.sup.5, aryl, or substituted aryl.
[0190] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are both --O--; R.sup.1 and R.sup.2 are each
independently H or alkyl.
[0191] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are both --O--; R.sup.1 and R.sup.2 are each
H.
[0192] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, -(substituted
alkylene)-O--C(O)--O--R.sup.5, aryl, or substituted aryl.
[0193] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.1 and R.sup.2 are each H.
[0194] In another embodiment of the compounds of formula Ia,
Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1 is alkyl,
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.1; and R.sup.2 is aryl or substituted
aryl.
[0195] In another embodiment of the compounds of formula Ia,
Y.sup.1 is --O--; Y.sup.2 is a covalent bond; R.sup.1 is H; and
R.sup.2 is alkyl, aryl, or substituted aryl.
[0196] In another embodiment of the compounds of formula Ia,
Y.sup.2 is a covalent bond; and R.sup.2 is carbocyclyl, substituted
carbocyclyl, heterocyclyl, or substituted heterocyclyl.
[0197] In another embodiment of the compounds of formula Ia,
Y.sup.2 is a covalent bond; and R.sup.2 is aryl, substituted aryl,
substituted or unsubstituted 5- to 7-membered non-aromatic
heterocyclyl containing 1 to 4 hetero atoms selected from a group
consisting of N, O, S, and a combination thereof.
[0198] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.2 is carbocyclyl, substituted carbocyclyl, heterocyclyl,
or substituted heterocyclyl.
[0199] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--;
and R.sup.2 is aryl, substituted aryl, heteroaryl, or substituted
heteroaryl.
[0200] In another embodiment of the compounds of formula Ia,
--Y.sup.1--R.sup.1 is --O--N.dbd.C(R.sup.6R.sup.7).
[0201] In another embodiment of the compounds of formula Ia,
--Y.sup.1--R.sup.1 is --O--N.dbd.C(CH.sub.3).sub.2.
[0202] In another embodiment of the compounds of formula Ia,
--Y.sup.1--R.sup.1 is --O--N.dbd.C(R.sup.6R.sup.7); Y.sup.2 is
--O-- or --NR.sup.5--.
[0203] In another embodiment of the compounds of formula Ia,
--Y.sup.1--R.sup.1 is --O--N.dbd.C(CH.sub.3).sub.2; Y.sup.2 is
--O-- or --NR.sup.5--.
[0204] In another embodiment of the compounds of formula Ia,
R.sup.4 is --OH, --O--C(O)--O--CH.sub.2CH.sub.3,
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2,
--NH--CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--NH.sub.2--CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.2).sub.2O, or
--SH.
[0205] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is
--O-- or a covalent bond; L.sup.1 is a covalent bond or arylene;
L.sup.2 is --O--; R.sup.1 is H, alkyl, -alkylene-C(O)--O--R.sup.5,
-(substituted alkylene)-C(O)--O--R.sup.5,
-alkylene-O--C(O)--R.sup.5, -(substituted
alkylene)-O--C(O)--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; R.sup.2 is H, alkyl,
or aryl; R.sup.3 is heteroalkyl; and R.sup.4 is --OH.
[0206] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene; Y.sup.1 is --O-- or --NR.sup.5--;
Y.sup.2 is --O-- or --NR.sup.5--; L.sup.1 is arylene; L.sup.2 is
--O--; R.sup.1 is H, alkyl, -alkylene-C(O)--O--R.sup.5,
-(substituted alkylene)-C(O)--O--R.sup.5,
-alkylene-O--C(O)--R.sup.5, -(substituted
alkylene)-O--C(O)--R.sup.5, -alkylene-O--C(O)--O--R.sup.5, or
-(substituted alkylene)-O--C(O)--O--R.sup.5; R.sup.2 is H, alkyl,
or aryl; R.sup.3 is alkyl or heteroalkyl; and R.sup.4 is
--NH(R.sup.5).
[0207] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene or substituted alkylene; Y.sup.1
is --O-- or --NR.sup.5--; Y.sup.2 is a covalent bond; and L.sup.1
is arylene or --O--; L.sup.2 is --O--; R.sup.1 is H, alkyl, or
substituted alkyl; and R.sup.2 is carbocyclyl, substituted
carbocyclyl, heterocyclyl, or substituted heterocyclyl.
[0208] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene or substituted alkylene; Y.sup.1
and Y.sup.2 are each independently --O-- or --NR.sup.5--; L.sup.1
is arylene or --O--; L.sup.2 is --O--; R.sup.1 is
-alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5; and R.sup.2 is carbocyclyl,
substituted carbocyclyl, heterocyclyl, or substituted
heterocyclyl.
[0209] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene or substituted alkylene;
Y.sup.1--R.sup.1 is --O--N.dbd.C(R.sup.6R.sup.7); Y.sup.2 is --O--
or --NR.sup.5--; L.sup.1 is arylene or --O--; L.sup.2 is --O--; and
R.sup.2 is -alkylene-C(O)--O--R.sup.5, -(substituted
alkylene)-C(O)--O--R.sup.5, -alkylene-O--C(O)--R.sup.5,
-(substituted alkylene)-O--C(O)--R.sup.5,
-alkylene-O--C(O)--O--R.sup.5, or -(substituted
alkylene)-O--C(O)--O--R.sup.5.
[0210] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--.
[0211] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--, R.sup.3 is alkyl or
heteroalkyl.
[0212] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--, R.sup.3 is
-alkylene-O-alkyl.
[0213] In another embodiment of the compounds of formula Ia,
L.sup.2 is --O--, --N(R.sup.5)--, or --S--, R.sup.3 is
--CH.sub.2CH.sub.2--O--CH.sub.3.
[0214] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene.
[0215] In another embodiment of the compounds of formula Ia,
X.sup.1 is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or --CH.sub.2CH(CH.sub.2)--.
[0216] In another embodiment of the compounds of formula Ia,
R.sup.4 is --OH.
[0217] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene.
[0218] In another embodiment of the compounds of formula Ia,
--X.sup.1-L.sup.1- is --CH.sub.2-phenylene-.
[0219] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is --O--.
[0220] In another embodiment of the compounds of formula Ia,
--X.sup.1-L.sup.1- is --CH.sub.2CH.sub.2--O-- or
--CH.sub.2CH(CH.sub.3)--O--.
[0221] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is a covalent bond.
[0222] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is alkylene.
[0223] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-CH.sub.2--.
[0224] In another embodiment of the compounds of formula Ia,
X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)-CH.sub.2--.
[0225] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is a covalent bond.
[0226] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is a covalent bond, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-.
[0227] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is a covalent bond, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)- or --CH.sub.2-(1,4-phenylene)-.
[0228] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is alkylene.
[0229] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is --CH.sub.2--.
[0230] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is --CH.sub.2--,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
[0231] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or
--NR.sup.5--.
[0232] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are both --O--.
[0233] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or a covalent
bond.
[0234] In another embodiment of the compounds of formula Ia,
R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0235] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and R.sup.2 are each
independently H or alkyl.
[0236] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and R.sup.2 are each
H.
[0237] In another embodiment of the compounds of formula Ia,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--,
R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0238] In another embodiment of the compounds of formula Ia,
Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1 is alkyl or
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl or substituted
aryl.
[0239] In another embodiment of the compounds of formula Ia,
Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1 is
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl.
[0240] In another embodiment of the compounds of formula Ia,
Y.sup.1 is -o; Y.sup.2 is a covalent bond; R.sup.1 is H; and
R.sup.2 is alkyl, aryl, or substituted aryl.
[0241] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is
--O-- or a covalent bond; L.sup.1 is a covalent bond or arylene;
L.sup.2 is --O--; R.sup.1 is H, alkyl, or
-alkylene-C(O)--O--R.sup.5; R.sup.2 is H, alkyl, or aryl; R.sup.3
is heteroalkyl; and R.sup.4 is --OH.
[0242] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 and Y.sup.1 are both --O--; R.sup.1
and R.sup.2 are both H; and L.sup.1 is phenylene.
[0243] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 and Y.sup.1 are both --O--; R.sup.1
and R.sup.2 are both H; and L.sup.1 and X.sup.2 are both a covalent
bond.
[0244] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 and Y.sup.1 are both --O--; L.sup.1 is
--O--; R.sup.1 is H or alkyl; R.sup.2 is H; and X.sup.2 is
alkylene.
[0245] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 is --O--; Y.sup.2 is a covalent bond;
L.sup.1 is phenylene; R.sup.1 is H; R.sup.2 is aryl; and X.sup.2 is
alkylene.
[0246] In another embodiment of the compounds of formula Ia,
X.sup.1 is alkylene; Y.sup.1 is --NH--;
[0247] Y.sup.2 is --O--; L.sup.1 is phenylene; X.sup.2 is alkylene;
R.sup.1 is -alkylene-C(O)--O--R.sup.5; and R.sup.2 is phenyl.
[0248] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene; Y.sup.1 is --O-- or --NR.sup.5--;
Y.sup.2 is --O-- or --NR.sup.5--; L.sup.1 is arylene; L.sup.2 is
--O--; R.sup.1 is H, alkyl, or -alkylene-C(O)--O--R.sup.5; R.sup.2
is H, alkyl, or aryl; R.sup.3 is alkyl or heteroalkyl; and R.sup.4
is --NH(R.sup.5).
[0249] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--.
[0250] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--, R.sup.3
is alkyl or heteroalkyl, wherein the alkyl and heteroalkyl are any
alkyl and heteroalkyl defined and exemplified herein. Non-limiting
examples of alkyl or substituted alkyl include --CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH(alkyl),
--CH(substituted alkyl), --CH(heteroalkyl), --C(alkyl).sub.2,
--C(substituted alkyl).sub.2, --C(heteroalkyl).sub.2, --C(alkyl)
(substituted alkyl), --C(heteroalkyl) (substituted alkyl), and
--C(alkyl)(heteroalkyl), wherein alkyl, substituted alkyl, and
heteroalkyl are as defined and exemplified herein. Non-limiting
examples of alkyl or substituted alkyl include --OCH.sub.3,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --SCH.sub.3,
--CH.sub.2CH.sub.2--O--CH.sub.3, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).sub.2, --CH.sub.2--S--CH.sub.3,
--CH.sub.2CH.sub.2--OH, --CH.sub.2NH.sub.2, and
--CH.sub.2CH.sub.2--SH.
[0251] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--, R.sup.3
is -alkylene-O-alkyl.
[0252] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--, R.sup.3
is --CH.sub.2CH.sub.2--O--CH.sub.3.
[0253] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene.
[0254] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is --CH.sub.2--, --CH.sub.2Cl.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or --CH.sub.2CH(CH.sub.2)--.
[0255] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene.
[0256] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --X.sup.1-L.sup.1- is --CH.sub.2-phenylene-.
[0257] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is --O--.
[0258] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --X.sup.1-L.sup.1- is --CH.sub.2CH.sub.2--O-- or
--CH.sub.2CH(CH.sub.3)--O--.
[0259] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is a covalent bond.
[0260] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is alkylene.
[0261] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-CH.sub.2--.
[0262] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)-CH.sub.2--.
[0263] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is a covalent bond.
[0264] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is a covalent bond,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-.
[0265] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is a covalent bond,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-(1,3-phenylene)- or
--CH.sub.2-(1,4-phenylene)-.
[0266] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is
alkylene.
[0267] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is
--CH.sub.2--.
[0268] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
[0269] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH.sub.2-- or
--CH(CH.sub.3)--O--CH.sub.2CH.sub.2--.
[0270] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(aryl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-aryl)-O--CH.sub.2--.
[0271] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(aryl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-aryl)CH.sub.2--O--CH.sub.2--.
[0272] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(aryl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-aryl)CH.sub.2--.
[0273] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(aryl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-aryl)-.
[0274] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-arylalkyl)-O--CH.sub.2--.
[0275] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0276] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted arylalkyl)CH.sub.2--.
[0277] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-arylalkyl)-.
[0278] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(--O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted --O-arylalkyl)-O--CH.sub.2--.
[0279] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(--O-arylalkyl)CH.sub.2--O--CH.sub.2-- or --CH(substituted
--O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0280] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(--O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-O-arylalkyl)CH.sub.2--.
[0281] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(--O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted --O-arylalkyl)-.
[0282] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(-alkylene-O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted -alkylene-O-arylalkyl)-O--CH.sub.2--.
[0283] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(-alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted -alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0284] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(-alkylene-O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted alkylene-O-arylalkyl)CH.sub.2--.
[0285] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(-alkylene-O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted alkylene-O-arylalkyl)-.
[0286] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 and Y.sup.2 are each independently --O-- or
--NR.sup.5--.
[0287] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 and Y.sup.2 are both --O--.
[0288] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 and Y.sup.2 are each independently --O-- or
a covalent bond.
[0289] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0290] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and
R.sup.2 are each independently H or alkyl.
[0291] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and
R.sup.2 are each H.
[0292] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 and Y.sup.2 are each independently --O-- or
--NR.sup.5--, R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0293] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1
is alkyl or -alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl or
substituted aryl.
[0294] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1
is -alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl.
[0295] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, Y.sup.1 is --O--; Y.sup.2 is a covalent bond;
R.sup.1 is H; and R.sup.2 is alkyl, aryl, or substituted aryl.
[0296] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both
--O--; R.sup.1 and R.sup.2 are both H; and L.sup.1 is
phenylene.
[0297] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both
--O--; R.sup.1 and R.sup.2 are both H; and L.sup.1 and X.sup.2 are
both a covalent bond.
[0298] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both
--O--; L.sup.1 is --O--; R.sup.1 is H or alkyl; R.sup.2 is H; and
X.sup.2 is alkylene.
[0299] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene; Y.sup.1 is --O--; Y.sup.2 is a
covalent bond; L.sup.1 is phenylene; R.sup.1 is H; R.sup.2 is aryl;
and X.sup.2 is alkylene.
[0300] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, X.sup.1 is alkylene; Y.sup.1 is --NH--; Y.sup.2 is
--O--; L.sup.1 is phenylene; X.sup.2 is alkylene; R.sup.1 is
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is phenyl.
[0301] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene; Y.sup.1 is --O-- or --NR.sup.5--;
Y.sup.2 is --O-- or --NR.sup.5--; L.sup.1 is arylene; L.sup.2 is
--O--; R.sup.1 is H, alkyl, or -alkylene-C(O)--O--R.sup.5; R.sup.2
is H, alkyl, or aryl; R.sup.3 is alkyl or heteroalkyl; and R.sup.4
is --NH(R.sup.5).
[0302] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), L.sup.2 is --O--, --N(R.sup.5)--, or
--S--.
[0303] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), L.sup.2 is --O--, --N(R.sup.5)--, or
--S--, R.sup.3 is alkyl or heteroalkyl, wherein the alkyl and
heteroalkyl are any alkyl and heteroalkyl defined and exemplified
herein.
[0304] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), L.sup.2 is --O--, --N(R.sup.5)--, or
--S--, R.sup.3 is -alkylene-O-alkyl.
[0305] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), L.sup.2 is --O--, --N(R.sup.5)--, or
--S--, R.sup.3 is --CH.sub.2CH.sub.2--O--CH.sub.3.
[0306] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene.
[0307] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CH.sub.2CH(CH.sub.2)--.
[0308] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is arylene
or substituted arylene.
[0309] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), --X.sup.1-L.sup.1- is
--CH.sub.2-phenylene-.
[0310] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is
--O--.
[0311] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), --X.sup.1-L.sup.1- is
--CH.sub.2CH.sub.2O-- or --CH.sub.2CH(CH.sub.3)--.
[0312] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is a
covalent bond.
[0313] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is arylene
or substituted arylene, X.sup.2 is alkylene.
[0314] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-CH.sub.2--.
[0315] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)-CH.sub.2--.
[0316] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is arylene
or substituted arylene, X.sup.2 is a covalent bond.
[0317] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is arylene
or substituted arylene, X.sup.2 is a covalent bond,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-.
[0318] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is arylene
or substituted arylene, X.sup.2 is a covalent bond,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-(1,3-phenylene)- or
--CH.sub.2-(1,4-phenylene)-.
[0319] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is --,
X.sup.2 is alkylene.
[0320] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene, L.sup.1 is --,
X.sup.2 is --CH.sub.2--.
[0321] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
[0322] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH.sub.2-- or
--CH(CH.sub.3)--O--CH.sub.2CH.sub.2--.
[0323] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(aryl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-aryl)-O--CH.sub.2--.
[0324] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH(aryl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-aryl)CH.sub.2--O--CH.sub.2--.
[0325] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(aryl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-aryl)CH.sub.2--.
[0326] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(aryl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-aryl)-.
[0327] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-arylalkyl)-O--CH.sub.2--.
[0328] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH(arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0329] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted arylalkyl)CH.sub.2--.
[0330] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-arylalkyl)-.
[0331] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(--O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted --O-arylalkyl)-O--CH.sub.2--.
[0332] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH(--O-arylalkyl)CH.sub.2--O--CH.sub.2-- or --CH(substituted
--O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0333] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(--O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-O-arylalkyl)CH.sub.2--.
[0334] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(--O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted --O-arylalkyl)-.
[0335] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(-alkylene-O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted -alkylene-O-arylalkyl)-O--CH.sub.2--.
[0336] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH(-alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted -alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0337] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(-alkylene-O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted alkylene-O-arylalkyl)CH.sub.2--.
[0338] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(-alkylene-O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted alkylene-O-arylalkyl)-.
[0339] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 and Y.sup.2 are each
independently --O-- or --NR.sup.5--.
[0340] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 and Y.sup.2 are both --O--.
[0341] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 and Y.sup.2 are each
independently --O-- or a covalent bond.
[0342] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), R.sup.1 and R.sup.2 are each
independently H, alkyl, -alkylene-C(O)--O--R.sup.5, aryl, or
substituted aryl.
[0343] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 and Y.sup.2 are both --O--,
R.sup.1 and R.sup.2 are each independently H or alkyl.
[0344] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 and Y.sup.2 are both --O--,
R.sup.1 and R.sup.2 are each H.
[0345] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 and Y.sup.2 are each
independently --O-- or --NR.sup.5--, R.sup.1 and R.sup.2 are each
independently H, alkyl, -alkylene-C(O)--O--R.sup.5, aryl, or
substituted aryl.
[0346] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 is --NR.sup.5--; Y.sup.2 is
--O--; R.sup.1 is alkyl or -alkylene-C(O)--O--R.sup.5; and R.sup.2
is aryl or substituted aryl.
[0347] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 is --NR.sup.5--; Y.sup.2 is
--O--; R.sup.1 is -alkylene-C(O)--O--R.sup.5; and R.sup.2 is
aryl.
[0348] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), Y.sup.1 is --O--; Y.sup.2 is a covalent
bond; R.sup.1 is H; and R.sup.2 is alkyl, aryl, or substituted
aryl.
[0349] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene; Y.sup.1 and Y.sup.2
are both --O--; R.sup.1 and R.sup.2 are both H; and L.sup.1 is
phenylene.
[0350] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene; Y.sup.1 and Y.sup.2
are both --O--; R.sup.1 and R.sup.2 are both H; and L.sup.1 and
X.sup.2 are both a covalent bond.
[0351] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene; Y.sup.1 and Y.sup.2
are both --O--; L.sup.1 is --; R.sup.1 is H or alkyl; R.sup.2 is H;
and X.sup.2 is alkylene.
[0352] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene; Y.sup.1 is --O--;
Y.sup.2 is a covalent bond; L.sup.1 is phenylene; R.sup.1 is H;
R.sup.2 is aryl; and X.sup.2 is alkylene.
[0353] In another embodiment of the compounds of formula Ia,
R.sup.4 is --NH(R.sup.5), X.sup.1 is alkylene; Y.sup.1 is --NH--;
Y.sup.2 is --O--; L.sup.1 is phenylene; X.sup.2 is alkylene;
R.sup.1 is -alkylene-C(O)--O--R.sup.5; and R.sup.2 is phenyl.
[0354] In another embodiment of the compounds of formula Ia,
X.sup.1 and X.sup.2 are alkylene; Y.sup.1 is --O-- or --NR.sup.5--;
Y.sup.2 is --O-- or --NR.sup.5--; L.sup.1 is arylene; L.sup.2 is
--O--; R.sup.1 is H, alkyl, or -alkylene-C(O)--O--R.sup.5; R.sup.2
is H, alkyl, or aryl; R.sup.3 is alkyl or heteroalkyl; and R.sup.4
is --SH.
[0355] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--.
[0356] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--,
R.sup.3 is alkyl or heteroalkyl, wherein the alkyl and heteroalkyl
are any alkyl and heteroalkyl defined and exemplified herein.
[0357] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--,
R.sup.3 is -alkylene-O-alkyl.
[0358] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, L.sup.2 is --O--, --N(R.sup.5)--, or --S--,
R.sup.3 is --CH.sub.2CH.sub.2--O--CH.sub.3.
[0359] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene.
[0360] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or --CH.sub.2CH(CH.sub.2)--.
[0361] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene.
[0362] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, --X.sup.1-L.sup.1- is --CH.sub.2-phenylene-.
[0363] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is --O--.
[0364] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, --X.sup.1-L.sup.1- is --CH.sub.2CH.sub.2--O-- or
--CH.sub.2CH(CH.sub.3)--O--.
[0365] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is a covalent
bond.
[0366] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is alkylene.
[0367] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-CH.sub.2--.
[0368] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)-CH.sub.2--.
[0369] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is a covalent bond.
[0370] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is a covalent bond,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-.
[0371] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is arylene or
substituted arylene, X.sup.2 is a covalent bond,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-(1,3-phenylene)- or
--CH.sub.2-(1,4-phenylene)-.
[0372] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is
alkylene.
[0373] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is
--CH.sub.2--.
[0374] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
[0375] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH.sub.2-- or
--CH(CH.sub.3)--O--CH.sub.2CH.sub.2--.
[0376] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(aryl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-aryl)-O--CH.sub.2--.
[0377] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(aryl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-aryl)CH.sub.2--O--CH.sub.2--.
[0378] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(aryl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-aryl)CH.sub.2--.
[0379] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(aryl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-aryl)-.
[0380] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-arylalkyl)-O--CH.sub.2--.
[0381] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0382] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted arylalkyl)CH.sub.2--.
[0383] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-arylalkyl)-.
[0384] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(--O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted --O-arylalkyl)-O--CH.sub.2--.
[0385] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(--O-arylalkyl)CH.sub.2--O--CH.sub.2-- or --CH(substituted
--O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0386] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(--O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-O-arylalkyl)CH.sub.2--.
[0387] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(--O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted --O-arylalkyl)-.
[0388] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(-alkylene-O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted -alkylene-O-arylalkyl)-O--CH.sub.2--.
[0389] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH(-alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted -alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0390] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(-alkylene-O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted alkylene-O-arylalkyl)CH.sub.2--.
[0391] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(-alkylene-O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted alkylene-O-arylalkyl)-.
[0392] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 and Y.sup.2 are each independently --O--
or --NR.sup.5--.
[0393] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 and Y.sup.2 are both --O--.
[0394] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 and Y.sup.2 are each independently --O--
or a covalent bond.
[0395] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, R.sup.1 and R.sup.2 are each independently H,
alkyl, -alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0396] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and
R.sup.2 are each independently H or alkyl.
[0397] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and
R.sup.2 are each H.
[0398] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 and Y.sup.2 are each independently --O--
or --NR.sup.5--, R.sup.1 and R.sup.2 are each independently H,
alkyl, -alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0399] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1
is alkyl or -alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl or
substituted aryl.
[0400] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1
is -alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl.
[0401] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, Y.sup.1 is --O--; Y.sup.2 is a covalent bond;
R.sup.1 is H; and R.sup.2 is alkyl, aryl, or substituted aryl.
[0402] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both
--O--; R.sup.1 and R.sup.2 are both H; and L.sup.1 is
phenylene.
[0403] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both
--O--; R.sup.1 and R.sup.2 are both H; and L.sup.1 and X.sup.2 are
both a covalent bond.
[0404] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both
--O--; L.sup.1 is --O--; R.sup.1 is H or alkyl; R.sup.2 is H; and
X.sup.2 is alkylene.
[0405] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene; Y.sup.1 is --O--; Y.sup.2 is
a covalent bond; L.sup.1 is phenylene; R.sup.1 is H; R.sup.2 is
aryl; and X.sup.2 is alkylene.
[0406] In another embodiment of the compounds of formula Ia,
R.sup.4 is --SH, X.sup.1 is alkylene; Y.sup.1 is --NH--; Y.sup.2 is
--O--; L.sup.1 is phenylene; X.sup.2 is alkylene; R.sup.1 is
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is phenyl.
[0407] In another embodiment of the compounds of Formula Ia,
R.sup.4 is OH, and
X.sup.1-L.sup.1-X.sup.2--P(O)(Y.sup.1R.sup.1)(Y.sup.2R.sup.2) is:
##STR7##
[0408] wherein Z.sup.2 is selected from the group consisting of
halo, alkyl, haloalkyl, and alkoxy.
[0409] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, --NH(R.sup.5), X.sup.1 and X.sup.2 are
alkylene; Y.sup.1 is --O-- or --NR.sup.5--; Y.sup.2 is --O-- or
--NR.sup.5--; L.sup.1 is arylene; R.sup.1 is H, alkyl, or
-alkylene-C(O)--O--R.sup.5; R.sup.2 is H, alkyl, or aryl; R.sup.3
is alkyl or heteroalkyl; L.sup.2 is a bond, R.sup.3 is a
substituted alkyl, wherein the substituted alkyl is alkyl defined
or exemplified herein. The substituents may include amino, amido,
heteroalkyl, etc. Non-limiting examples of substituted alkyl
include --CH.sub.2--NH.sub.2, --CH.sub.2--NH--C(O)--CH.sub.3,
--CH.sub.2--C(O)--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--C(O)--CH.sub.3,
--CH.sub.2--CH.sub.2--C(O)--NH--CH.sub.3,
--CH.sub.2--NH--C(O)--CH.sub.2--CH.sub.3,
--CH.sub.2--C(O)--NH--CH.sub.2--CH.sub.3,
--CH.sub.2CH.sub.2--O--CH.sub.3,
--CH.sub.2CH(CH.sub.3)--O--CH.sub.3,
--CH.sub.2--O--CH.sub.2--CH.sub.3,
--CH.sub.2--O--CH(CH.sub.3)CH.sub.3,
--CH.sub.2CH.sub.2--S--CH.sub.3 or
--CH.sub.2--S--CH(CH.sub.3)CH.sub.3,
--CH.sub.2--S--CH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2--NH.sub.2--CH.sub.3,
--CH.sub.2CH(CH.sub.3)--NH.sub.2--CH.sub.3,
--CH.sub.2--NH.sub.2--CH.sub.2CH.sub.3,
--CH.sub.2--NH.sub.2--CH(CH.sub.3)CH.sub.3.
[0410] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent,
R.sup.3 is --CH.sub.2--NH.sub.2, --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or --CH.sub.2CH(CH.sub.2)--.
[0411] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene.
[0412] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
--X.sup.1-L.sup.1- is --CH.sub.2-phenylene-.
[0413] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is --O--.
[0414] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
--X.sup.1-L.sup.1- is --CH.sub.2CH.sub.2--O-- or
--CH.sub.2CH(CH.sub.3)--O--.
[0415] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is a covalent bond.
[0416] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is alkylene.
[0417] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2-phenylene-CH.sub.2--.
[0418] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)-CH.sub.2--.
[0419] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is a covalent bond.
[0420] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2, or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is a covalent bond, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-phenylene-.
[0421] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is arylene or substituted arylene,
X.sup.2 is a covalent bond, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2-(1,3-phenylene)- or --CH.sub.2-(1,4-phenylene)-.
[0422] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is alkylene.
[0423] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, L.sup.1 is --O--, X.sup.2 is --CH.sub.2--.
[0424] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH.sub.2--O--CH.sub.2-- or
--CH.sub.2CH(CH.sub.3)--O--CH.sub.2--.
[0425] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH.sub.2-- or
--CH(CH.sub.3)--O--CH.sub.2CH.sub.2--.
[0426] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(aryl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-aryl)-O--CH.sub.2--.
[0427] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH(aryl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-aryl)CH.sub.2--O--CH.sub.2--.
[0428] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(aryl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-aryl)CH.sub.2--.
[0429] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(aryl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-aryl)-.
[0430] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted-arylalkyl)-O--CH.sub.2--.
[0431] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH(arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0432] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted arylalkyl)CH.sub.2--.
[0433] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted-arylalkyl)-.
[0434] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(--O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted --O-arylalkyl)-O--CH.sub.2--.
[0435] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH(--O-arylalkyl)CH.sub.2--O--CH.sub.2-- or --CH(substituted
--O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0436] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(--O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted-O-arylalkyl)CH.sub.2--.
[0437] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(--O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted --O-arylalkyl)-.
[0438] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH(-alkylene-O-arylalkyl)-O--CH.sub.2-- or
--CH.sub.2CH(substituted -alkylene-O-arylalkyl)-O--CH.sub.2--.
[0439] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH(-alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2-- or
--CH(substituted -alkylene-O-arylalkyl)CH.sub.2--O--CH.sub.2--.
[0440] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH(-alkylene-O-arylalkyl)CH.sub.2-- or
--CH.sub.2--O--CH(substituted alkylene-O-arylalkyl)CH.sub.2--.
[0441] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene, X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2--O--CH.sub.2CH(-alkylene-O-arylalkyl)- or
--CH.sub.2--O--CH.sub.2CH(substituted alkylene-O-arylalkyl)-.
[0442] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 and Y.sup.2 are each independently --O-- or
--NR.sup.5--.
[0443] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 and Y.sup.2 are both --O--.
[0444] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 and Y.sup.2 are each independently --O-- or a covalent
bond.
[0445] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0446] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and R.sup.2 are each
independently H or alkyl.
[0447] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 and Y.sup.2 are both --O--, R.sup.1 and R.sup.2 are each
H.
[0448] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 and Y.sup.2 are each independently --O-- or --NR.sup.5--,
R.sup.1 and R.sup.2 are each independently H, alkyl,
-alkylene-C(O)--O--R.sup.5, aryl, or substituted aryl.
[0449] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1 is alkyl or
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl or substituted
aryl.
[0450] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 is --NR.sup.5--; Y.sup.2 is --O--; R.sup.1 is
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is aryl.
[0451] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
Y.sup.1 is --O--; Y.sup.2 is a covalent bond; R.sup.1 is H; and
R.sup.2 is alkyl, aryl, or substituted aryl.
[0452] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both --O--; R.sup.1
and R.sup.2 are both H; and L.sup.1 is phenylene.
[0453] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both --O--; R.sup.1
and R.sup.2 are both H; and L.sup.1 and X.sup.2 are both a covalent
bond.
[0454] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene; Y.sup.1 and Y.sup.2 are both --O--; L.sup.1 is
--O--; R.sup.1 is H or alkyl; R.sup.2 is H; and X.sup.2 is
alkylene.
[0455] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene; Y.sup.1 is --O--; Y.sup.2 is a covalent bond;
L.sup.1 is phenylene; R.sup.1 is H; R.sup.2 is aryl; and X.sup.2 is
alkylene.
[0456] In another embodiment of the compounds of formula Ia,
R.sup.4 is OH, --SH, or --NH(R.sup.5), L.sup.2 is a covalent bond,
R.sup.3 is --CH.sub.2--NH.sub.2 or --CH.sub.2--NH--C(O)--CH.sub.3,
X.sup.1 is alkylene; Y.sup.1 is --NH--; Y.sup.2 is --O--; L.sup.1
is phenylene; X.sup.2 is alkylene; R.sup.1 is
-alkylene-C(O)--O--R.sup.5; and R.sup.2 is phenyl.
[0457] In the above embodiments of the compounds of formula Ia,
each R.sup.5, R.sup.6, and R.sup.7 are independently H, alkyl,
substituted alkyl, carbocyclyl, substituted carbocyclyl,
heterocyclyl, substituted heterocyclyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.
[0458] In another embodiment of the compounds of formula Ia, the
compound is selected from the group consisting of: ##STR8##
##STR9## ##STR10## ##STR11## ##STR12## ##STR13## ##STR14##
##STR15## ##STR16## ##STR17## ##STR18##
[0459] or pharmaceutically acceptable salts, solvates, and/or
esters thereof.
Compounds of Formula IIa
[0460] In one embodiment, the present application provides
compounds according to Formula IIa, as described herein.
[0461] In another embodiment of the compounds of formula IIa,
X.sup.1 is alkylene, substituted alkylene, alkenylene, substituted
alkenylene, alkynylene, or substituted alkynylene.
[0462] In another embodiment of the compounds of formula IIa,
X.sup.1 is --CH.sub.2-- or --CH.sub.2CH.sub.2--.
[0463] In another embodiment of the compounds of formula IIa,
X.sup.1 is carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene.
[0464] In another embodiment of the compounds of formula IIa,
X.sup.1 is ##STR19## wherein Z is O, NR.sup.7, or S; each R.sup.6
is independently halo, hydroxyl, amino, cyano, alkyl, substituted
alkyl, alkoxy, N-alkyl amino, N,N-dialkyl amino, carbocyclyl,
substituted carbocyclyl, heterocyclyl, substituted heterocyclyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; R.sup.7 is H, alkyl, substituted alkyl,
carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted
heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or
substituted heterocyclylalkyl; n is 1, 2, 3, 4, or 5; and when n is
1, then m is 0, 1, or 2; when n is 2, then m is 0, 1, 2, or 3; when
n is 3, then m is 0, 1, 2, 3, or 4; when n is 4, then m is 0, 1, 2,
3, 4, or 5; and when n is 5, then m is 0, 1, 2, 3, 4, 5, or 6.
[0465] In another embodiment of the compounds of formula IIa,
L.sup.1 is a covalent bond.
[0466] In another embodiment of the compounds of formula Ia,
L.sup.1 is --NR.sup.3-- or --O--.
[0467] In another embodiment of the compounds of formula IIa,
L.sup.1 is arylene, substituted arylene, heterocyclylene,
substituted heterocyclylene, carbocyclylene, or substituted
carbocyclylene.
[0468] In another embodiment of the compounds of formula IIa,
L.sup.1 is ##STR20## wherein m is 0, 1, 2, 3, or 4; and each
R.sup.6 is independently H, halo, hydroxyl, amino, cyano, alkyl
substituted alkyl, alkoxy, N-alkyl amino, N,N-dialkyl amino,
carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted
heterocyclyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or
substituted heterocyclylalkyl.
[0469] In another embodiment of the compounds of formula IIa,
Y.sup.1 is a covalent bond; and Y.sup.2 is --O-- or
--NR.sup.4--.
[0470] In another embodiment of the compounds of formula IIa,
Y.sup.1 is --O--; and Y.sup.2 NR.sup.4--.
[0471] In another embodiment of the compounds of formula IIa,
Y.sup.1 and Y.sup.2 are both --O--.
[0472] In another embodiment of the compounds of formula IIa,
Y.sup.1 and Y.sup.2 are both --NR.sup.4--.
[0473] In another embodiment of the compounds of formula IIa,
R.sup.1 and R.sup.2 are each independently H, alkyl, or substituted
alkyl.
[0474] In another embodiment of the compounds of formula IIa,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is a covalent
bond; and X.sup.2 is a covalent bond, alkylene, or substituted
alkylene.
[0475] In another embodiment of the compounds of formula IIa,
--X.sup.1-L.sup.1-X.sup.2-- is --CH.sub.2CH.sub.2--.
[0476] In another embodiment of the compounds of formula IIa,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is a covalent
bond; and X.sup.2 is a covalent bond, alkylene, or substituted
alkylene; Y.sup.1 and Y.sup.2 are both --O--; and R.sup.1 and
R.sup.2 are each independently H, alkyl, or substituted alkyl.
[0477] In another embodiment of the compounds of formula IIa,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is
--NR.sup.3-- or --O--; and X.sup.2 is a covalent bond, alkylene, or
substituted alkylene.
[0478] In another embodiment of the compounds of formula IIa,
--X.sup.1-L.sup.1-X.sup.2-- is
--CH.sub.2CH.sub.2--O--CH.sub.2--.
[0479] In another embodiment of the compounds of formula IIa,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is
--NR.sup.3-- or --O--; and X.sup.2 is a covalent bond, alkylene, or
substituted alkylene; Y.sup.1 and Y.sup.2 are both --O--; and
R.sup.1 and R.sup.2 are each independently H, alkyl, or substituted
alkyl.
[0480] In another embodiment of the compounds of formula IIa,
X.sup.1 is alkylene or substituted alkylene; L.sup.1 is arylene,
substituted arylene, heterocyclylene, substituted heterocyclylene,
carbocyclylene, or substituted carbocyclylene; and X.sup.2 is a
covalent bond, alkylene, or substituted alkylene.
[0481] In another embodiment of the compounds of formula IIa,
X.sup.1 is carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; L.sup.1 is a
covalent bond; and X.sup.2 is a covalent bond, alkylene, or
substituted alkylene.
[0482] In another embodiment of the compounds of formula IIa,
--X.sup.1-L.sup.1-X.sup.2-- is ##STR21##
[0483] In another embodiment of the compounds of formula IIa,
X.sup.1 is carbocyclylene, substituted carbocyclylene,
heterocyclylene, or substituted heterocyclylene; L.sup.1 is a
covalent bond; X.sup.2 is a covalent bond, alkylene, or substituted
alkylene; Y.sup.1 and Y.sup.2 are both --O--; and R.sup.1 and
R.sup.2 are each independently H, alkyl, or substituted alkyl.
[0484] In the above embodiments of the compounds of formula Ia,
each R.sup.3, R.sup.4, and R.sup.1 are independently H, alkyl,
substituted alkyl, carbocyclyl, substituted carbocyclyl,
heterocyclyl, substituted heterocyclyl, alkenyl, substituted
alkenyl, alkynyl, substituted alkynyl, arylalkyl, substituted
arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.
[0485] In another embodiment of the compounds of formula IIa, the
compound is selected from the group consisting of: ##STR22##
[0486] or pharmaceutically acceptable salts, solvates, and/or
esters thereof.
[0487] In still yet another embodiment, compounds of Formula I or
II are named below in tabular format (Table 6) as compounds of
general Formula III: ##STR23##
[0488] Compounds of general Formula I or II are depicted as a
"core" structure (C) substituted with four moieties T1, T2, T3 and
T4. The core structures C are depicted in Table 1. The points of
attachment of T1, T2, T3 and T4 are indicated on each of the core
structures depicted in Table 1. Tables 2-5, respectively, show the
structures of the T1, T2, T3 and T4 moieties. The point of
attachment of the core structure C is indicated in each of the
structures of T1, T2, T3 and T4. The core structure C in Table 1,
and each substituent T1, T2, T3 and T4 in Tables 2-5 are
represented by a "code" comprising a letter and a number. Each
structure of a compound of Formula III can be designated in tabular
form by combining the "code" representing each structural moiety
using the following syntax: T1.T2.T3.T4. Thus, for example, T1A,
T2A, T3A and T4A represents the following structure: ##STR24##
[0489] In the structures depicted in Tables 1-5, the term "Alk"
means a substituted or unsubstituted alkyl or alkylene group,
wherein the terms "alkyl" and "alkylene" are as defined herein.
"Alk" means an alkyl group when depicted as monovalent, and an
alkylene group when depicted as divalent. "Het" is a substituted or
unsubstituted heterocyclyl or heterocyclylene group, wherein the
term "heterocyclyl" is as defined herein, and the term
"heterocyclylene" means a heterocyclyl group as defined herein, in
which a hydrogen atom has been replaced by an open valence (in
analogy to alkylene), thereby defining a divalent heterocyclyl.
"Het" is a heterocyclyl when depicted as monovalent, and
heterocyclylene when depicted as divalent. "Ar" is a substitute or
unsubstituted aryl or arylene group, wherein the term "aryl" is as
defined herein, and the term "arylene" means an aryl group as
defined herein, in which a hydrogen atom has been replaced by an
open valence (in analogy to alkylene), thereby defining a divalent
aryl. "Ar" is aryl when depicted as monovalent, and arylene when
depicted as divalent. When substituted, "Alk", "Het", and "Ar" can
be substituted with any of the substituents defined or exemplified
herein. For example, substituents of "Alk" can include ether,
halogen, --OH, amide, amine, etc., substituents of "Het" can
include alkyl, aryl, carbonyl, --OH, halogen, and substituents of
"Ar" can include alkyl, aryl, --OH, halogen, etc., with the proviso
that the resulting structure is chemically reasonable, and would
provide compounds which are sufficiently stable for formulation in
a pharmaceutically acceptable composition. TABLE-US-00001 TABLE 1
Core Structure Code Subgenus Structure C1 ##STR25##
[0490] TABLE-US-00002 TABLE 2 T1 Structures Label T1 Structure T1A
--O-alkyl T1B --O-alkylene-O-alkyl T1C --S-alkyl T1D
--NH-substituted or unsubstituted alkyl T1E alkyl
[0491] TABLE-US-00003 TABLE 3 T2 Structures Label T2 Structure T2A
--OH T2B --SH T2C --NH-alkyl T2D --NH-aryl T2E --NH.sub.2 T2F
--NH-(heterocyclylalkyl)
[0492] TABLE-US-00004 TABLE 4 T3 Structures Label T3 Structure T3A
-alkylene-arylene-alkylene-T4 (substituted or unsubstituted) T3B
-alkylene-O-alkylene-T4 (substituted or unsubstituted) T3C
-alkylene-T4 (substituted or unsubstituted) T3D
-alkylene-arylene-T4 (substituted or unsubstituted) T3E
-alkylene-carbocyclylene-alkylene-T4 (substituted or unsubstituted)
T3F -alkylene-heteroarylene-alkylene-T4 (substituted or
unsubstituted) T3G -alkylene-heteroarylene-T4 (substituted or
unsubstituted)
[0493] TABLE-US-00005 TABLE 5 T4 Structures Label T4 Structure T4A
--P(O)(OH).sub.2 T4B --P(O)(O-aryl)(NH-substituted or unsubstituted
alkylene-C(O)--O-alkyl) T4C --P(O)(substituted or unsubstituted
alkyl)(OH) T4D --P(O)(aryl)(O-substituted or unsubstituted alkyl)
T4E --P(O)(NH-substituted or unsubstituted
alkylene-C(O)--O-alkyl).sub.2 T4F --P(O)(arylalkyl)(OH)
[0494] TABLE-US-00006 TABLE 6 List of Compound Structure of Formula
III with the core structure (C1) T1A.T2A.T3A.T4A, T1B.T2A.T3A.T4A,
T1C.T2A.T3A.T4A, T1D.T2A.T3A.T4A, T1E.T2A.T3A.T4A, T1A.T2B.T3A.T4A,
T1B.T2B.T3A.T4A, T1C.T2B.T3A.T4A, T1D.T2B.T3A.T4A, T1E.T2B.T3A.T4A,
T1A.T2C.T3A.T4A, T1B.T2C.T3A.T4A, T1C.T2C.T3A.T4A, T1D.T2C.T3A.T4A,
T1E.T2C.T3A.T4A, T1A.T2D.T3A.T4A, T1B.T2D.T3A.T4A, T1C.T2D.T3A.T4A,
T1D.T2D.T3A.T4A, T1E.T2D.T3A.T4A, T1A.T2E.T3A.T4A, T1B.T2E.T3A.T4A,
T1C.T2E.T3A.T4A, T1D.T2E.T3A.T4A, T1E.T2E.T3A.T4A, T1A.T2F.T3A.T4A,
T1B.T2F.T3A.T4A, T1C.T2F.T3A.T4A, T1D.T2F.T3A.T4A, T1E.T2F.T3A.T4A,
T1A.T2A.T3B.T4A, T1B.T2A.T3B.T4A, T1C.T2A.T3B.T4A, T1D.T2A.T3B.T4A,
T1E.T2A.T3B.T4A, T1A.T2B.T3B.T4A, T1B.T2B.T3B.T4A, T1C.T2B.T3B.T4A,
T1D.T2B.T3B.T4A, T1E.T2B.T3B.T4A, T1A.T2C.T3B.T4A, T1B.T2C.T3B.T4A,
T1C.T2C.T3B.T4A, T1D.T2C.T3B.T4A, T1E.T2C.T3B.T4A, T1A.T2D.T3B.T4A,
T1B.T2D.T3B.T4A, T1C.T2D.T3B.T4A, T1D.T2D.T3B.T4A, T1E.T2D.T3B.T4A,
T1A.T2E.T3B.T4A, T1B.T2E.T3B.T4A, T1C.T2E.T3B.T4A, T1D.T2E.T3B.T4A,
T1E.T2E.T3B.T4A, T1A.T2F.T3B.T4A, T1B.T2F.T3B.T4A, T1C.T2F.T3B.T4A,
T1D.T2F.T3B.T4A, T1E.T2F.T3B.T4A, T1A.T2A.T3C.T4A, T1B.T2A.T3C.T4A,
T1C.T2A.T3C.T4A, T1D.T2A.T3C.T4A, T1E.T2A.T3C.T4A, T1A.T2B.T3C.T4A,
T1B.T2B.T3C.T4A, T1C.T2B.T3C.T4A, T1D.T2B.T3C.T4A, T1E.T2B.T3C.T4A,
T1A.T2C.T3C.T4A, T1B.T2C.T3C.T4A, T1C.T2C.T3C.T4A, T1D.T2C.T3C.T4A,
T1E.T2C.T3C.T4A, T1A.T2D.T3C.T4A, T1B.T2D.T3C.T4A, T1C.T2D.T3C.T4A,
T1D.T2D.T3C.T4A, T1E.T2D.T3C.T4A, T1A.T2E.T3C.T4A, T1B.T2E.T3C.T4A,
T1C.T2E.T3C.T4A, T1D.T2E.T3C.T4A, T1E.T2E.T3C.T4A, T1A.T2F.T3C.T4A,
T1B.T2F.T3C.T4A, T1C.T2F.T3C.T4A, T1D.T2F.T3C.T4A, T1E.T2F.T3C.T4A,
T1A.T2A.T3D.T4A, T1B.T2A.T3D.T4A, T1C.T2A.T3D.T4A, T1D.T2A.T3D.T4A,
T1E.T2A.T3D.T4A, T1A.T2B.T3D.T4A, T1B.T2B.T3D.T4A, T1C.T2B.T3D.T4A,
T1D.T2B.T3D.T4A, T1E.T2B.T3D.T4A, T1A.T2C.T3D.T4A, T1B.T2C.T3D.T4A,
T1C.T2C.T3D.T4A, T1D.T2C.T3D.T4A, T1E.T2C.T3D.T4A, T1A.T2D.T3D.T4A,
T1B.T2D.T3D.T4A, T1C.T2D.T3D.T4A, T1D.T2D.T3D.T4A, T1E.T2D.T3D.T4A,
T1A.T2E.T3D.T4A, T1B.T2E.T3D.T4A, T1C.T2E.T3D.T4A, T1D.T2E.T3D.T4A,
T1E.T2E.T3D.T4A, T1A.T2F.T3D.T4A, T1B.T2F.T3D.T4A, T1C.T2F.T3D.T4A,
T1D.T2F.T3D.T4A, T1E.T2F.T3D.T4A, T1A.T2A.T3E.T4A, T1B.T2A.T3E.T4A,
T1C.T2A.T3E.T4A, T1D.T2A.T3E.T4A, T1E.T2A.T3E.T4A, T1A.T2B.T3E.T4A,
T1B.T2B.T3E.T4A, T1C.T2B.T3E.T4A, T1D.T2B.T3E.T4A, T1E.T2B.T3E.T4A,
T1A.T2C.T3E.T4A, T1B.T2C.T3E.T4A, T1C.T2C.T3E.T4A, T1D.T2C.T3E.T4A,
T1E.T2C.T3E.T4A, T1A.T2D.T3E.T4A, T1B.T2D.T3E.T4A, T1C.T2D.T3E.T4A,
T1D.T2D.T3E.T4A, T1E.T2D.T3E.T4A, T1A.T2E.T3E.T4A, T1B.T2E.T3E.T4A,
T1C.T2E.T3E.T4A, T1D.T2E.T3E.T4A, T1E.T2E.T3E.T4A, T1A.T2F.T3E.T4A,
T1B.T2F.T3E.T4A, T1C.T2F.T3E.T4A, T1D.T2F.T3E.T4A, T1E.T2F.T3E.T4A,
T1A.T2A.T3F.T4A, T1B.T2A.T3F.T4A, T1C.T2A.T3F.T4A, T1D.T2A.T3F.T4A,
T1E.T2A.T3F.T4A, T1A.T2B.T3F.T4A, T1B.T2B.T3F.T4A, T1C.T2B.T3F.T4A,
T1D.T2B.T3F.T4A, T1E.T2B.T3F.T4A, T1A.T2C.T3F.T4A, T1B.T2C.T3F.T4A,
T1C.T2C.T3F.T4A, T1D.T2C.T3F.T4A, T1E.T2C.T3F.T4A, T1A.T2D.T3F.T4A,
T1B.T2D.T3F.T4A, T1C.T2D.T3F.T4A, T1D.T2D.T3F.T4A, T1E.T2D.T3F.T4A,
T1A.T2E.T3F.T4A, T1B.T2E.T3F.T4A, T1C.T2E.T3F.T4A, T1D.T2E.T3F.T4A,
T1E.T2E.T3F.T4A, T1A.T2F.T3F.T4A, T1B.T2F.T3F.T4A, T1C.T2F.T3F.T4A,
T1D.T2F.T3F.T4A, T1E.T2F.T3F.T4A, T1A.T2A.T3G.T4A, T1B.T2A.T3G.T4A,
T1C.T2A.T3G.T4A, T1D.T2A.T3G.T4A, T1E.T2A.T3G.T4A, T1A.T2B.T3G.T4A,
T1B.T2B.T3G.T4A, T1C.T2B.T3G.T4A, T1D.T2B.T3G.T4A, T1E.T2B.T3G.T4A,
T1A.T2C.T3G.T4A, T1B.T2C.T3G.T4A, T1C.T2C.T3G.T4A, T1D.T2C.T3G.T4A,
T1E.T2C.T3G.T4A, T1A.T2D.T3G.T4A, T1B.T2D.T3G.T4A, T1C.T2D.T3G.T4A,
T1D.T2D.T3G.T4A, T1E.T2D.T3G.T4A, T1A.T2E.T3G.T4A, T1B.T2E.T3G.T4A,
T1C.T2E.T3G.T4A, T1D.T2E.T3G.T4A, T1E.T2E.T3G.T4A, T1A.T2F.T3G.T4A,
T1B.T2F.T3G.T4A, T1C.T2F.T3G.T4A, T1D.T2F.T3G.T4A, T1E.T2F.T3G.T4A,
T1A.T2A.T3A.T4B, T1B.T2A.T3A.T4B, T1C.T2A.T3A.T4B, T1D.T2A.T3A.T4B,
T1E.T2A.T3A.T4B, T1A.T2B.T3A.T4B, T1B.T2B.T3A.T4B, T1C.T2B.T3A.T4B,
T1D.T2B.T3A.T4B, T1E.T2B.T3A.T4B, T1A.T2C.T3A.T4B, T1B.T2C.T3A.T4B,
T1C.T2C.T3A.T4B, T1D.T2C.T3A.T4B, T1E.T2C.T3A.T4B, T1A.T2D.T3A.T4B,
T1B.T2D.T3A.T4B, T1C.T2D.T3A.T4B, T1D.T2D.T3A.T4B, T1E.T2D.T3A.T4B,
T1A.T2E.T3A.T4B, T1B.T2E.T3A.T4B, T1C.T2E.T3A.T4B, T1D.T2E.T3A.T4B,
T1E.T2E.T3A.T4B, T1A.T2F.T3A.T4B, T1B.T2F.T3A.T4B, T1C.T2F.T3A.T4B,
T1D.T2F.T3A.T4B, T1E.T2F.T3A.T4B, T1A.T2A.T3B.T4B, T1B.T2A.T3B.T4B,
T1C.T2A.T3B.T4B, T1D.T2A.T3B.T4B, T1E.T2A.T3B.T4B, T1A.T2B.T3B.T4B,
T1B.T2B.T3B.T4B, T1C.T2B.T3B.T4B, T1D.T2B.T3B.T4B, T1E.T2B.T3B.T4B,
T1A.T2C.T3B.T4B, T1B.T2C.T3B.T4B, T1C.T2C.T3B.T4B, T1D.T2C.T3B.T4B,
T1E.T2C.T3B.T4B, T1A.T2D.T3B.T4B, T1B.T2D.T3B.T4B, T1C.T2D.T3B.T4B,
T1D.T2D.T3B.T4B, T1E.T2D.T3B.T4B, T1A.T2E.T3B.T4B, T1B.T2E.T3B.T4B,
T1C.T2E.T3B.T4B, T1D.T2E.T3B.T4B, T1E.T2E.T3B.T4B, T1A.T2F.T3B.T4B,
T1B.T2F.T3B.T4B, T1C.T2F.T3B.T4B, T1D.T2F.T3B.T4B, T1E.T2F.T3B.T4B,
T1A.T2A.T3C.T4B, T1B.T2A.T3C.T4B, T1C.T2A.T3C.T4B, T1D.T2A.T3C.T4B,
T1E.T2A.T3C.T4B, T1A.T2B.T3C.T4B, T1B.T2B.T3C.T4B, T1C.T2B.T3C.T4B,
T1D.T2B.T3C.T4B, T1E.T2B.T3C.T4B, T1A.T2C.T3C.T4B, T1B.T2C.T3C.T4B,
T1C.T2C.T3C.T4B, T1D.T2C.T3C.T4B, T1E.T2C.T3C.T4B, T1A.T2D.T3C.T4B,
T1B.T2D.T3C.T4B, T1C.T2D.T3C.T4B, T1D.T2D.T3C.T4B, T1E.T2D.T3C.T4B,
T1A.T2E.T3C.T4B, T1B.T2E.T3C.T4B, T1C.T2E.T3C.T4B, T1D.T2E.T3C.T4B,
T1E.T2E.T3C.T4B, T1A.T2F.T3C.T4B, T1B.T2F.T3C.T4B, T1C.T2F.T3C.T4B,
T1D.T2F.T3C.T4B, T1E.T2F.T3C.T4B, T1A.T2A.T3D.T4B, T1B.T2A.T3D.T4B,
T1C.T2A.T3D.T4B, T1D.T2A.T3D.T4B, T1E.T2A.T3D.T4B, T1A.T2B.T3D.T4B,
T1B.T2B.T3D.T4B, T1C.T2B.T3D.T4B, T1D.T2B.T3D.T4B, T1E.T2B.T3D.T4B,
T1A.T2C.T3D.T4B, T1B.T2C.T3D.T4B, T1C.T2C.T3D.T4B, T1D.T2C.T3D.T4B,
T1E.T2C.T3D.T4B, T1A.T2D.T3D.T4B, T1B.T2D.T3D.T4B, T1C.T2D.T3D.T4B,
T1D.T2D.T3D.T4B, T1E.T2D.T3D.T4B, T1A.T2E.T3D.T4B, T1B.T2E.T3D.T4B,
T1C.T2E.T3D.T4B, T1D.T2E.T3D.T4B, T1E.T2E.T3D.T4B, T1A.T2F.T3D.T4B,
T1B.T2F.T3D.T4B, T1C.T2F.T3D.T4B, T1D.T2F.T3D.T4B, T1E.T2F.T3D.T4B,
T1A.T2A.T3E.T4B, T1B.T2A.T3E.T4B, T1C.T2A.T3E.T4B, T1D.T2A.T3E.T4B,
T1E.T2A.T3E.T4B, T1A.T2B.T3E.T4B, T1B.T2B.T3E.T4B, T1C.T2B.T3E.T4B,
T1D.T2B.T3E.T4B, T1E.T2B.T3E.T4B, T1A.T2C.T3E.T4B, T1B.T2C.T3E.T4B,
T1C.T2C.T3E.T4B, T1D.T2C.T3E.T4B, T1E.T2C.T3E.T4B, T1A.T2D.T3E.T4B,
T1B.T2D.T3E.T4B, T1C.T2D.T3E.T4B, T1D.T2D.T3E.T4B, T1E.T2D.T3E.T4B,
T1A.T2E.T3E.T4B, T1B.T2E.T3E.T4B, T1C.T2E.T3E.T4B, T1D.T2E.T3E.T4B,
T1E.T2E.T3E.T4B, T1A.T2F.T3E.T4B, T1B.T2F.T3E.T4B, T1C.T2F.T3E.T4B,
T1D.T2F.T3E.T4B, T1E.T2F.T3E.T4B, T1A.T2A.T3F.T4B, T1B.T2A.T3F.T4B,
T1C.T2A.T3F.T4B, T1D.T2A.T3F.T4B, T1E.T2A.T3F.T4B, T1A.T2B.T3F.T4B,
T1B.T2B.T3F.T4B, T1C.T2B.T3F.T4B, T1D.T2B.T3F.T4B, T1E.T2B.T3F.T4B,
T1A.T2C.T3F.T4B, T1B.T2C.T3F.T4B, T1C.T2C.T3F.T4B, T1D.T2C.T3F.T4B,
T1E.T2C.T3F.T4B, T1A.T2D.T3F.T4B, T1B.T2D.T3F.T4B, T1C.T2D.T3F.T4B,
T1D.T2D.T3F.T4B, T1E.T2D.T3F.T4B, T1A.T2E.T3F.T4B, T1B.T2E.T3F.T4B,
T1C.T2E.T3F.T4B, T1D.T2E.T3F.T4B, T1E.T2E.T3F.T4B, T1A.T2F.T3F.T4B,
T1B.T2F.T3F.T4B, T1C.T2F.T3F.T4B, T1D.T2F.T3F.T4B, T1E.T2F.T3F.T4B,
T1A.T2A.T3G.T4B, T1B.T2A.T3G.T4B, T1C.T2A.T3G.T4B, T1D.T2A.T3G.T4B,
T1E.T2A.T3G.T4B, T1A.T2B.T3G.T4B, T1B.T2B.T3G.T4B, T1C.T2B.T3G.T4B,
T1D.T2B.T3G.T4B, T1E.T2B.T3G.T4B, T1A.T2C.T3G.T4B, T1B.T2C.T3G.T4B,
T1C.T2C.T3G.T4B, T1D.T2C.T3G.T4B, T1E.T2C.T3G.T4B, T1A.T2D.T3G.T4B,
T1B.T2D.T3G.T4B, T1C.T2D.T3G.T4B, T1D.T2D.T3G.T4B, T1E.T2D.T3G.T4B,
T1A.T2E.T3G.T4B, T1B.T2E.T3G.T4B, T1C.T2E.T3G.T4B, T1D.T2E.T3G.T4B,
T1E.T2E.T3G.T4B, T1A.T2F.T3G.T4B, T1B.T2F.T3G.T4B, T1C.T2F.T3G.T4B,
T1D.T2F.T3G.T4B, T1E.T2F.T3G.T4B, T1A.T2A.T3A.T4C, T1B.T2A.T3A.T4C,
T1C.T2A.T3A.T4C, T1D.T2A.T3A.T4C, T1E.T2A.T3A.T4C, T1A.T2B.T3A.T4C,
T1B.T2B.T3A.T4C, T1C.T2B.T3A.T4C, T1D.T2B.T3A.T4C, T1E.T2B.T3A.T4C,
T1A.T2C.T3A.T4C, T1B.T2C.T3A.T4C, T1C.T2C.T3A.T4C, T1D.T2C.T3A.T4C,
T1E.T2C.T3A.T4C, T1A.T2D.T3A.T4C, T1B.T2D.T3A.T4C, T1C.T2D.T3A.T4C,
T1D.T2D.T3A.T4C, T1E.T2D.T3A.T4C, T1A.T2E.T3A.T4C, T1B.T2E.T3A.T4C,
T1C.T2E.T3A.T4C, T1D.T2E.T3A.T4C, T1E.T2E.T3A.T4C, T1A.T2F.T3A.T4C,
T1B.T2F.T3A.T4C, T1C.T2F.T3A.T4C, T1D.T2F.T3A.T4C, T1E.T2F.T3A.T4C,
T1A.T2A.T3B.T4C, T1B.T2A.T3B.T4C, T1C.T2A.T3B.T4C, T1D.T2A.T3B.T4C,
T1E.T2A.T3B.T4C, T1A.T2B.T3B.T4C, T1B.T2B.T3B.T4C, T1C.T2B.T3B.T4C,
T1D.T2B.T3B.T4C, T1E.T2B.T3B.T4C, T1A.T2C.T3B.T4C, T1B.T2C.T3B.T4C,
T1C.T2C.T3B.T4C, T1D.T2C.T3B.T4C, T1E.T2C.T3B.T4C, T1A.T2D.T3B.T4C,
T1B.T2D.T3B.T4C, T1C.T2D.T3B.T4C, T1D.T2D.T3B.T4C, T1E.T2D.T3B.T4C,
T1A.T2E.T3B.T4C, T1B.T2E.T3B.T4C, T1C.T2E.T3B.T4C, T1D.T2E.T3B.T4C,
T1E.T2E.T3B.T4C, T1A.T2F.T3B.T4C, T1B.T2F.T3B.T4C, T1C.T2F.T3B.T4C,
T1D.T2F.T3B.T4C, T1E.T2F.T3B.T4C, T1A.T2A.T3C.T4C, T1B.T2A.T3C.T4C,
T1C.T2A.T3C.T4C, T1D.T2A.T3C.T4C, T1E.T2A.T3C.T4C, T1A.T2B.T3C.T4C,
T1B.T2B.T3C.T4C, T1C.T2B.T3C.T4C, T1D.T2B.T3C.T4C, T1E.T2B.T3C.T4C,
T1A.T2C.T3C.T4C, T1B.T2C.T3C.T4C, T1C.T2C.T3C.T4C, T1D.T2C.T3C.T4C,
T1E.T2C.T3C.T4C, T1A.T2D.T3C.T4C, T1B.T2D.T3C.T4C, T1C.T2D.T3C.T4C,
T1D.T2D.T3C.T4C, T1E.T2D.T3C.T4C, T1A.T2E.T3C.T4C, T1B.T2E.T3C.T4C,
T1C.T2E.T3C.T4C, T1D.T2E.T3C.T4C, T1E.T2E.T3C.T4C, T1A.T2F.T3C.T4C,
T1B.T2F.T3C.T4C, T1C.T2F.T3C.T4C, T1D.T2F.T3C.T4C, T1E.T2F.T3C.T4C,
T1A.T2A.T3D.T4C, T1B.T2A.T3D.T4C, T1C.T2A.T3D.T4C, T1D.T2A.T3D.T4C,
T1E.T2A.T3D.T4C, T1A.T2B.T3D.T4C, T1B.T2B.T3D.T4C, T1C.T2B.T3D.T4C,
T1D.T2B.T3D.T4C, T1E.T2B.T3D.T4C, T1A.T2C.T3D.T4C, T1B.T2C.T3D.T4C,
T1C.T2C.T3D.T4C, T1D.T2C.T3D.T4C, T1E.T2C.T3D.T4C, T1A.T2D.T3D.T4C,
T1B.T2D.T3D.T4C, T1C.T2D.T3D.T4C, T1D.T2D.T3D.T4C, T1E.T2D.T3D.T4C,
T1A.T2E.T3D.T4C, T1B.T2E.T3D.T4C, T1C.T2E.T3D.T4C, T1D.T2E.T3D.T4C,
T1E.T2E.T3D.T4C, T1A.T2F.T3D.T4C, T1B.T2F.T3D.T4C, T1C.T2F.T3D.T4C,
T1D.T2F.T3D.T4C, T1E.T2F.T3D.T4C, T1A.T2A.T3E.T4C, T1B.T2A.T3E.T4C,
T1C.T2A.T3E.T4C, T1D.T2A.T3E.T4C, T1E.T2A.T3E.T4C, T1A.T2B.T3E.T4C,
T1B.T2B.T3E.T4C, T1C.T2B.T3E.T4C, T1D.T2B.T3E.T4C, T1E.T2B.T3E.T4C,
T1A.T2C.T3E.T4C, T1B.T2C.T3E.T4C, T1C.T2C.T3E.T4C, T1D.T2C.T3E.T4C,
T1E.T2C.T3E.T4C, T1A.T2D.T3E.T4C, T1B.T2D.T3E.T4C, T1C.T2D.T3E.T4C,
T1D.T2D.T3E.T4C, T1E.T2D.T3E.T4C, T1A.T2E.T3E.T4C, T1B.T2E.T3E.T4C,
T1C.T2E.T3E.T4C, T1D.T2E.T3E.T4C, T1E.T2E.T3E.T4C, T1A.T2F.T3E.T4C,
T1B.T2F.T3E.T4C, T1C.T2F.T3E.T4C, T1D.T2F.T3E.T4C, T1E.T2F.T3E.T4C,
T1A.T2A.T3F.T4C, T1B.T2A.T3F.T4C, T1C.T2A.T3F.T4C, T1D.T2A.T3F.T4C,
T1E.T2A.T3F.T4C, T1A.T2B.T3F.T4C, T1B.T2B.T3F.T4C, T1C.T2B.T3F.T4C,
T1D.T2B.T3F.T4C, T1E.T2B.T3F.T4C, T1A.T2C.T3F.T4C, T1B.T2C.T3F.T4C,
T1C.T2C.T3F.T4C, T1D.T2C.T3F.T4C, T1E.T2C.T3F.T4C, T1A.T2D.T3F.T4C,
T1B.T2D.T3F.T4C, T1C.T2D.T3F.T4C, T1D.T2D.T3F.T4C, T1E.T2D.T3F.T4C,
T1A.T2E.T3F.T4C, T1B.T2E.T3F.T4C, T1C.T2E.T3F.T4C, T1D.T2E.T3F.T4C,
T1E.T2E.T3F.T4C, T1A.T2F.T3F.T4C, T1B.T2F.T3F.T4C, T1C.T2F.T3F.T4C,
T1D.T2F.T3F.T4C, T1E.T2F.T3F.T4C, T1A.T2A.T3G.T4C, T1B.T2A.T3G.T4C,
T1C.T2A.T3G.T4C, T1D.T2A.T3G.T4C, T1E.T2A.T3G.T4C, T1A.T2B.T3G.T4C,
T1B.T2B.T3G.T4C, T1C.T2B.T3G.T4C, T1D.T2B.T3G.T4C, T1E.T2B.T3G.T4C,
T1A.T2C.T3G.T4C, T1B.T2C.T3G.T4C, T1C.T2C.T3G.T4C, T1D.T2C.T3G.T4C,
T1E.T2C.T3G.T4C, T1A.T2D.T3G.T4C, T1B.T2D.T3G.T4C, T1C.T2D.T3G.T4C,
T1D.T2D.T3G.T4C, T1E.T2D.T3G.T4C, T1A.T2E.T3G.T4C, T1B.T2E.T3G.T4C,
T1C.T2E.T3G.T4C, T1D.T2E.T3G.T4C, T1E.T2E.T3G.T4C, T1A.T2F.T3G.T4C,
T1B.T2F.T3G.T4C, T1C.T2F.T3G.T4C, T1D.T2F.T3G.T4C, T1E.T2F.T3G.T4C,
T1A.T2A.T3A.T4D, T1B.T2A.T3A.T4D, T1C.T2A.T3A.T4D, T1D.T2A.T3A.T4D,
T1E.T2A.T3A.T4D, T1A.T2B.T3A.T4D, T1B.T2B.T3A.T4D, T1C.T2B.T3A.T4D,
T1D.T2B.T3A.T4D, T1E.T2B.T3A.T4D, T1A.T2C.T3A.T4D, T1B.T2C.T3A.T4D,
T1C.T2C.T3A.T4D, T1D.T2C.T3A.T4D, T1E.T2C.T3A.T4D, T1A.T2D.T3A.T4D,
T1B.T2D.T3A.T4D, T1C.T2D.T3A.T4D, T1D.T2D.T3A.T4D, T1E.T2D.T3A.T4D,
T1A.T2E.T3A.T4D, T1B.T2E.T3A.T4D, T1C.T2E.T3A.T4D, T1D.T2E.T3A.T4D,
T1E.T2E.T3A.T4D, T1A.T2F.T3A.T4D, T1B.T2F.T3A.T4D, T1C.T2F.T3A.T4D,
T1D.T2F.T3A.T4D, T1E.T2F.T3A.T4D, T1A.T2A.T3B.T4D, T1B.T2A.T3B.T4D,
T1C.T2A.T3B.T4D, T1D.T2A.T3B.T4D, T1E.T2A.T3B.T4D, T1A.T2B.T3B.T4D,
T1B.T2B.T3B.T4D, T1C.T2B.T3B.T4D, T1D.T2B.T3B.T4D, T1E.T2B.T3B.T4D,
T1A.T2C.T3B.T4D, T1B.T2C.T3B.T4D, T1C.T2C.T3B.T4D, T1D.T2C.T3B.T4D,
T1E.T2C.T3B.T4D, T1A.T2D.T3B.T4D, T1B.T2D.T3B.T4D, T1C.T2D.T3B.T4D,
T1D.T2D.T3B.T4D, T1E.T2D.T3B.T4D, T1A.T2E.T3B.T4D, T1B.T2E.T3B.T4D,
T1C.T2E.T3B.T4D, T1D.T2E.T3B.T4D, T1E.T2E.T3B.T4D, T1A.T2F.T3B.T4D,
T1B.T2F.T3B.T4D, T1C.T2F.T3B.T4D, T1D.T2F.T3B.T4D, T1E.T2F.T3B.T4D,
T1A.T2A.T3C.T4D, T1B.T2A.T3C.T4D, T1C.T2A.T3C.T4D, T1D.T2A.T3C.T4D,
T1E.T2A.T3C.T4D, T1A.T2B.T3C.T4D, T1B.T2B.T3C.T4D, T1C.T2B.T3C.T4D,
T1D.T2B.T3C.T4D, T1E.T2B.T3C.T4D, T1A.T2C.T3C.T4D, T1B.T2C.T3C.T4D,
T1C.T2C.T3C.T4D, T1D.T2C.T3C.T4D, T1E.T2C.T3C.T4D, T1A.T2D.T3C.T4D,
T1B.T2D.T3C.T4D, T1C.T2D.T3C.T4D, T1D.T2D.T3C.T4D, T1E.T2D.T3C.T4D,
T1A.T2E.T3C.T4D, T1B.T2E.T3C.T4D, T1C.T2E.T3C.T4D, T1D.T2E.T3C.T4D,
T1E.T2E.T3C.T4D, T1A.T2F.T3C.T4D, T1B.T2F.T3C.T4D, T1C.T2F.T3C.T4D,
T1D.T2F.T3C.T4D, T1E.T2F.T3C.T4D, T1A.T2A.T3D.T4D, T1B.T2A.T3D.T4D,
T1C.T2A.T3D.T4D, T1D.T2A.T3D.T4D, T1E.T2A.T3D.T4D, T1A.T2B.T3D.T4D,
T1B.T2B.T3D.T4D, T1C.T2B.T3D.T4D, T1D.T2B.T3D.T4D, T1E.T2B.T3D.T4D,
T1A.T2C.T3D.T4D, T1B.T2C.T3D.T4D, T1C.T2C.T3D.T4D, T1D.T2C.T3D.T4D,
T1E.T2C.T3D.T4D, T1A.T2D.T3D.T4D, T1B.T2D.T3D.T4D, T1C.T2D.T3D.T4D,
T1D.T2D.T3D.T4D, T1E.T2D.T3D.T4D, T1A.T2E.T3D.T4D, T1B.T2E.T3D.T4D,
T1C.T2E.T3D.T4D, T1D.T2E.T3D.T4D, T1E.T2E.T3D.T4D, T1A.T2F.T3D.T4D,
T1B.T2F.T3D.T4D, T1C.T2F.T3D.T4D, T1D.T2F.T3D.T4D, T1E.T2F.T3D.T4D,
T1A.T2A.T3E.T4D, T1B.T2A.T3E.T4D, T1C.T2A.T3E.T4D, T1D.T2A.T3E.T4D,
T1E.T2A.T3E.T4D, T1A.T2B.T3E.T4D, T1B.T2B.T3E.T4D, T1C.T2B.T3E.T4D,
T1D.T2B.T3E.T4D, T1E.T2B.T3E.T4D, T1A.T2C.T3E.T4D, T1B.T2C.T3E.T4D,
T1C.T2C.T3E.T4D, T1D.T2C.T3E.T4D, T1E.T2C.T3E.T4D, T1A.T2D.T3E.T4D,
T1B.T2D.T3E.T4D, T1C.T2D.T3E.T4D, T1D.T2D.T3E.T4D, T1E.T2D.T3E.T4D,
T1A.T2E.T3E.T4D, T1B.T2E.T3E.T4D, T1C.T2E.T3E.T4D, T1D.T2E.T3E.T4D,
T1E.T2E.T3E.T4D, T1A.T2F.T3E.T4D, T1B.T2F.T3E.T4D, T1C.T2F.T3E.T4D,
T1D.T2F.T3E.T4D, T1E.T2F.T3E.T4D, T1A.T2A.T3F.T4D, T1B.T2A.T3F.T4D,
T1C.T2A.T3F.T4D, T1D.T2A.T3F.T4D, T1E.T2A.T3F.T4D, T1A.T2B.T3F.T4D,
T1B.T2B.T3F.T4D, T1C.T2B.T3F.T4D, T1D.T2B.T3F.T4D, T1E.T2B.T3F.T4D,
T1A.T2C.T3F.T4D, T1B.T2C.T3F.T4D, T1C.T2C.T3F.T4D, T1D.T2C.T3F.T4D,
T1E.T2C.T3F.T4D, T1A.T2D.T3F.T4D, T1B.T2D.T3F.T4D, T1C.T2D.T3F.T4D,
T1D.T2D.T3F.T4D, T1E.T2D.T3F.T4D, T1A.T2E.T3F.T4D, T1B.T2E.T3F.T4D,
T1C.T2E.T3F.T4D, T1D.T2E.T3F.T4D, T1E.T2E.T3F.T4D, T1A.T2F.T3F.T4D,
T1B.T2F.T3F.T4D, T1C.T2F.T3F.T4D, T1D.T2F.T3F.T4D, T1E.T2F.T3F.T4D,
T1A.T2A.T3G.T4D, T1B.T2A.T3G.T4D, T1C.T2A.T3G.T4D, T1D.T2A.T3G.T4D,
T1E.T2A.T3G.T4D, T1A.T2B.T3G.T4D, T1B.T2B.T3G.T4D, T1C.T2B.T3G.T4D,
T1D.T2B.T3G.T4D, T1E.T2B.T3G.T4D, T1A.T2C.T3G.T4D, T1B.T2C.T3G.T4D,
T1C.T2C.T3G.T4D, T1D.T2C.T3G.T4D, T1E.T2C.T3G.T4D, T1A.T2D.T3G.T4D,
T1B.T2D.T3G.T4D, T1C.T2D.T3G.T4D, T1D.T2D.T3G.T4D, T1E.T2D.T3G.T4D,
T1A.T2E.T3G.T4D, T1B.T2E.T3G.T4D, T1C.T2E.T3G.T4D, T1D.T2E.T3G.T4D,
T1E.T2E.T3G.T4D, T1A.T2F.T3G.T4D, T1B.T2F.T3G.T4D, T1C.T2F.T3G.T4D,
T1D.T2F.T3G.T4D, T1E.T2F.T3G.T4D, T1A.T2A.T3A.T4E, T1B.T2A.T3A.T4E,
T1C.T2A.T3A.T4E, T1D.T2A.T3A.T4E, T1E.T2A.T3A.T4E, T1A.T2B.T3A.T4E,
T1B.T2B.T3A.T4E, T1C.T2B.T3A.T4E, T1D.T2B.T3A.T4E, T1E.T2B.T3A.T4E,
T1A.T2C.T3A.T4E, T1B.T2C.T3A.T4E, T1C.T2C.T3A.T4E, T1D.T2C.T3A.T4E,
T1E.T2C.T3A.T4E, T1A.T2D.T3A.T4E, T1B.T2D.T3A.T4E, T1C.T2D.T3A.T4E,
T1D.T2D.T3A.T4E, T1E.T2D.T3A.T4E, T1A.T2E.T3A.T4E, T1B.T2E.T3A.T4E,
T1C.T2E.T3A.T4E, T1D.T2E.T3A.T4E, T1E.T2E.T3A.T4E, T1A.T2F.T3A.T4E,
T1B.T2F.T3A.T4E, T1C.T2F.T3A.T4E, T1D.T2F.T3A.T4E, T1E.T2F.T3A.T4E,
T1A.T2A.T3B.T4E, T1B.T2A.T3B.T4E, T1C.T2A.T3B.T4E, T1D.T2A.T3B.T4E,
T1E.T2A.T3B.T4E, T1A.T2B.T3B.T4E, T1B.T2B.T3B.T4E, T1C.T2B.T3B.T4E,
T1D.T2B.T3B.T4E, T1E.T2B.T3B.T4E, T1A.T2C.T3B.T4E, T1B.T2C.T3B.T4E,
T1C.T2C.T3B.T4E, T1D.T2C.T3B.T4E, T1E.T2C.T3B.T4E, T1A.T2D.T3B.T4E,
T1B.T2D.T3B.T4E, T1C.T2D.T3B.T4E, T1D.T2D.T3B.T4E, T1E.T2D.T3B.T4E,
T1A.T2E.T3B.T4E, T1B.T2E.T3B.T4E, T1C.T2E.T3B.T4E, T1D.T2E.T3B.T4E,
T1E.T2E.T3B.T4E, T1A.T2F.T3B.T4E, T1B.T2F.T3B.T4E, T1C.T2F.T3B.T4E,
T1D.T2F.T3B.T4E, T1E.T2F.T3B.T4E, T1A.T2A.T3C.T4E, T1B.T2A.T3C.T4E,
T1C.T2A.T3C.T4E, T1D.T2A.T3C.T4E, T1E.T2A.T3C.T4E, T1A.T2B.T3C.T4E,
T1B.T2B.T3C.T4E, T1C.T2B.T3C.T4E, T1D.T2B.T3C.T4E, T1E.T2B.T3C.T4E,
T1A.T2C.T3C.T4E, T1B.T2C.T3C.T4E, T1C.T2C.T3C.T4E, T1D.T2C.T3C.T4E,
T1E.T2C.T3C.T4E, T1A.T2D.T3C.T4E, T1B.T2D.T3C.T4E, T1C.T2D.T3C.T4E,
T1D.T2D.T3C.T4E, T1E.T2D.T3C.T4E, T1A.T2E.T3C.T4E, T1B.T2E.T3C.T4E,
T1C.T2E.T3C.T4E, T1D.T2E.T3C.T4E, T1E.T2E.T3C.T4E, T1A.T2F.T3C.T4E,
T1B.T2F.T3C.T4E, T1C.T2F.T3C.T4E, T1D.T2F.T3C.T4E, T1E.T2F.T3C.T4E,
T1A.T2A.T3D.T4E, T1B.T2A.T3D.T4E, T1C.T2A.T3D.T4E, T1D.T2A.T3D.T4E,
T1E.T2A.T3D.T4E, T1A.T2B.T3D.T4E, T1B.T2B.T3D.T4E, T1C.T2B.T3D.T4E,
T1D.T2B.T3D.T4E, T1E.T2B.T3D.T4E, T1A.T2C.T3D.T4E, T1B.T2C.T3D.T4E,
T1C.T2C.T3D.T4E, T1D.T2C.T3D.T4E, T1E.T2C.T3D.T4E, T1A.T2D.T3D.T4E,
T1B.T2D.T3D.T4E, T1C.T2D.T3D.T4E, T1D.T2D.T3D.T4E, T1E.T2D.T3D.T4E,
T1A.T2E.T3D.T4E, T1B.T2E.T3D.T4E, T1C.T2E.T3D.T4E, T1D.T2E.T3D.T4E,
T1E.T2E.T3D.T4E, T1A.T2F.T3D.T4E, T1B.T2F.T3D.T4E, T1C.T2F.T3D.T4E,
T1D.T2F.T3D.T4E, T1E.T2F.T3D.T4E, T1A.T2A.T3E.T4E, T1B.T2A.T3E.T4E,
T1C.T2A.T3E.T4E, T1D.T2A.T3E.T4E, T1E.T2A.T3E.T4E, T1A.T2B.T3E.T4E,
T1B.T2B.T3E.T4E, T1C.T2B.T3E.T4E, T1D.T2B.T3E.T4E, T1E.T2B.T3E.T4E,
T1A.T2C.T3E.T4E, T1B.T2C.T3E.T4E, T1C.T2C.T3E.T4E, T1D.T2C.T3E.T4E,
T1E.T2C.T3E.T4E, T1A.T2D.T3E.T4E,
T1B.T2D.T3E.T4E, T1C.T2D.T3E.T4E, T1D.T2D.T3E.T4E, T1E.T2D.T3E.T4E,
T1A.T2E.T3E.T4E, T1B.T2E.T3E.T4E, T1C.T2E.T3E.T4E, T1D.T2E.T3E.T4E,
T1E.T2E.T3E.T4E, T1A.T2F.T3E.T4E, T1B.T2F.T3E.T4E, T1C.T2F.T3E.T4E,
T1D.T2F.T3E.T4E, T1E.T2F.T3E.T4E, T1A.T2A.T3F.T4E, T1B.T2A.T3F.T4E,
T1C.T2A.T3F.T4E, T1D.T2A.T3F.T4E, T1E.T2A.T3F.T4E, T1A.T2B.T3F.T4E,
T1B.T2B.T3F.T4E, T1C.T2B.T3F.T4E, T1D.T2B.T3F.T4E, T1E.T2B.T3F.T4E,
T1A.T2C.T3F.T4E, T1B.T2C.T3F.T4E, T1C.T2C.T3F.T4E, T1D.T2C.T3F.T4E,
T1E.T2C.T3F.T4E, T1A.T2D.T3F.T4E, T1B.T2D.T3F.T4E, T1C.T2D.T3F.T4E,
T1D.T2D.T3F.T4E, T1E.T2D.T3F.T4E, T1A.T2E.T3F.T4E, T1B.T2E.T3F.T4E,
T1C.T2E.T3F.T4E, T1D.T2E.T3F.T4E, T1E.T2E.T3F.T4E, T1A.T2F.T3F.T4E,
T1B.T2F.T3F.T4E, T1C.T2F.T3F.T4E, T1D.T2F.T3F.T4E, T1E.T2F.T3F.T4E,
T1A.T2A.T3G.T4E, T1B.T2A.T3G.T4E, T1C.T2A.T3G.T4E, T1D.T2A.T3G.T4E,
T1E.T2A.T3G.T4E, T1A.T2B.T3G.T4E, T1B.T2B.T3G.T4E, T1C.T2B.T3G.T4E,
T1D.T2B.T3G.T4E, T1E.T2B.T3G.T4E, T1A.T2C.T3G.T4E, T1B.T2C.T3G.T4E,
T1C.T2C.T3G.T4E, T1D.T2C.T3G.T4E, T1E.T2C.T3G.T4E, T1A.T2D.T3G.T4E,
T1B.T2D.T3G.T4E, T1C.T2D.T3G.T4E, T1D.T2D.T3G.T4E, T1E.T2D.T3G.T4E,
T1A.T2E.T3G.T4E, T1B.T2E.T3G.T4E, T1C.T2E.T3G.T4E, T1D.T2E.T3G.T4E,
T1E.T2E.T3G.T4E, T1A.T2F.T3G.T4E, T1B.T2F.T3G.T4E, T1C.T2F.T3G.T4E,
T1D.T2F.T3G.T4E, T1E.T2F.T3G.T4E, T1A.T2A.T3A.T4F, T1B.T2A.T3A.T4F,
T1C.T2A.T3A.T4F, T1D.T2A.T3A.T4F, T1E.T2A.T3A.T4F, T1A.T2B.T3A.T4F,
T1B.T2B.T3A.T4F, T1C.T2B.T3A.T4F, T1D.T2B.T3A.T4F, T1E.T2B.T3A.T4F,
T1A.T2C.T3A.T4F, T1B.T2C.T3A.T4F, T1C.T2C.T3A.T4F, T1D.T2C.T3A.T4F,
T1E.T2C.T3A.T4F, T1A.T2D.T3A.T4F, T1B.T2D.T3A.T4F, T1C.T2D.T3A.T4F,
T1D.T2D.T3A.T4F, T1E.T2D.T3A.T4F, T1A.T2E.T3A.T4F, T1B.T2E.T3A.T4F,
T1C.T2E.T3A.T4F, T1D.T2E.T3A.T4F, T1E.T2E.T3A.T4F, T1A.T2F.T3A.T4F,
T1B.T2F.T3A.T4F, T1C.T2F.T3A.T4F, T1D.T2F.T3A.T4F, T1E.T2F.T3A.T4F,
T1A.T2A.T3B.T4F, T1B.T2A.T3B.T4F, T1C.T2A.T3B.T4F, T1D.T2A.T3B.T4F,
T1E.T2A.T3B.T4F, T1A.T2B.T3B.T4F, T1B.T2B.T3B.T4F, T1C.T2B.T3B.T4F,
T1D.T2B.T3B.T4F, T1E.T2B.T3B.T4F, T1A.T2C.T3B.T4F, T1B.T2C.T3B.T4F,
T1C.T2C.T3B.T4F, T1D.T2C.T3B.T4F, T1E.T2C.T3B.T4F, T1A.T2D.T3B.T4F,
T1B.T2D.T3B.T4F, T1C.T2D.T3B.T4F, T1D.T2D.T3B.T4F, T1E.T2D.T3B.T4F,
T1A.T2E.T3B.T4F, T1B.T2E.T3B.T4F, T1C.T2E.T3B.T4F, T1D.T2E.T3B.T4F,
T1E.T2E.T3B.T4F, T1A.T2F.T3B.T4F, T1B.T2F.T3B.T4F, T1C.T2F.T3B.T4F,
T1D.T2F.T3B.T4F, T1E.T2F.T3B.T4F, T1A.T2A.T3C.T4F, T1B.T2A.T3C.T4F,
T1C.T2A.T3C.T4F, T1D.T2A.T3C.T4F, T1E.T2A.T3C.T4F, T1A.T2B.T3C.T4F,
T1B.T2B.T3C.T4F, T1C.T2B.T3C.T4F, T1D.T2B.T3C.T4F, T1E.T2B.T3C.T4F,
T1A.T2C.T3C.T4F, T1B.T2C.T3C.T4F, T1C.T2C.T3C.T4F, T1D.T2C.T3C.T4F,
T1E.T2C.T3C.T4F, T1A.T2D.T3C.T4F, T1B.T2D.T3C.T4F, T1C.T2D.T3C.T4F,
T1D.T2D.T3C.T4F, T1E.T2D.T3C.T4F, T1A.T2E.T3C.T4F, T1B.T2E.T3C.T4F,
T1C.T2E.T3C.T4F, T1D.T2E.T3C.T4F, T1E.T2E.T3C.T4F, T1A.T2F.T3C.T4F,
T1B.T2F.T3C.T4F, T1C.T2F.T3C.T4F, T1D.T2F.T3C.T4F, T1E.T2F.T3C.T4F,
T1A.T2A.T3D.T4F, T1B.T2A.T3D.T4F, T1C.T2A.T3D.T4F, T1D.T2A.T3D.T4F,
T1E.T2A.T3D.T4F, T1A.T2B.T3D.T4F, T1B.T2B.T3D.T4F, T1C.T2B.T3D.T4F,
T1D.T2B.T3D.T4F, T1E.T2B.T3D.T4F, T1A.T2C.T3D.T4F, T1B.T2C.T3D.T4F,
T1C.T2C.T3D.T4F, T1D.T2C.T3D.T4F, T1E.T2C.T3D.T4F, T1A.T2D.T3D.T4F,
T1B.T2D.T3D.T4F, T1C.T2D.T3D.T4F, T1D.T2D.T3D.T4F, T1E.T2D.T3D.T4F,
T1A.T2E.T3D.T4F, T1B.T2E.T3D.T4F, T1C.T2E.T3D.T4F, T1D.T2E.T3D.T4F,
T1E.T2E.T3D.T4F, T1A.T2F.T3D.T4F, T1B.T2F.T3D.T4F, T1C.T2F.T3D.T4F,
T1D.T2F.T3D.T4F, T1E.T2F.T3D.T4F, T1A.T2A.T3E.T4F, T1B.T2A.T3E.T4F,
T1C.T2A.T3E.T4F, T1D.T2A.T3E.T4F, T1E.T2A.T3E.T4F, T1A.T2B.T3E.T4F,
T1B.T2B.T3E.T4F, T1C.T2B.T3E.T4F, T1D.T2B.T3E.T4F, T1E.T2B.T3E.T4F,
T1A.T2C.T3E.T4F, T1B.T2C.T3E.T4F, T1C.T2C.T3E.T4F, T1D.T2C.T3E.T4F,
T1E.T2C.T3E.T4F, T1A.T2D.T3E.T4F, T1B.T2D.T3E.T4F, T1C.T2D.T3E.T4F,
T1D.T2D.T3E.T4F, T1E.T2D.T3E.T4F, T1A.T2E.T3E.T4F, T1B.T2E.T3E.T4F,
T1C.T2E.T3E.T4F, T1D.T2E.T3E.T4F, T1E.T2E.T3E.T4F, T1A.T2F.T3E.T4F,
T1B.T2F.T3E.T4F, T1C.T2F.T3E.T4F, T1D.T2F.T3E.T4F, T1E.T2F.T3E.T4F,
T1A.T2A.T3F.T4F, T1B.T2A.T3F.T4F, T1C.T2A.T3F.T4F, T1D.T2A.T3F.T4F,
T1E.T2A.T3F.T4F, T1A.T2B.T3F.T4F, T1B.T2B.T3F.T4F, T1C.T2B.T3F.T4F,
T1D.T2B.T3F.T4F, T1E.T2B.T3F.T4F, T1A.T2C.T3F.T4F, T1B.T2C.T3F.T4F,
T1C.T2C.T3F.T4F, T1D.T2C.T3F.T4F, T1E.T2C.T3F.T4F, T1A.T2D.T3F.T4F,
T1B.T2D.T3F.T4F, T1C.T2D.T3F.T4F, T1D.T2D.T3F.T4F, T1E.T2D.T3F.T4F,
T1A.T2E.T3F.T4F, T1B.T2E.T3F.T4F, T1C.T2E.T3F.T4F, T1D.T2E.T3F.T4F,
T1E.T2E.T3F.T4F, T1A.T2F.T3F.T4F, T1B.T2F.T3F.T4F, T1C.T2F.T3F.T4F,
T1D.T2F.T3F.T4F, T1E.T2F.T3F.T4F, T1A.T2A.T3G.T4F, T1B.T2A.T3G.T4F,
T1C.T2A.T3G.T4F, T1D.T2A.T3G.T4F, T1E.T2A.T3G.T4F, T1A.T2B.T3G.T4F,
T1B.T2B.T3G.T4F, T1C.T2B.T3G.T4F, T1D.T2B.T3G.T4F, T1E.T2B.T3G.T4F,
T1A.T2C.T3G.T4F, T1B.T2C.T3G.T4F, T1C.T2C.T3G.T4F, T1D.T2C.T3G.T4F,
T1E.T2C.T3G.T4F, T1A.T2D.T3G.T4F, T1B.T2D.T3G.T4F, T1C.T2D.T3G.T4F,
T1D.T2D.T3G.T4F, T1E.T2D.T3G.T4F, T1A.T2E.T3G.T4F, T1B.T2E.T3G.T4F,
T1C.T2E.T3G.T4F, T1D.T2E.T3G.T4F, T1E.T2E.T3G.T4F, T1A.T2F.T3G.T4F,
T1B.T2F.T3G.T4F, T1C.T2F.T3G.T4F, T1D.T2F.T3G.T4F, T1E.T2F.T3G.T4F,
T1A.T2A.T3A.T4G, T1B.T2A.T3A.T4G, T1C.T2A.T3A.T4G, T1D.T2A.T3A.T4G,
T1E.T2A.T3A.T4G, T1A.T2B.T3A.T4G, T1B.T2B.T3A.T4G, T1C.T2B.T3A.T4G,
T1D.T2B.T3A.T4G, T1E.T2B.T3A.T4G, T1A.T2C.T3A.T4G, T1B.T2C.T3A.T4G,
T1C.T2C.T3A.T4G, T1D.T2C.T3A.T4G, T1E.T2C.T3A.T4G, T1A.T2D.T3A.T4G,
T1B.T2D.T3A.T4G, T1C.T2D.T3A.T4G, T1D.T2D.T3A.T4G, T1E.T2D.T3A.T4G,
T1A.T2E.T3A.T4G, T1B.T2E.T3A.T4G, T1C.T2E.T3A.T4G, T1D.T2E.T3A.T4G,
T1E.T2E.T3A.T4G, T1A.T2F.T3A.T4G, T1B.T2F.T3A.T4G, T1C.T2F.T3A.T4G,
T1D.T2F.T3A.T4G, T1E.T2F.T3A.T4G, T1A.T2A.T3B.T4G, T1B.T2A.T3B.T4G,
T1C.T2A.T3B.T4G, T1D.T2A.T3B.T4G, T1E.T2A.T3B.T4G, T1A.T2B.T3B.T4G,
T1B.T2B.T3B.T4G, T1C.T2B.T3B.T4G, T1D.T2B.T3B.T4G, T1E.T2B.T3B.T4G,
T1A.T2C.T3B.T4G, T1B.T2C.T3B.T4G, T1C.T2C.T3B.T4G, T1D.T2C.T3B.T4G,
T1E.T2C.T3B.T4G, T1A.T2D.T3B.T4G, T1B.T2D.T3B.T4G, T1C.T2D.T3B.T4G,
T1D.T2D.T3B.T4G, T1E.T2D.T3B.T4G, T1A.T2E.T3B.T4G, T1B.T2E.T3B.T4G,
T1C.T2E.T3B.T4G, T1D.T2E.T3B.T4G, T1E.T2E.T3B.T4G, T1A.T2F.T3B.T4G,
T1B.T2F.T3B.T4G, T1C.T2F.T3B.T4G, T1D.T2F.T3B.T4G, T1E.T2F.T3B.T4G,
T1A.T2A.T3C.T4G, T1B.T2A.T3C.T4G, T1C.T2A.T3C.T4G, T1D.T2A.T3C.T4G,
T1E.T2A.T3C.T4G, T1A.T2B.T3C.T4G, T1B.T2B.T3C.T4G, T1C.T2B.T3C.T4G,
T1D.T2B.T3C.T4G, T1E.T2B.T3C.T4G, T1A.T2C.T3C.T4G, T1B.T2C.T3C.T4G,
T1C.T2C.T3C.T4G, T1D.T2C.T3C.T4G, T1E.T2C.T3C.T4G, T1A.T2D.T3C.T4G,
T1B.T2D.T3C.T4G, T1C.T2D.T3C.T4G, T1D.T2D.T3C.T4G, T1E.T2D.T3C.T4G,
T1A.T2E.T3C.T4G, T1B.T2E.T3C.T4G, T1C.T2E.T3C.T4G, T1D.T2E.T3C.T4G,
T1E.T2E.T3C.T4G, T1A.T2F.T3C.T4G, T1B.T2F.T3C.T4G, T1C.T2F.T3C.T4G,
T1D.T2F.T3C.T4G, T1E.T2F.T3C.T4G, T1A.T2A.T3D.T4G, T1B.T2A.T3D.T4G,
T1C.T2A.T3D.T4G, T1D.T2A.T3D.T4G, T1E.T2A.T3D.T4G, T1A.T2B.T3D.T4G,
T1B.T2B.T3D.T4G, T1C.T2B.T3D.T4G, T1D.T2B.T3D.T4G, T1E.T2B.T3D.T4G,
T1A.T2C.T3D.T4G, T1B.T2C.T3D.T4G, T1C.T2C.T3D.T4G, T1D.T2C.T3D.T4G,
T1E.T2C.T3D.T4G, T1A.T2D.T3D.T4G, T1B.T2D.T3D.T4G, T1C.T2D.T3D.T4G,
T1D.T2D.T3D.T4G, T1E.T2D.T3D.T4G, T1A.T2E.T3D.T4G, T1B.T2E.T3D.T4G,
T1C.T2E.T3D.T4G, T1D.T2E.T3D.T4G, T1E.T2E.T3D.T4G, T1A.T2F.T3D.T4G,
T1B.T2F.T3D.T4G, T1C.T2F.T3D.T4G, T1D.T2F.T3D.T4G, T1E.T2F.T3D.T4G,
T1A.T2A.T3E.T4G, T1B.T2A.T3E.T4G, T1C.T2A.T3E.T4G, T1D.T2A.T3E.T4G,
T1E.T2A.T3E.T4G, T1A.T2B.T3E.T4G, T1B.T2B.T3E.T4G, T1C.T2B.T3E.T4G,
T1D.T2B.T3E.T4G, T1E.T2B.T3E.T4G, T1A.T2C.T3E.T4G, T1B.T2C.T3E.T4G,
T1C.T2C.T3E.T4G, T1D.T2C.T3E.T4G, T1E.T2C.T3E.T4G, T1A.T2D.T3E.T4G,
T1B.T2D.T3E.T4G, T1C.T2D.T3E.T4G, T1D.T2D.T3E.T4G, T1E.T2D.T3E.T4G,
T1A.T2E.T3E.T4G, T1B.T2E.T3E.T4G, T1C.T2E.T3E.T4G, T1D.T2E.T3E.T4G,
T1E.T2E.T3E.T4G, T1A.T2F.T3E.T4G, T1B.T2F.T3E.T4G, T1C.T2F.T3E.T4G,
T1D.T2F.T3E.T4G, T1E.T2F.T3E.T4G, T1A.T2A.T3F.T4G, T1B.T2A.T3F.T4G,
T1C.T2A.T3F.T4G, T1D.T2A.T3F.T4G, T1E.T2A.T3F.T4G, T1A.T2B.T3F.T4G,
T1B.T2B.T3F.T4G, T1C.T2B.T3F.T4G, T1D.T2B.T3F.T4G, T1E.T2B.T3F.T4G,
T1A.T2C.T3F.T4G, T1B.T2C.T3F.T4G, T1C.T2C.T3F.T4G, T1D.T2C.T3F.T4G,
T1E.T2C.T3F.T4G, T1A.T2D.T3F.T4G, T1B.T2D.T3F.T4G, T1C.T2D.T3F.T4G,
T1D.T2D.T3F.T4G, T1E.T2D.T3F.T4G, T1A.T2E.T3F.T4G, T1B.T2E.T3F.T4G,
T1C.T2E.T3F.T4G, T1D.T2E.T3F.T4G, T1E.T2E.T3F.T4G, T1A.T2F.T3F.T4G,
T1B.T2F.T3F.T4G, T1C.T2F.T3F.T4G, T1D.T2F.T3F.T4G, T1E.T2F.T3F.T4G,
T1A.T2A.T3G.T4G, T1B.T2A.T3G.T4G, T1C.T2A.T3G.T4G, T1D.T2A.T3G.T4G,
T1E.T2A.T3G.T4G, T1A.T2B.T3G.T4G, T1B.T2B.T3G.T4G, T1C.T2B.T3G.T4G,
T1D.T2B.T3G.T4G, T1E.T2B.T3G.T4G, T1A.T2C.T3G.T4G, T1B.T2C.T3G.T4G,
T1C.T2C.T3G.T4G, T1D.T2C.T3G.T4G, T1E.T2C.T3G.T4G, T1A.T2D.T3G.T4G,
T1B.T2D.T3G.T4G, T1C.T2D.T3G.T4G, T1D.T2D.T3G.T4G, T1E.T2D.T3G.T4G,
T1A.T2E.T3G.T4G, T1B.T2E.T3G.T4G, T1C.T2E.T3G.T4G, T1D.T2E.T3G.T4G,
T1E.T2E.T3G.T4G, T1A.T2F.T3G.T4G, T1B.T2F.T3G.T4G, T1C.T2F.T3G.T4G,
T1D.T2F.T3G.T4G, T1E.T2F.T3G.T4G.
Phosphonate Embodiments of Compounds of Formula I
[0495] In another embodiment, the compounds of the present
invention can have one of the structures shown in Table 1.1,
wherein M represents alkyl, substituted alkyl, heteroalkyl,
substituted heteroalkyl, alkenyl, substituted alkenyl, aryl,
substituted aryl, arylalkyl, substituted arylalkyl, heterocyclyl,
substituted heterocyclyl, heterocyclylalkyl, or substituted
heterocyclylalkyl; and Z represents halo, alkyl, haloalkyl, or
alkoxy.
[0496] Pd.sup.1 and Pd.sup.2 are each independently selected from
species in Tables 20.1 to 20.37. The variables used in Tables 20.1
to 20.37 (e.g., W.sup.3, R.sup.1, etc.) pertain only to Tables
20.1-20.37, unless otherwise indicated. Additional phosphonate
groups are disclosed in U.S. patent publication No. 2004/100960,
the entirety of which is incorporated herein by reference.
[0497] The variables used in Tables 20.1 to 20.37 have the
following definitions:
[0498] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0499] R.sup.2 is independently H, R.sup.1, R.sup.3 or R.sup.4
wherein each R.sup.4 is independently substituted with 0 to 3
R.sup.3 groups or taken together at a carbon atom, two R.sup.2
groups form a ring of 3 to 8 carbons and the ring may be
substituted with 0 to 3 R.sup.3 groups;
[0500] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0501] R.sup.3a is F, Cl, Br, I, --CN, N3 or --NO.sub.2;
[0502] R.sup.3b is Y.sup.1;
[0503] R.sup.3c is --R.sup.x, --N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), N(R.sup.x)C(Y.sup.1)R.sup.x,
--N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0504] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0505] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0506] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0507] R.sup.5a is independently alkylene of 1 to 18 carbon atoms,
alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.3 groups;
[0508] W.sup.3 is W.sup.4 or W.sup.5;
[0509] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0510] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0511] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0512] M2 is 0, 1 or 2;
[0513] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0514] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0515] M1a, M1c, and M1d are independently 0 or 1; and
[0516] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
TABLE-US-00007 TABLE 1.1 ##STR26## ##STR27## ##STR28##
##STR29##
[0517] TABLE-US-00008 TABLE 20.1 ##STR30## ##STR31## ##STR32##
##STR33## ##STR34## ##STR35## ##STR36## ##STR37##
[0518] TABLE-US-00009 TABLE 20.2 ##STR38## ##STR39## ##STR40##
[0519] TABLE-US-00010 TABLE 20.3 ##STR41## ##STR42## ##STR43##
##STR44## ##STR45## ##STR46## ##STR47## ##STR48##
[0520] TABLE-US-00011 TABLE 20.4 ##STR49## ##STR50## ##STR51##
[0521] TABLE-US-00012 TABLE 20.5 ##STR52## ##STR53## ##STR54##
##STR55## ##STR56## ##STR57## ##STR58## ##STR59##
[0522] TABLE-US-00013 TABLE 20.6 ##STR60## ##STR61## ##STR62##
[0523] TABLE-US-00014 TABLE 20.7 ##STR63## ##STR64## ##STR65##
##STR66## ##STR67## ##STR68## ##STR69## ##STR70##
[0524] TABLE-US-00015 TABLE 20.8 ##STR71## ##STR72## ##STR73##
##STR74## ##STR75## ##STR76## ##STR77## ##STR78##
[0525] TABLE-US-00016 TABLE 20.9 ##STR79## ##STR80## ##STR81##
##STR82## ##STR83## ##STR84## ##STR85## ##STR86##
[0526] TABLE-US-00017 TABLE 20.10 ##STR87## ##STR88## ##STR89##
[0527] TABLE-US-00018 TABLE 20.11 ##STR90## ##STR91## ##STR92##
##STR93## ##STR94## ##STR95## ##STR96## ##STR97##
[0528] TABLE-US-00019 TABLE 20.12 ##STR98## ##STR99##
##STR100##
[0529] TABLE-US-00020 TABLE 20.13 ##STR101## ##STR102## ##STR103##
##STR104## ##STR105## ##STR106## ##STR107## ##STR108##
[0530] TABLE-US-00021 TABLE 20.14 ##STR109## ##STR110##
##STR111##
[0531] TABLE-US-00022 TABLE 20.15 ##STR112## ##STR113## ##STR114##
##STR115## ##STR116## ##STR117## ##STR118## ##STR119##
[0532] TABLE-US-00023 TABLE 20.16 ##STR120## ##STR121## ##STR122##
##STR123## ##STR124## ##STR125## ##STR126## ##STR127##
[0533] TABLE-US-00024 TABLE 20.17 ##STR128## ##STR129## ##STR130##
##STR131## ##STR132## ##STR133## ##STR134## ##STR135##
[0534] TABLE-US-00025 TABLE 20.18 ##STR136## ##STR137##
##STR138##
[0535] TABLE-US-00026 TABLE 20.19 ##STR139## ##STR140## ##STR141##
##STR142## ##STR143## ##STR144## ##STR145## ##STR146##
[0536] TABLE-US-00027 TABLE 20.20 ##STR147## ##STR148##
##STR149##
[0537] TABLE-US-00028 TABLE 20.21 ##STR150## ##STR151## ##STR152##
##STR153## ##STR154## ##STR155## ##STR156## ##STR157##
[0538] TABLE-US-00029 TABLE 20.22 ##STR158## ##STR159##
##STR160##
[0539] TABLE-US-00030 TABLE 20.23 ##STR161## ##STR162## ##STR163##
##STR164## ##STR165## ##STR166## ##STR167## ##STR168##
[0540] TABLE-US-00031 TABLE 20.24 ##STR169## ##STR170## ##STR171##
##STR172## ##STR173## ##STR174## ##STR175## ##STR176##
[0541] TABLE-US-00032 TABLE 20.25 ##STR177## ##STR178## ##STR179##
##STR180## ##STR181## ##STR182## ##STR183## ##STR184## ##STR185##
##STR186## ##STR187## ##STR188##
[0542] TABLE-US-00033 TABLE 20.26 ##STR189## ##STR190## ##STR191##
##STR192## ##STR193## ##STR194## ##STR195## ##STR196## ##STR197##
##STR198## ##STR199## ##STR200##
[0543] TABLE-US-00034 TABLE 20.27 ##STR201## ##STR202## ##STR203##
##STR204## ##STR205## ##STR206## ##STR207## ##STR208##
[0544] TABLE-US-00035 TABLE 20.28 ##STR209## ##STR210## ##STR211##
##STR212## ##STR213## ##STR214##
[0545] TABLE-US-00036 TABLE 20.29 ##STR215## ##STR216## ##STR217##
##STR218## ##STR219## ##STR220## ##STR221## ##STR222##
[0546] TABLE-US-00037 TABLE 20.30 ##STR223## ##STR224## ##STR225##
##STR226## ##STR227## ##STR228##
[0547] TABLE-US-00038 TABLE 20.31 ##STR229## ##STR230## ##STR231##
##STR232## ##STR233## ##STR234## ##STR235## ##STR236##
[0548] TABLE-US-00039 TABLE 20.32 ##STR237## ##STR238## ##STR239##
##STR240## ##STR241## ##STR242##
[0549] TABLE-US-00040 TABLE 20.33 ##STR243## ##STR244## ##STR245##
##STR246## ##STR247## ##STR248## ##STR249## ##STR250##
[0550] TABLE-US-00041 TABLE 20.34 ##STR251## ##STR252## ##STR253##
##STR254## ##STR255## ##STR256##
[0551] TABLE-US-00042 TABLE 20.35 ##STR257## ##STR258## ##STR259##
##STR260## ##STR261## ##STR262## ##STR263## ##STR264##
[0552] TABLE-US-00043 TABLE 20.36 ##STR265## ##STR266## ##STR267##
##STR268## ##STR269## ##STR270## ##STR271## ##STR272##
[0553] TABLE-US-00044 TABLE 20.37 ##STR273## ##STR274## ##STR275##
##STR276##
[0554] In the following embodiments, the term "Sc" refers to one of
the structures of Table 1.1.
[0555] In one embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0556] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0557] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0558] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0559] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0560] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0561] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0562] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0563] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0564] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0565] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2, Pd.sup.2 is
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2.
[0566] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3,
Pd.sup.2 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3.
[0567] In another embodiment of the compounds of Formula I, Sc is
Formula A; Pd.sup.1 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3,
Pd.sup.2 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3.
[0568] In one embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0569] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0570] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0571] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0572] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0573] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.12CH.sub.3;
Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0574] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0575] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0576] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0577] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0578] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2, Pd.sup.2 is
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2.
[0579] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3,
Pd.sup.2 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3.
[0580] In another embodiment of the compounds of Formula I, Sc is
Formula B; Pd.sup.1 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3,
Pd.sup.2 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3.
[0581] In one embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0582] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0583] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0584] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0585] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0586] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0587] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0588] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0589] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0590] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0591] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2, Pd.sup.2 is
--O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2.
[0592] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3,
Pd.sup.2 is --CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3.
[0593] In another embodiment of the compounds of Formula I, Sc is
Formula C; Pd.sup.1 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3,
Pd.sup.2 is --CH.sub.2--O--C(O)--C(CH.sub.3).sub.3.
[0594] In one embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0595] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0596] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0597] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --O-Ph; Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0598] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3.
[0599] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3. In
another embodiment of the compounds of Formula I, Sc is Formula D;
Pd.sup.1 is --NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.3; Pd.sup.2
is
--NH--CH(CH.sub.3)--C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0600] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3.
[0601] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0602] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.3;
Pd.sup.2 is
--NH--CH(benzyl)-C(O)--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.3. In
another embodiment of the compounds of Formula I, Sc is Formula D;
Pd.sup.1 is --O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2, Pd.sup.2
is --O--CH.sub.2--O--C(O)--O--CH(CH.sub.3).sub.2.
[0603] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3,
Pd.sup.2 is --O--CH.sub.2--O--C(O)--O--CH.sub.2CH.sub.3.
[0604] In another embodiment of the compounds of Formula I, Sc is
Formula D; Pd.sup.1 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3,
Pd.sup.2 is --O--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3.
[0605] In still another embodiment, selected compounds of Formula I
are named below in tabular format (Table 11) as compounds of
general Formula IV (below): X-A-Y-Z Formula IV
[0606] where A, X, Y and Z are defined in Tables 7-10, below. Each
compound is designated in tabular form by combining the "code"
representing each structural moiety using the following syntax:
A.X.Y.Z Thus, for example, A1.X1.Y1.Z1. represents the following
structure: ##STR277## TABLE-US-00045 TABLE 7 "A" Structures Code
"A" Structure A1 ##STR278## A2 ##STR279## A3 ##STR280## A4
##STR281## A5 ##STR282##
[0607] TABLE-US-00046 TABLE 8 "X" Structures Code "X" Structure X1
##STR283## X2 ##STR284## X3 ##STR285## X4 ##STR286## X5
--NH.sub.2
[0608] TABLE-US-00047 TABLE 9 "Y" Structures Code "Y" Structure Y1
##STR287## Y2 ##STR288## Y3 ##STR289## Y4 ##STR290## Y5
--N(CH.sub.3)-(3-pyridyl)
[0609] TABLE-US-00048 TABLE 10 "Z" Structures Code "Z" Structure Z1
##STR291## Z2 ##STR292## Z3 ##STR293## Z4 ##STR294## Z5 ##STR295##
Z6 ##STR296## Z7 ##STR297## Z8 ##STR298## Z9 ##STR299## Z10
##STR300## Z11 ##STR301## Z12 ##STR302## Z13 ##STR303## Z14
##STR304##
[0610] TABLE-US-00049 TABLE 11 A1.X1.Y1.Z1, A1.X1.Y1.Z2,
A1.X1.Y1.Z3, A1.X1.Y1.Z4, A1.X1.Y1.Z5, A1.X1.Y1.Z6, A1.X1.Y1.Z7,
A1.X1.Y1.Z8, A1.X1.Y1.Z9, A1.X1.Y1.Z10, A1.X1.Y1.Z11, A1.X1.Y1.Z12,
A1.X1.Y1.Z13, A1.X1.Y1.Z14, A1.X1.Y2.Z1, A1.X1.Y2.Z2, A1.X1.Y2.Z3,
A1.X1.Y2.Z4, A1.X1.Y2.Z5, A1.X1.Y2.Z6, A1.X1.Y2.Z7, A1.X1.Y2.Z8,
A1.X1.Y2.Z9, A1.X1.Y2.Z10, A1.X1.Y2.Z11, A1.X1.Y2.Z12,
A1.X1.Y2.Z13, A1.X1.Y2.Z14, A1.X1.Y3.Z1, A1.X1.Y3.Z2, A1.X1.Y3.Z3,
A1.X1.Y3.Z4, A1.X1.Y3.Z5, A1.X1.Y3.Z6, A1.X1.Y3.Z7, A1.X1.Y3.Z8,
A1.X1.Y3.Z9, A1.X1.Y3.Z10, A1.X1.Y3.Z11, A1.X1.Y3.Z12,
A1.X1.Y3.Z13, A1.X1.Y3.Z14, A1.X1.Y4.Z1, A1.X1.Y4.Z2, A1.X1.Y4.Z3,
A1.X1.Y4.Z4, A1.X1.Y4.Z5, A1.X1.Y4.Z6, A1.X1.Y4.Z7, A1.X1.Y4.Z8,
A1.X1.Y4.Z9, A1.X1.Y4.Z10, A1.X1.Y4.Z11, A1.X1.Y4.Z12,
A1.X1.Y4.Z13, A1.X1.Y4.Z14, A1.X1.Y5.Z1, A1.X1.Y5.Z2, A1.X1.Y5.Z3,
A1.X1.Y5.Z4, A1.X1.Y5.Z5, A1.X1.Y5.Z6, A1.X1.Y5.Z7, A1.X1.Y5.Z8,
A1.X1.Y5.Z9, A1.X1.Y5.Z10, A1.X1.Y5.Z11, A1.X1.Y5.Z12,
A1.X1.Y5.Z13, A1.X1.Y5.Z14, A1.X2.Y1.Z1, A1.X2.Y1.Z2, A1.X2.Y1.Z3,
A1.X2.Y1.Z4, A1.X2.Y1.Z5, A1.X2.Y1.Z6, A1.X2.Y1.Z7, A1.X2.Y1.Z8,
A1.X2.Y1.Z9, A1.X2.Y1.Z10, A1.X2.Y1.Z11, A1.X2.Y1.Z12,
A1.X2.Y1.Z13, A1.X2.Y1.Z14, A1.X2.Y2.Z1, A1.X2.Y2.Z2, A1.X2.Y2.Z3,
A1.X2.Y2.Z4, A1.X2.Y2.Z5, A1.X2.Y2.Z6, A1.X2.Y2.Z7, A1.X2.Y2.Z8,
A1.X2.Y2.Z9, A1.X2.Y2.Z10, A1.X2.Y2.Z11, A1.X2.Y2.Z12,
A1.X2.Y2.Z13, A1.X2.Y2.Z14, A1.X2.Y3.Z1, A1.X2.Y3.Z2, A1.X2.Y3.Z3,
A1.X2.Y3.Z4, A1.X2.Y3.Z5, A1.X2.Y3.Z6, A1.X2.Y3.Z7, A1.X2.Y3.Z8,
A1.X2.Y3.Z9, A1.X2.Y3.Z10, A1.X2.Y3.Z11, A1.X2.Y3.Z12,
A1.X2.Y3.Z13, A1.X2.Y3.Z14, A1.X2.Y4.Z1, A1.X2.Y4.Z2, A1.X2.Y4.Z3,
A1.X2.Y4.Z4, A1.X2.Y4.Z5, A1.X2.Y4.Z6, A1.X2.Y4.Z7, A1.X2.Y4.Z8,
A1.X2.Y4.Z9, A1.X2.Y4.Z10, A1.X2.Y4.Z11, A1.X2.Y4.Z12,
A1.X2.Y4.Z13, A1.X2.Y4.Z14, A1.X2.Y5.Z1, A1.X2.Y5.Z2, A1.X2.Y5.Z3,
A1.X2.Y5.Z4, A1.X2.Y5.Z5, A1.X2.Y5.Z6, A1.X2.Y5.Z7, A1.X2.Y5.Z8,
A1.X2.Y5.Z9, A1.X2.Y5.Z10, A1.X2.Y5.Z11, A1.X2.Y5.Z12,
A1.X2.Y5.Z13, A1.X2.Y5.Z14, A1.X3.Y1.Z1, A1.X3.Y1.Z2, A1.X3.Y1.Z3,
A1.X3.Y1.Z4, A1.X3.Y1.Z5, A1.X3.Y1.Z6, A1.X3.Y1.Z7, A1.X3.Y1.Z8,
A1.X3.Y1.Z9, A1.X3.Y1.Z10, A1.X3.Y1.Z11, A1.X3.Y1.Z12,
A1.X3.Y1.Z13, A1.X3.Y1.Z14, A1.X3.Y2.Z1, A1.X3.Y2.Z2, A1.X3.Y2.Z3,
A1.X3.Y2.Z4, A1.X3.Y2.Z5, A1.X3.Y2.Z6, A1.X3.Y2.Z7, A1.X3.Y2.Z8,
A1.X3.Y2.Z9, A1.X3.Y2.Z10, A1.X3.Y2.Z11, A1.X3.Y2.Z12,
A1.X3.Y2.Z13, A1.X3.Y2.Z14, A1.X3.Y3.Z1, A1.X3.Y3.Z2, A1.X3.Y3.Z3,
A1.X3.Y3.Z4, A1.X3.Y3.Z5, A1.X3.Y3.Z6, A1.X3.Y3.Z7, A1.X3.Y3.Z8,
A1.X3.Y3.Z9, A1.X3.Y3.Z10, A1.X3.Y3.Z11, A1.X3.Y3.Z12,
A1.X3.Y3.Z13, A1.X3.Y3.Z14, A1.X3.Y4.Z1, A1.X3.Y4.Z2, A1.X3.Y4.Z3,
A1.X3.Y4.Z4, A1.X3.Y4.Z5, A1.X3.Y4.Z6, A1.X3.Y4.Z7, A1.X3.Y4.Z8,
A1.X3.Y4.Z9, A1.X3.Y4.Z10, A1.X3.Y4.Z11, A1.X3.Y4.Z12,
A1.X3.Y4.Z13, A1.X3.Y4.Z14, A1.X3.Y5.Z1, A1.X3.Y5.Z2, A1.X3.Y5.Z3,
A1.X3.Y5.Z4, A1.X3.Y5.Z5, A1.X3.Y5.Z6, A1.X3.Y5.Z7, A1.X3.Y5.Z8,
A1.X3.Y5.Z9, A1.X3.Y5.Z10, A1.X3.Y5.Z11, A1.X3.Y5.Z12,
A1.X3.Y5.Z13, A1.X3.Y5.Z14, A1.X4.Y1.Z1, A1.X4.Y1.Z2, A1.X4.Y1.Z3,
A1.X4.Y1.Z4, A1.X4.Y1.Z5, A1.X4.Y1.Z6, A1.X4.Y1.Z7, A1.X4.Y1.Z8,
A1.X4.Y1.Z9, A1.X4.Y1.Z10, A1.X4.Y1.Z11, A1.X4.Y1.Z12,
A1.X4.Y1.Z13, A1.X4.Y1.Z14, A1.X4.Y2.Z1, A1.X4.Y2.Z2, A1.X4.Y2.Z3,
A1.X4.Y2.Z4, A1.X4.Y2.Z5, A1.X4.Y2.Z6, A1.X4.Y2.Z7, A1.X4.Y2.Z8,
A1.X4.Y2.Z9, A1.X4.Y2.Z10, A1.X4.Y2.Z11, A1.X4.Y2.Z12,
A1.X4.Y2.Z13, A1.X4.Y2.Z14, A1.X4.Y3.Z1, A1.X4.Y3.Z2, A1.X4.Y3.Z3,
A1.X4.Y3.Z4, A1.X4.Y3.Z5, A1.X4.Y3.Z6, A1.X4.Y3.Z7, A1.X4.Y3.Z8,
A1.X4.Y3.Z9, A1.X4.Y3.Z10, A1.X4.Y3.Z11, A1.X4.Y3.Z12,
A1.X4.Y3.Z13, A1.X4.Y3.Z14, A1.X4.Y4.Z1, A1.X4.Y4.Z2, A1.X4.Y4.Z3,
A1.X4.Y4.Z4, A1.X4.Y4.Z5, A1.X4.Y4.Z6, A1.X4.Y4.Z7, A1.X4.Y4.Z8,
A1.X4.Y4.Z9, A1.X4.Y4.Z10, A1.X4.Y4.Z11, A1.X4.Y4.Z12,
A1.X4.Y4.Z13, A1.X4.Y4.Z14, A1.X4.Y5.Z1, A1.X4.Y5.Z2, A1.X4.Y5.Z3,
A1.X4.Y5.Z4, A1.X4.Y5.Z5, A1.X4.Y5.Z6, A1.X4.Y5.Z7, A1.X4.Y5.Z8,
A1.X4.Y5.Z9, A1.X4.Y5.Z10, A1.X4.Y5.Z11, A1.X4.Y5.Z12,
A1.X4.Y5.Z13, A1.X4.Y5.Z14, A1.X5.Y1.Z1, A1.X5.Y1.Z2, A1.X5.Y1.Z3,
A1.X5.Y1.Z4, A1.X5.Y1.Z5, A1.X5.Y1.Z6, A1.X5.Y1.Z7, A1.X5.Y1.Z8,
A1.X5.Y1.Z9, A1.X5.Y1.Z10, A1.X5.Y1.Z11, A1.X5.Y1.Z12,
A1.X5.Y1.Z13, A1.X5.Y1.Z14, A1.X5.Y2.Z1, A1.X5.Y2.Z2, A1.X5.Y2.Z3,
A1.X5.Y2.Z4, A1.X5.Y2.Z5, A1.X5.Y2.Z6, A1.X5.Y2.Z7, A1.X5.Y2.Z8,
A1.X5.Y2.Z9, A1.X5.Y2.Z10, A1.X5.Y2.Z11, A1.X5.Y2.Z12,
A1.X5.Y2.Z13, A1.X5.Y2.Z14, A1.X5.Y3.Z1, A1.X5.Y3.Z2, A1.X5.Y3.Z3,
A1.X5.Y3.Z4, A1.X5.Y3.Z5, A1.X5.Y3.Z6, A1.X5.Y3.Z7, A1.X5.Y3.Z8,
A1.X5.Y3.Z9, A1.X5.Y3.Z10, A1.X5.Y3.Z11, A1.X5.Y3.Z12,
A1.X5.Y3.Z13, A1.X5.Y3.Z14, A1.X5.Y4.Z1, A1.X5.Y4.Z2, A1.X5.Y4.Z3,
A1.X5.Y4.Z4, A1.X5.Y4.Z5, A1.X5.Y4.Z6, A1.X5.Y4.Z7, A1.X5.Y4.Z8,
A1.X5.Y4.Z9, A1.X5.Y4.Z10, A1.X5.Y4.Z11, A1.X5.Y4.Z12,
A1.X5.Y4.Z13, A1.X5.Y4.Z14, A1.X5.Y5.Z1, A1.X5.Y5.Z2, A1.X5.Y5.Z3,
A1.X5.Y5.Z4, A1.X5.Y5.Z5, A1.X5.Y5.Z6, A1.X5.Y5.Z7, A1.X5.Y5.Z8,
A1.X5.Y5.Z9, A1.X5.Y5.Z10, A1.X5.Y5.Z11, A1.X5.Y5.Z12,
A1.X5.Y5.Z13, A1.X5.Y5.Z14, A2.X1.Y1.Z1, A2.X1.Y1.Z2, A2.X1.Y1.Z3,
A2.X1.Y1.Z4, A2.X1.Y1.Z5, A2.X1.Y1.Z6, A2.X1.Y1.Z7, A2.X1.Y1.Z8,
A2.X1.Y1.Z9, A2.X1.Y1.Z10, A2.X1.Y1.Z11, A2.X1.Y1.Z12,
A2.X1.Y1.Z13, A2.X1.Y1.Z14, A2.X1.Y2.Z1, A2.X1.Y2.Z2, A2.X1.Y2.Z3,
A2.X1.Y2.Z4, A2.X1.Y2.Z5, A2.X1.Y2.Z6, A2.X1.Y2.Z7, A2.X1.Y2.Z8,
A2.X1.Y2.Z9, A2.X1.Y2.Z10, A2.X1.Y2.Z11, A2.X1.Y2.Z12,
A2.X1.Y2.Z13, A2.X1.Y2.Z14, A2.X1.Y3.Z1, A2.X1.Y3.Z2, A2.X1.Y3.Z3,
A2.X1.Y3.Z4, A2.X1.Y3.Z5, A2.X1.Y3.Z6, A2.X1.Y3.Z7, A2.X1.Y3.Z8,
A2.X1.Y3.Z9, A2.X1.Y3.Z10, A2.X1.Y3.Z11, A2.X1.Y3.Z12,
A2.X1.Y3.Z13, A2.X1.Y3.Z14, A2.X1.Y4.Z1, A2.X1.Y4.Z2, A2.X1.Y4.Z3,
A2.X1.Y4.Z4, A2.X1.Y4.Z5, A2.X1.Y4.Z6, A2.X1.Y4.Z7, A2.X1.Y4.Z8,
A2.X1.Y4.Z9, A2.X1.Y4.Z10, A2.X1.Y4.Z11, A2.X1.Y4.Z12,
A2.X1.Y4.Z13, A2.X1.Y4.Z14, A2.X1.Y5.Z1, A2.X1.Y5.Z2, A2.X1.Y5.Z3,
A2.X1.Y5.Z4, A2.X1.Y5.Z5, A2.X1.Y5.Z6, A2.X1.Y5.Z7, A2.X1.Y5.Z8,
A2.X1.Y5.Z9, A2.X1.Y5.Z10, A2.X1.Y5.Z11, A2.X1.Y5.Z12,
A2.X1.Y5.Z13, A2.X1.Y5.Z14, A2.X2.Y1.Z1, A2.X2.Y1.Z2, A2.X2.Y1.Z3,
A2.X2.Y1.Z4, A2.X2.Y1.Z5, A2.X2.Y1.Z6, A2.X2.Y1.Z7, A2.X2.Y1.Z8,
A2.X2.Y1.Z9, A2.X2.Y1.Z10, A2.X2.Y1.Z11, A2.X2.Y1.Z12,
A2.X2.Y1.Z13, A2.X2.Y1.Z14, A2.X2.Y2.Z1, A2.X2.Y2.Z2, A2.X2.Y2.Z3,
A2.X2.Y2.Z4, A2.X2.Y2.Z5, A2.X2.Y2.Z6, A2.X2.Y2.Z7, A2.X2.Y2.Z8,
A2.X2.Y2.Z9, A2.X2.Y2.Z10, A2.X2.Y2.Z11, A2.X2.Y2.Z12,
A2.X2.Y2.Z13, A2.X2.Y2.Z14, A2.X2.Y3.Z1, A2.X2.Y3.Z2, A2.X2.Y3.Z3,
A2.X2.Y3.Z4, A2.X2.Y3.Z5, A2.X2.Y3.Z6, A2.X2.Y3.Z7, A2.X2.Y3.Z8,
A2.X2.Y3.Z9, A2.X2.Y3.Z10, A2.X2.Y3.Z11, A2.X2.Y3.Z12,
A2.X2.Y3.Z13, A2.X2.Y3.Z14, A2.X2.Y4.Z1, A2.X2.Y4.Z2, A2.X2.Y4.Z3,
A2.X2.Y4.Z4, A2.X2.Y4.Z5, A2.X2.Y4.Z6, A2.X2.Y4.Z7, A2.X2.Y4.Z8,
A2.X2.Y4.Z9, A2.X2.Y4.Z10, A2.X2.Y4.Z11, A2.X2.Y4.Z12,
A2.X2.Y4.Z13, A2.X2.Y4.Z14, A2.X2.Y5.Z1, A2.X2.Y5.Z2, A2.X2.Y5.Z3,
A2.X2.Y5.Z4, A2.X2.Y5.Z5, A2.X2.Y5.Z6, A2.X2.Y5.Z7, A2.X2.Y5.Z8,
A2.X2.Y5.Z9, A2.X2.Y5.Z10, A2.X2.Y5.Z11, A2.X2.Y5.Z12,
A2.X2.Y5.Z13, A2.X2.Y5.Z14, A2.X3.Y1.Z1, A2.X3.Y1.Z2, A2.X3.Y1.Z3,
A2.X3.Y1.Z4, A2.X3.Y1.Z5, A2.X3.Y1.Z6, A2.X3.Y1.Z7, A2.X3.Y1.Z8,
A2.X3.Y1.Z9, A2.X3.Y1.Z10, A2.X3.Y1.Z11, A2.X3.Y1.Z12,
A2.X3.Y1.Z13, A2.X3.Y1.Z14, A2.X3.Y2.Z1, A2.X3.Y2.Z2, A2.X3.Y2.Z3,
A2.X3.Y2.Z4, A2.X3.Y2.Z5, A2.X3.Y2.Z6, A2.X3.Y2.Z7, A2.X3.Y2.Z8,
A2.X3.Y2.Z9, A2.X3.Y2.Z10, A2.X3.Y2.Z11, A2.X3.Y2.Z12,
A2.X3.Y2.Z13, A2.X3.Y2.Z14, A2.X3.Y3.Z1, A2.X3.Y3.Z2, A2.X3.Y3.Z3,
A2.X3.Y3.Z4, A2.X3.Y3.Z5, A2.X3.Y3.Z6, A2.X3.Y3.Z7, A2.X3.Y3.Z8,
A2.X3.Y3.Z9, A2.X3.Y3.Z10, A2.X3.Y3.Z11, A2.X3.Y3.Z12,
A2.X3.Y3.Z13, A2.X3.Y3.Z14, A2.X3.Y4.Z1, A2.X3.Y4.Z2, A2.X3.Y4.Z3,
A2.X3.Y4.Z4, A2.X3.Y4.Z5, A2.X3.Y4.Z6, A2.X3.Y4.Z7, A2.X3.Y4.Z8,
A2.X3.Y4.Z9, A2.X3.Y4.Z10, A2.X3.Y4.Z11, A2.X3.Y4.Z12,
A2.X3.Y4.Z13, A2.X3.Y4.Z14, A2.X3.Y5.Z1, A2.X3.Y5.Z2, A2.X3.Y5.Z3,
A2.X3.Y5.Z4, A2.X3.Y5.Z5, A2.X3.Y5.Z6, A2.X3.Y5.Z7, A2.X3.Y5.Z8,
A2.X3.Y5.Z9, A2.X3.Y5.Z10, A2.X3.Y5.Z11, A2.X3.Y5.Z12,
A2.X3.Y5.Z13, A2.X3.Y5.Z14, A2.X4.Y1.Z1, A2.X4.Y1.Z2, A2.X4.Y1.Z3,
A2.X4.Y1.Z4, A2.X4.Y1.Z5, A2.X4.Y1.Z6, A2.X4.Y1.Z7, A2.X4.Y1.Z8,
A2.X4.Y1.Z9, A2.X4.Y1.Z10, A2.X4.Y1.Z11, A2.X4.Y1.Z12,
A2.X4.Y1.Z13, A2.X4.Y1.Z14, A2.X4.Y2.Z1, A2.X4.Y2.Z2, A2.X4.Y2.Z3,
A2.X4.Y2.Z4, A2.X4.Y2.Z5, A2.X4.Y2.Z6, A2.X4.Y2.Z7, A2.X4.Y2.Z8,
A2.X4.Y2.Z9, A2.X4.Y2.Z10, A2.X4.Y2.Z11, A2.X4.Y2.Z12,
A2.X4.Y2.Z13, A2.X4.Y2.Z14, A2.X4.Y3.Z1, A2.X4.Y3.Z2, A2.X4.Y3.Z3,
A2.X4.Y3.Z4, A2.X4.Y3.Z5, A2.X4.Y3.Z6, A2.X4.Y3.Z7, A2.X4.Y3.Z8,
A2.X4.Y3.Z9, A2.X4.Y3.Z10, A2.X4.Y3.Z11, A2.X4.Y3.Z12,
A2.X4.Y3.Z13, A2.X4.Y3.Z14, A2.X4.Y4.Z1, A2.X4.Y4.Z2, A2.X4.Y4.Z3,
A2.X4.Y4.Z4, A2.X4.Y4.Z5, A2.X4.Y4.Z6, A2.X4.Y4.Z7, A2.X4.Y4.Z8,
A2.X4.Y4.Z9, A2.X4.Y4.Z10, A2.X4.Y4.Z11, A2.X4.Y4.Z12,
A2.X4.Y4.Z13, A2.X4.Y4.Z14, A2.X4.Y5.Z1, A2.X4.Y5.Z2, A2.X4.Y5.Z3,
A2.X4.Y5.Z4, A2.X4.Y5.Z5, A2.X4.Y5.Z6, A2.X4.Y5.Z7, A2.X4.Y5.Z8,
A2.X4.Y5.Z9, A2.X4.Y5.Z10, A2.X4.Y5.Z11, A2.X4.Y5.Z12,
A2.X4.Y5.Z13, A2.X4.Y5.Z14, A2.X5.Y1.Z1, A2.X5.Y1.Z2, A2.X5.Y1.Z3,
A2.X5.Y1.Z4, A2.X5.Y1.Z5, A2.X5.Y1.Z6, A2.X5.Y1.Z7, A2.X5.Y1.Z8,
A2.X5.Y1.Z9, A2.X5.Y1.Z10, A2.X5.Y1.Z11, A2.X5.Y1.Z12,
A2.X5.Y1.Z13, A2.X5.Y1.Z14, A2.X5.Y2.Z1, A2.X5.Y2.Z2, A2.X5.Y2.Z3,
A2.X5.Y2.Z4, A2.X5.Y2.Z5, A2.X5.Y2.Z6, A2.X5.Y2.Z7, A2.X5.Y2.Z8,
A2.X5.Y2.Z9, A2.X5.Y2.Z10, A2.X5.Y2.Z11, A2.X5.Y2.Z12,
A2.X5.Y2.Z13, A2.X5.Y2.Z14, A2.X5.Y3.Z1, A2.X5.Y3.Z2, A2.X5.Y3.Z3,
A2.X5.Y3.Z4, A2.X5.Y3.Z5, A2.X5.Y3.Z6, A2.X5.Y3.Z7, A2.X5.Y3.Z8,
A2.X5.Y3.Z9, A2.X5.Y3.Z10, A2.X5.Y3.Z11, A2.X5.Y3.Z12,
A2.X5.Y3.Z13, A2.X5.Y3.Z14, A2.X5.Y4.Z1, A2.X5.Y4.Z2, A2.X5.Y4.Z3,
A2.X5.Y4.Z4, A2.X5.Y4.Z5, A2.X5.Y4.Z6, A2.X5.Y4.Z7, A2.X5.Y4.Z8,
A2.X5.Y4.Z9, A2.X5.Y4.Z10, A2.X5.Y4.Z11, A2.X5.Y4.Z12,
A2.X5.Y4.Z13, A2.X5.Y4.Z14, A2.X5.Y5.Z1, A2.X5.Y5.Z2, A2.X5.Y5.Z3,
A2.X5.Y5.Z4, A2.X5.Y5.Z5, A2.X5.Y5.Z6, A2.X5.Y5.Z7, A2.X5.Y5.Z8,
A2.X5.Y5.Z9, A2.X5.Y5.Z10, A2.X5.Y5.Z11, A2.X5.Y5.Z12,
A2.X5.Y5.Z13, A2.X5.Y5.Z14, A3.X1.Y1.Z1, A3.X1.Y1.Z2, A3.X1.Y1.Z3,
A3.X1.Y1.Z4, A3.X1.Y1.Z5, A3.X1.Y1.Z6, A3.X1.Y1.Z7, A3.X1.Y1.Z8,
A3.X1.Y1.Z9, A3.X1.Y1.Z10, A3.X1.Y1.Z11, A3.X1.Y1.Z12,
A3.X1.Y1.Z13, A3.X1.Y1.Z14, A3.X1.Y2.Z1, A3.X1.Y2.Z2, A3.X1.Y2.Z3,
A3.X1.Y2.Z4, A3.X1.Y2.Z5, A3.X1.Y2.Z6, A3.X1.Y2.Z7, A3.X1.Y2.Z8,
A3.X1.Y2.Z9, A3.X1.Y2.Z10, A3.X1.Y2.Z11, A3.X1.Y2.Z12,
A3.X1.Y2.Z13, A3.X1.Y2.Z14, A3.X1.Y3.Z1, A3.X1.Y3.Z2, A3.X1.Y3.Z3,
A3.X1.Y3.Z4, A3.X1.Y3.Z5, A3.X1.Y3.Z6, A3.X1.Y3.Z7, A3.X1.Y3.Z8,
A3.X1.Y3.Z9, A3.X1.Y3.Z10, A3.X1.Y3.Z11, A3.X1.Y3.Z12,
A3.X1.Y3.Z13, A3.X1.Y3.Z14, A3.X1.Y4.Z1, A3.X1.Y4.Z2, A3.X1.Y4.Z3,
A3.X1.Y4.Z4, A3.X1.Y4.Z5, A3.X1.Y4.Z6, A3.X1.Y4.Z7, A3.X1.Y4.Z8,
A3.X1.Y4.Z9, A3.X1.Y4.Z10, A3.X1.Y4.Z11, A3.X1.Y4.Z12,
A3.X1.Y4.Z13, A3.X1.Y4.Z14, A3.X1.Y5.Z1, A3.X1.Y5.Z2, A3.X1.Y5.Z3,
A3.X1.Y5.Z4, A3.X1.Y5.Z5, A3.X1.Y5.Z6, A3.X1.Y5.Z7, A3.X1.Y5.Z8,
A3.X1.Y5.Z9, A3.X1.Y5.Z10, A3.X1.Y5.Z11, A3.X1.Y5.Z12,
A3.X1.Y5.Z13, A3.X1.Y5.Z14, A3.X2.Y1.Z1, A3.X2.Y1.Z2, A3.X2.Y1.Z3,
A3.X2.Y1.Z4, A3.X2.Y1.Z5, A3.X2.Y1.Z6, A3.X2.Y1.Z7, A3.X2.Y1.Z8,
A3.X2.Y1.Z9, A3.X2.Y1.Z10, A3.X2.Y1.Z11, A3.X2.Y1.Z12,
A3.X2.Y1.Z13, A3.X2.Y1.Z14, A3.X2.Y2.Z1, A3.X2.Y2.Z2, A3.X2.Y2.Z3,
A3.X2.Y2.Z4, A3.X2.Y2.Z5, A3.X2.Y2.Z6, A3.X2.Y2.Z7, A3.X2.Y2.Z8,
A3.X2.Y2.Z9, A3.X2.Y2.Z10, A3.X2.Y2.Z11, A3.X2.Y2.Z12,
A3.X2.Y2.Z13, A3.X2.Y2.Z14, A3.X2.Y3.Z1, A3.X2.Y3.Z2, A3.X2.Y3.Z3,
A3.X2.Y3.Z4, A3.X2.Y3.Z5, A3.X2.Y3.Z6, A3.X2.Y3.Z7, A3.X2.Y3.Z8,
A3.X2.Y3.Z9, A3.X2.Y3.Z10, A3.X2.Y3.Z11, A3.X2.Y3.Z12,
A3.X2.Y3.Z13, A3.X2.Y3.Z14, A3.X2.Y4.Z1, A3.X2.Y4.Z2, A3.X2.Y4.Z3,
A3.X2.Y4.Z4, A3.X2.Y4.Z5, A3.X2.Y4.Z6, A3.X2.Y4.Z7, A3.X2.Y4.Z8,
A3.X2.Y4.Z9, A3.X2.Y4.Z10, A3.X2.Y4.Z11, A3.X2.Y4.Z12,
A3.X2.Y4.Z13, A3.X2.Y4.Z14, A3.X2.Y5.Z1, A3.X2.Y5.Z2, A3.X2.Y5.Z3,
A3.X2.Y5.Z4, A3.X2.Y5.Z5, A3.X2.Y5.Z6, A3.X2.Y5.Z7, A3.X2.Y5.Z8,
A3.X2.Y5.Z9, A3.X2.Y5.Z10, A3.X2.Y5.Z11, A3.X2.Y5.Z12,
A3.X2.Y5.Z13, A3.X2.Y5.Z14, A3.X3.Y1.Z1, A3.X3.Y1.Z2, A3.X3.Y1.Z3,
A3.X3.Y1.Z4, A3.X3.Y1.Z5, A3.X3.Y1.Z6, A3.X3.Y1.Z7, A3.X3.Y1.Z8,
A3.X3.Y1.Z9, A3.X3.Y1.Z10, A3.X3.Y1.Z11, A3.X3.Y1.Z12,
A3.X3.Y1.Z13, A3.X3.Y1.Z14, A3.X3.Y2.Z1, A3.X3.Y2.Z2, A3.X3.Y2.Z3,
A3.X3.Y2.Z4, A3.X3.Y2.Z5, A3.X3.Y2.Z6,
A3.X3.Y2.Z7, A3.X3.Y2.Z8, A3.X3.Y2.Z9, A3.X3.Y2.Z10, A3.X3.Y2.Z11,
A3.X3.Y2.Z12, A3.X3.Y2.Z13, A3.X3.Y2.Z14, A3.X3.Y3.Z1, A3.X3.Y3.Z2,
A3.X3.Y3.Z3, A3.X3.Y3.Z4, A3.X3.Y3.Z5, A3.X3.Y3.Z6, A3.X3.Y3.Z7,
A3.X3.Y3.Z8, A3.X3.Y3.Z9, A3.X3.Y3.Z10, A3.X3.Y3.Z11, A3.X3.Y3.Z12,
A3.X3.Y3.Z13, A3.X3.Y3.Z14, A3.X3.Y4.Z1, A3.X3.Y4.Z2, A3.X3.Y4.Z3,
A3.X3.Y4.Z4, A3.X3.Y4.Z5, A3.X3.Y4.Z6, A3.X3.Y4.Z7, A3.X3.Y4.Z8,
A3.X3.Y4.Z9, A3.X3.Y4.Z10, A3.X3.Y4.Z11, A3.X3.Y4.Z12,
A3.X3.Y4.Z13, A3.X3.Y4.Z14, A3.X3.Y5.Z1, A3.X3.Y5.Z2, A3.X3.Y5.Z3,
A3.X3.Y5.Z4, A3.X3.Y5.Z5, A3.X3.Y5.Z6, A3.X3.Y5.Z7, A3.X3.Y5.Z8,
A3.X3.Y5.Z9, A3.X3.Y5.Z10, A3.X3.Y5.Z11, A3.X3.Y5.Z12,
A3.X3.Y5.Z13, A3.X3.Y5.Z14, A3.X4.Y1.Z1, A3.X4.Y1.Z2, A3.X4.Y1.Z3,
A3.X4.Y1.Z4, A3.X4.Y1.Z5, A3.X4.Y1.Z6, A3.X4.Y1.Z7, A3.X4.Y1.Z8,
A3.X4.Y1.Z9, A3.X4.Y1.Z10, A3.X4.Y1.Z11, A3.X4.Y1.Z12,
A3.X4.Y1.Z13, A3.X4.Y1.Z14, A3.X4.Y2.Z1, A3.X4.Y2.Z2, A3.X4.Y2.Z3,
A3.X4.Y2.Z4, A3.X4.Y2.Z5, A3.X4.Y2.Z6, A3.X4.Y2.Z7, A3.X4.Y2.Z8,
A3.X4.Y2.Z9, A3.X4.Y2.Z10, A3.X4.Y2.Z11, A3.X4.Y2.Z12,
A3.X4.Y2.Z13, A3.X4.Y2.Z14, A3.X4.Y3.Z1, A3.X4.Y3.Z2, A3.X4.Y3.Z3,
A3.X4.Y3.Z4, A3.X4.Y3.Z5, A3.X4.Y3.Z6, A3.X4.Y3.Z7, A3.X4.Y3.Z8,
A3.X4.Y3.Z9, A3.X4.Y3.Z10, A3.X4.Y3.Z11, A3.X4.Y3.Z12,
A3.X4.Y3.Z13, A3.X4.Y3.Z14, A3.X4.Y4.Z1, A3.X4.Y4.Z2, A3.X4.Y4.Z3,
A3.X4.Y4.Z4, A3.X4.Y4.Z5, A3.X4.Y4.Z6, A3.X4.Y4.Z7, A3.X4.Y4.Z8,
A3.X4.Y4.Z9, A3.X4.Y4.Z10, A3.X4.Y4.Z11, A3.X4.Y4.Z12,
A3.X4.Y4.Z13, A3.X4.Y4.Z14, A3.X4.Y5.Z1, A3.X4.Y5.Z2, A3.X4.Y5.Z3,
A3.X4.Y5.Z4, A3.X4.Y5.Z5, A3.X4.Y5.Z6, A3.X4.Y5.Z7, A3.X4.Y5.Z8,
A3.X4.Y5.Z9, A3.X4.Y5.Z10, A3.X4.Y5.Z11, A3.X4.Y5.Z12,
A3.X4.Y5.Z13, A3.X4.Y5.Z14, A3.X5.Y1.Z1, A3.X5.Y1.Z2, A3.X5.Y1.Z3,
A3.X5.Y1.Z4, A3.X5.Y1.Z5, A3.X5.Y1.Z6, A3.X5.Y1.Z7, A3.X5.Y1.Z8,
A3.X5.Y1.Z9, A3.X5.Y1.Z10, A3.X5.Y1.Z11, A3.X5.Y1.Z12,
A3.X5.Y1.Z13, A3.X5.Y1.Z14, A3.X5.Y2.Z1, A3.X5.Y2.Z2, A3.X5.Y2.Z3,
A3.X5.Y2.Z4, A3.X5.Y2.Z5, A3.X5.Y2.Z6, A3.X5.Y2.Z7, A3.X5.Y2.Z8,
A3.X5.Y2.Z9, A3.X5.Y2.Z10, A3.X5.Y2.Z11, A3.X5.Y2.Z12,
A3.X5.Y2.Z13, A3.X5.Y2.Z14, A3.X5.Y3.Z1, A3.X5.Y3.Z2, A3.X5.Y3.Z3,
A3.X5.Y3.Z4, A3.X5.Y3.Z5, A3.X5.Y3.Z6, A3.X5.Y3.Z7, A3.X5.Y3.Z8,
A3.X5.Y3.Z9, A3.X5.Y3.Z10, A3.X5.Y3.Z11, A3.X5.Y3.Z12,
A3.X5.Y3.Z13, A3.X5.Y3.Z14, A3.X5.Y4.Z1, A3.X5.Y4.Z2, A3.X5.Y4.Z3,
A3.X5.Y4.Z4, A3.X5.Y4.Z5, A3.X5.Y4.Z6, A3.X5.Y4.Z7, A3.X5.Y4.Z8,
A3.X5.Y4.Z9, A3.X5.Y4.Z10, A3.X5.Y4.Z11, A3.X5.Y4.Z12,
A3.X5.Y4.Z13, A3.X5.Y4.Z14, A3.X5.Y5.Z1, A3.X5.Y5.Z2, A3.X5.Y5.Z3,
A3.X5.Y5.Z4, A3.X5.Y5.Z5, A3.X5.Y5.Z6, A3.X5.Y5.Z7, A3.X5.Y5.Z8,
A3.X5.Y5.Z9, A3.X5.Y5.Z10, A3.X5.Y5.Z11, A3.X5.Y5.Z12,
A3.X5.Y5.Z13, A3.X5.Y5.Z14, A4.X1.Y1.Z1, A4.X1.Y1.Z2, A4.X1.Y1.Z3,
A4.X1.Y1.Z4, A4.X1.Y1.Z5, A4.X1.Y1.Z6, A4.X1.Y1.Z7, A4.X1.Y1.Z8,
A4.X1.Y1.Z9, A4.X1.Y1.Z10, A4.X1.Y1.Z11, A4.X1.Y1.Z12,
A4.X1.Y1.Z13, A4.X1.Y1.Z14, A4.X1.Y2.Z1, A4.X1.Y2.Z2, A4.X1.Y2.Z3,
A4.X1.Y2.Z4, A4.X1.Y2.Z5, A4.X1.Y2.Z6, A4.X1.Y2.Z7, A4.X1.Y2.Z8,
A4.X1.Y2.Z9, A4.X1.Y2.Z10, A4.X1.Y2.Z11, A4.X1.Y2.Z12,
A4.X1.Y2.Z13, A4.X1.Y2.Z14, A4.X1.Y3.Z1, A4.X1.Y3.Z2, A4.X1.Y3.Z3,
A4.X1.Y3.Z4, A4.X1.Y3.Z5, A4.X1.Y3.Z6, A4.X1.Y3.Z7, A4.X1.Y3.Z8,
A4.X1.Y3.Z9, A4.X1.Y3.Z10, A4.X1.Y3.Z11, A4.X1.Y3.Z12,
A4.X1.Y3.Z13, A4.X1.Y3.Z14, A4.X1.Y4.Z1, A4.X1.Y4.Z2, A4.X1.Y4.Z3,
A4.X1.Y4.Z4, A4.X1.Y4.Z5, A4.X1.Y4.Z6, A4.X1.Y4.Z7, A4.X1.Y4.Z8,
A4.X1.Y4.Z9, A4.X1.Y4.Z10, A4.X1.Y4.Z11, A4.X1.Y4.Z12,
A4.X1.Y4.Z13, A4.X1.Y4.Z14, A4.X1.Y5.Z1, A4.X1.Y5.Z2, A4.X1.Y5.Z3,
A4.X1.Y5.Z4, A4.X1.Y5.Z5, A4.X1.Y5.Z6, A4.X1.Y5.Z7, A4.X1.Y5.Z8,
A4.X1.Y5.Z9, A4.X1.Y5.Z10, A4.X1.Y5.Z11, A4.X1.Y5.Z12,
A4.X1.Y5.Z13, A4.X1.Y5.Z14, A4.X2.Y1.Z1, A4.X2.Y1.Z2, A4.X2.Y1.Z3,
A4.X2.Y1.Z4, A4.X2.Y1.Z5, A4.X2.Y1.Z6, A4.X2.Y1.Z7, A4.X2.Y1.Z8,
A4.X2.Y1.Z9, A4.X2.Y1.Z10, A4.X2.Y1.Z11, A4.X2.Y1.Z12,
A4.X2.Y1.Z13, A4.X2.Y1.Z14, A4.X2.Y2.Z1, A4.X2.Y2.Z2, A4.X2.Y2.Z3,
A4.X2.Y2.Z4, A4.X2.Y2.Z5, A4.X2.Y2.Z6, A4.X2.Y2.Z7, A4.X2.Y2.Z8,
A4.X2.Y2.Z9, A4.X2.Y2.Z10, A4.X2.Y2.Z11, A4.X2.Y2.Z12,
A4.X2.Y2.Z13, A4.X2.Y2.Z14, A4.X2.Y3.Z1, A4.X2.Y3.Z2, A4.X2.Y3.Z3,
A4.X2.Y3.Z4, A4.X2.Y3.Z5, A4.X2.Y3.Z6, A4.X2.Y3.Z7, A4.X2.Y3.Z8,
A4.X2.Y3.Z9, A4.X2.Y3.Z10, A4.X2.Y3.Z11, A4.X2.Y3.Z12,
A4.X2.Y3.Z13, A4.X2.Y3.Z14, A4.X2.Y4.Z1, A4.X2.Y4.Z2, A4.X2.Y4.Z3,
A4.X2.Y4.Z4, A4.X2.Y4.Z5, A4.X2.Y4.Z6, A4.X2.Y4.Z7, A4.X2.Y4.Z8,
A4.X2.Y4.Z9, A4.X2.Y4.Z10, A4.X2.Y4.Z11, A4.X2.Y4.Z12,
A4.X2.Y4.Z13, A4.X2.Y4.Z14, A4.X2.Y5.Z1, A4.X2.Y5.Z2, A4.X2.Y5.Z3,
A4.X2.Y5.Z4, A4.X2.Y5.Z5, A4.X2.Y5.Z6, A4.X2.Y5.Z7, A4.X2.Y5.Z8,
A4.X2.Y5.Z9, A4.X2.Y5.Z10, A4.X2.Y5.Z11, A4.X2.Y5.Z12,
A4.X2.Y5.Z13, A4.X2.Y5.Z14, A4.X3.Y1.Z1, A4.X3.Y1.Z2, A4.X3.Y1.Z3,
A4.X3.Y1.Z4, A4.X3.Y1.Z5, A4.X3.Y1.Z6, A4.X3.Y1.Z7, A4.X3.Y1.Z8,
A4.X3.Y1.Z9, A4.X3.Y1.Z10, A4.X3.Y1.Z11, A4.X3.Y1.Z12,
A4.X3.Y1.Z13, A4.X3.Y1.Z14, A4.X3.Y2.Z1, A4.X3.Y2.Z2, A4.X3.Y2.Z3,
A4.X3.Y2.Z4, A4.X3.Y2.Z5, A4.X3.Y2.Z6, A4.X3.Y2.Z7, A4.X3.Y2.Z8,
A4.X3.Y2.Z9, A4.X3.Y2.Z10, A4.X3.Y2.Z11, A4.X3.Y2.Z12,
A4.X3.Y2.Z13, A4.X3.Y2.Z14, A4.X3.Y3.Z1, A4.X3.Y3.Z2, A4.X3.Y3.Z3,
A4.X3.Y3.Z4, A4.X3.Y3.Z5, A4.X3.Y3.Z6, A4.X3.Y3.Z7, A4.X3.Y3.Z8,
A4.X3.Y3.Z9, A4.X3.Y3.Z10, A4.X3.Y3.Z11, A4.X3.Y3.Z12,
A4.X3.Y3.Z13, A4.X3.Y3.Z14, A4.X3.Y4.Z1, A4.X3.Y4.Z2, A4.X3.Y4.Z3,
A4.X3.Y4.Z4, A4.X3.Y4.Z5, A4.X3.Y4.Z6, A4.X3.Y4.Z7, A4.X3.Y4.Z8,
A4.X3.Y4.Z9, A4.X3.Y4.Z10, A4.X3.Y4.Z11, A4.X3.Y4.Z12,
A4.X3.Y4.Z13, A4.X3.Y4.Z14, A4.X3.Y5.Z1, A4.X3.Y5.Z2, A4.X3.Y5.Z3,
A4.X3.Y5.Z4, A4.X3.Y5.Z5, A4.X3.Y5.Z6, A4.X3.Y5.Z7, A4.X3.Y5.Z8,
A4.X3.Y5.Z9, A4.X3.Y5.Z10, A4.X3.Y5.Z11, A4.X3.Y5.Z12,
A4.X3.Y5.Z13, A4.X3.Y5.Z14, A4.X4.Y1.Z1, A4.X4.Y1.Z2, A4.X4.Y1.Z3,
A4.X4.Y1.Z4, A4.X4.Y1.Z5, A4.X4.Y1.Z6, A4.X4.Y1.Z7, A4.X4.Y1.Z8,
A4.X4.Y1.Z9, A4.X4.Y1.Z10, A4.X4.Y1.Z11, A4.X4.Y1.Z12,
A4.X4.Y1.Z13, A4.X4.Y1.Z14, A4.X4.Y2.Z1, A4.X4.Y2.Z2, A4.X4.Y2.Z3,
A4.X4.Y2.Z4, A4.X4.Y2.Z5, A4.X4.Y2.Z6, A4.X4.Y2.Z7, A4.X4.Y2.Z8,
A4.X4.Y2.Z9, A4.X4.Y2.Z10, A4.X4.Y2.Z11, A4.X4.Y2.Z12,
A4.X4.Y2.Z13, A4.X4.Y2.Z14, A4.X4.Y3.Z1, A4.X4.Y3.Z2, A4.X4.Y3.Z3,
A4.X4.Y3.Z4, A4.X4.Y3.Z5, A4.X4.Y3.Z6, A4.X4.Y3.Z7, A4.X4.Y3.Z8,
A4.X4.Y3.Z9, A4.X4.Y3.Z10, A4.X4.Y3.Z11, A4.X4.Y3.Z12,
A4.X4.Y3.Z13, A4.X4.Y3.Z14, A4.X4.Y4.Z1, A4.X4.Y4.Z2, A4.X4.Y4.Z3,
A4.X4.Y4.Z4, A4.X4.Y4.Z5, A4.X4.Y4.Z6, A4.X4.Y4.Z7, A4.X4.Y4.Z8,
A4.X4.Y4.Z9, A4.X4.Y4.Z10, A4.X4.Y4.Z11, A4.X4.Y4.Z12,
A4.X4.Y4.Z13, A4.X4.Y4.Z14, A4.X4.Y5.Z1, A4.X4.Y5.Z2, A4.X4.Y5.Z3,
A4.X4.Y5.Z4, A4.X4.Y5.Z5, A4.X4.Y5.Z6, A4.X4.Y5.Z7, A4.X4.Y5.Z8,
A4.X4.Y5.Z9, A4.X4.Y5.Z10, A4.X4.Y5.Z11, A4.X4.Y5.Z12,
A4.X4.Y5.Z13, A4.X4.Y5.Z14, A4.X5.Y1.Z1, A4.X5.Y1.Z2, A4.X5.Y1.Z3,
A4.X5.Y1.Z4, A4.X5.Y1.Z5, A4.X5.Y1.Z6, A4.X5.Y1.Z7, A4.X5.Y1.Z8,
A4.X5.Y1.Z9, A4.X5.Y1.Z10, A4.X5.Y1.Z11, A4.X5.Y1.Z12,
A4.X5.Y1.Z13, A4.X5.Y1.Z14, A4.X5.Y2.Z1, A4.X5.Y2.Z2, A4.X5.Y2.Z3,
A4.X5.Y2.Z4, A4.X5.Y2.Z5, A4.X5.Y2.Z6, A4.X5.Y2.Z7, A4.X5.Y2.Z8,
A4.X5.Y2.Z9, A4.X5.Y2.Z10, A4.X5.Y2.Z11, A4.X5.Y2.Z12,
A4.X5.Y2.Z13, A4.X5.Y2.Z14, A4.X5.Y3.Z1, A4.X5.Y3.Z2, A4.X5.Y3.Z3,
A4.X5.Y3.Z4, A4.X5.Y3.Z5, A4.X5.Y3.Z6, A4.X5.Y3.Z7, A4.X5.Y3.Z8,
A4.X5.Y3.Z9, A4.X5.Y3.Z10, A4.X5.Y3.Z11, A4.X5.Y3.Z12,
A4.X5.Y3.Z13, A4.X5.Y3.Z14, A4.X5.Y4.Z1, A4.X5.Y4.Z2, A4.X5.Y4.Z3,
A4.X5.Y4.Z4, A4.X5.Y4.Z5, A4.X5.Y4.Z6, A4.X5.Y4.Z7, A4.X5.Y4.Z8,
A4.X5.Y4.Z9, A4.X5.Y4.Z10, A4.X5.Y4.Z11, A4.X5.Y4.Z12,
A4.X5.Y4.Z13, A4.X5.Y4.Z14, A4.X5.Y5.Z1, A4.X5.Y5.Z2, A4.X5.Y5.Z3,
A4.X5.Y5.Z4, A4.X5.Y5.Z5, A4.X5.Y5.Z6, A4.X5.Y5.Z7, A4.X5.Y5.Z8,
A4.X5.Y5.Z9, A4.X5.Y5.Z10, A4.X5.Y5.Z11, A4.X5.Y5.Z12,
A4.X5.Y5.Z13, A4.X5.Y5.Z14, A5.X1.Y1.Z1, A5.X1.Y1.Z2, A5.X1.Y1.Z3,
A5.X1.Y1.Z4, A5.X1.Y1.Z5, A5.X1.Y1.Z6, A5.X1.Y1.Z7, A5.X1.Y1.Z8,
A5.X1.Y1.Z9, A5.X1.Y1.Z10, A5.X1.Y1.Z11, A5.X1.Y1.Z12,
A5.X1.Y1.Z13, A5.X1.Y1.Z14, A5.X1.Y2.Z1, A5.X1.Y2.Z2, A5.X1.Y2.Z3,
A5.X1.Y2.Z4, A5.X1.Y2.Z5, A5.X1.Y2.Z6, A5.X1.Y2.Z7, A5.X1.Y2.Z8,
A5.X1.Y2.Z9, A5.X1.Y2.Z10, A5.X1.Y2.Z11, A5.X1.Y2.Z12,
A5.X1.Y2.Z13, A5.X1.Y2.Z14, A5.X1.Y3.Z1, A5.X1.Y3.Z2, A5.X1.Y3.Z3,
A5.X1.Y3.Z4, A5.X1.Y3.Z5, A5.X1.Y3.Z6, A5.X1.Y3.Z7, A5.X1.Y3.Z8,
A5.X1.Y3.Z9, A5.X1.Y3.Z10, A5.X1.Y3.Z11, A5.X1.Y3.Z12,
A5.X1.Y3.Z13, A5.X1.Y3.Z14, A5.X1.Y4.Z1, A5.X1.Y4.Z2, A5.X1.Y4.Z3,
A5.X1.Y4.Z4, A5.X1.Y4.Z5, A5.X1.Y4.Z6, A5.X1.Y4.Z7, A5.X1.Y4.Z8,
A5.X1.Y4.Z9, A5.X1.Y4.Z10, A5.X1.Y4.Z11, A5.X1.Y4.Z12,
A5.X1.Y4.Z13, A5.X1.Y4.Z14, A5.X1.Y5.Z1, A5.X1.Y5.Z2, A5.X1.Y5.Z3,
A5.X1.Y5.Z4, A5.X1.Y5.Z5, A5.X1.Y5.Z6, A5.X1.Y5.Z7, A5.X1.Y5.Z8,
A5.X1.Y5.Z9, A5.X1.Y5.Z10, A5.X1.Y5.Z11, A5.X1.Y5.Z12,
A5.X1.Y5.Z13, A5.X1.Y5.Z14, A5.X2.Y1.Z1, A5.X2.Y1.Z2, A5.X2.Y1.Z3,
A5.X2.Y1.Z4, A5.X2.Y1.Z5, A5.X2.Y1.Z6, A5.X2.Y1.Z7, A5.X2.Y1.Z8,
A5.X2.Y1.Z9, A5.X2.Y1.Z10, A5.X2.Y1.Z11, A5.X2.Y1.Z12,
A5.X2.Y1.Z13, A5.X2.Y1.Z14, A5.X2.Y2.Z1, A5.X2.Y2.Z2, A5.X2.Y2.Z3,
A5.X2.Y2.Z4, A5.X2.Y2.Z5, A5.X2.Y2.Z6, A5.X2.Y2.Z7, A5.X2.Y2.Z8,
A5.X2.Y2.Z9, A5.X2.Y2.Z10, A5.X2.Y2.Z11, A5.X2.Y2.Z12,
A5.X2.Y2.Z13, A5.X2.Y2.Z14, A5.X2.Y3.Z1, A5.X2.Y3.Z2, A5.X2.Y3.Z3,
A5.X2.Y3.Z4, A5.X2.Y3.Z5, A5.X2.Y3.Z6, A5.X2.Y3.Z7, A5.X2.Y3.Z8,
A5.X2.Y3.Z9, A5.X2.Y3.Z10, A5.X2.Y3.Z11, A5.X2.Y3.Z12,
A5.X2.Y3.Z13, A5.X2.Y3.Z14, A5.X2.Y4.Z1, A5.X2.Y4.Z2, A5.X2.Y4.Z3,
A5.X2.Y4.Z4, A5.X2.Y4.Z5, A5.X2.Y4.Z6, A5.X2.Y4.Z7, A5.X2.Y4.Z8,
A5.X2.Y4.Z9, A5.X2.Y4.Z10, A5.X2.Y4.Z11, A5.X2.Y4.Z12,
A5.X2.Y4.Z13, A5.X2.Y4.Z14, A5.X2.Y5.Z1, A5.X2.Y5.Z2, A5.X2.Y5.Z3,
A5.X2.Y5.Z4, A5.X2.Y5.Z5, A5.X2.Y5.Z6, A5.X2.Y5.Z7, A5.X2.Y5.Z8,
A5.X2.Y5.Z9, A5.X2.Y5.Z10, A5.X2.Y5.Z11, A5.X2.Y5.Z12,
A5.X2.Y5.Z13, A5.X2.Y5.Z14, A5.X3.Y1.Z1, A5.X3.Y1.Z2, A5.X3.Y1.Z3,
A5.X3.Y1.Z4, A5.X3.Y1.Z5, A5.X3.Y1.Z6, A5.X3.Y1.Z7, A5.X3.Y1.Z8,
A5.X3.Y1.Z9, A5.X3.Y1.Z10, A5.X3.Y1.Z11, A5.X3.Y1.Z12,
A5.X3.Y1.Z13, A5.X3.Y1.Z14, A5.X3.Y2.Z1, A5.X3.Y2.Z2, A5.X3.Y2.Z3,
A5.X3.Y2.Z4, A5.X3.Y2.Z5, A5.X3.Y2.Z6, A5.X3.Y2.Z7, A5.X3.Y2.Z8,
A5.X3.Y2.Z9, A5.X3.Y2.Z10, A5.X3.Y2.Z11, A5.X3.Y2.Z12,
A5.X3.Y2.Z13, A5.X3.Y2.Z14, A5.X3.Y3.Z1, A5.X3.Y3.Z2, A5.X3.Y3.Z3,
A5.X3.Y3.Z4, A5.X3.Y3.Z5, A5.X3.Y3.Z6, A5.X3.Y3.Z7, A5.X3.Y3.Z8,
A5.X3.Y3.Z9, A5.X3.Y3.Z10, A5.X3.Y3.Z11, A5.X3.Y3.Z12,
A5.X3.Y3.Z13, A5.X3.Y3.Z14, A5.X3.Y4.Z1, A5.X3.Y4.Z2, A5.X3.Y4.Z3,
A5.X3.Y4.Z4, A5.X3.Y4.Z5, A5.X3.Y4.Z6, A5.X3.Y4.Z7, A5.X3.Y4.Z8,
A5.X3.Y4.Z9, A5.X3.Y4.Z10, A5.X3.Y4.Z11, A5.X3.Y4.Z12,
A5.X3.Y4.Z13, A5.X3.Y4.Z14, A5.X3.Y5.Z1, A5.X3.Y5.Z2, A5.X3.Y5.Z3,
A5.X3.Y5.Z4, A5.X3.Y5.Z5, A5.X3.Y5.Z6, A5.X3.Y5.Z7, A5.X3.Y5.Z8,
A5.X3.Y5.Z9, A5.X3.Y5.Z10, A5.X3.Y5.Z11, A5.X3.Y5.Z12,
A5.X3.Y5.Z13, A5.X3.Y5.Z14, A5.X4.Y1.Z1, A5.X4.Y1.Z2, A5.X4.Y1.Z3,
A5.X4.Y1.Z4, A5.X4.Y1.Z5, A5.X4.Y1.Z6, A5.X4.Y1.Z7, A5.X4.Y1.Z8,
A5.X4.Y1.Z9, A5.X4.Y1.Z10, A5.X4.Y1.Z11, A5.X4.Y1.Z12,
A5.X4.Y1.Z13, A5.X4.Y1.Z14, A5.X4.Y2.Z1, A5.X4.Y2.Z2, A5.X4.Y2.Z3,
A5.X4.Y2.Z4, A5.X4.Y2.Z5, A5.X4.Y2.Z6, A5.X4.Y2.Z7, A5.X4.Y2.Z8,
A5.X4.Y2.Z9, A5.X4.Y2.Z10, A5.X4.Y2.Z11, A5.X4.Y2.Z12,
A5.X4.Y2.Z13, A5.X4.Y2.Z14, A5.X4.Y3.Z1, A5.X4.Y3.Z2, A5.X4.Y3.Z3,
A5.X4.Y3.Z4, A5.X4.Y3.Z5, A5.X4.Y3.Z6, A5.X4.Y3.Z7, A5.X4.Y3.Z8,
A5.X4.Y3.Z9, A5.X4.Y3.Z10, A5.X4.Y3.Z11, A5.X4.Y3.Z12,
A5.X4.Y3.Z13, A5.X4.Y3.Z14, A5.X4.Y4.Z1, A5.X4.Y4.Z2, A5.X4.Y4.Z3,
A5.X4.Y4.Z4, A5.X4.Y4.Z5, A5.X4.Y4.Z6, A5.X4.Y4.Z7, A5.X4.Y4.Z8,
A5.X4.Y4.Z9, A5.X4.Y4.Z10, A5.X4.Y4.Z11, A5.X4.Y4.Z12,
A5.X4.Y4.Z13, A5.X4.Y4.Z14, A5.X4.Y5.Z1, A5.X4.Y5.Z2, A5.X4.Y5.Z3,
A5.X4.Y5.Z4, A5.X4.Y5.Z5, A5.X4.Y5.Z6, A5.X4.Y5.Z7, A5.X4.Y5.Z8,
A5.X4.Y5.Z9, A5.X4.Y5.Z10, A5.X4.Y5.Z11, A5.X4.Y5.Z12,
A5.X4.Y5.Z13, A5.X4.Y5.Z14, A5.X5.Y1.Z1, A5.X5.Y1.Z2, A5.X5.Y1.Z3,
A5.X5.Y1.Z4, A5.X5.Y1.Z5, A5.X5.Y1.Z6, A5.X5.Y1.Z7, A5.X5.Y1.Z8,
A5.X5.Y1.Z9, A5.X5.Y1.Z10, A5.X5.Y1.Z11, A5.X5.Y1.Z12,
A5.X5.Y1.Z13, A5.X5.Y1.Z14, A5.X5.Y2.Z1, A5.X5.Y2.Z2, A5.X5.Y2.Z3,
A5.X5.Y2.Z4, A5.X5.Y2.Z5, A5.X5.Y2.Z6, A5.X5.Y2.Z7, A5.X5.Y2.Z8,
A5.X5.Y2.Z9, A5.X5.Y2.Z10, A5.X5.Y2.Z11, A5.X5.Y2.Z12,
A5.X5.Y2.Z13, A5.X5.Y2.Z14, A5.X5.Y3.Z1, A5.X5.Y3.Z2, A5.X5.Y3.Z3,
A5.X5.Y3.Z4, A5.X5.Y3.Z5, A5.X5.Y3.Z6, A5.X5.Y3.Z7, A5.X5.Y3.Z8,
A5.X5.Y3.Z9, A5.X5.Y3.Z10, A5.X5.Y3.Z11, A5.X5.Y3.Z12,
A5.X5.Y3.Z13, A5.X5.Y3.Z14, A5.X5.Y4.Z1, A5.X5.Y4.Z2, A5.X5.Y4.Z3,
A5.X5.Y4.Z4, A5.X5.Y4.Z5, A5.X5.Y4.Z6, A5.X5.Y4.Z7,
A5.X5.Y4.Z8, A5.X5.Y4.Z9, A5.X5.Y4.Z10, A5.X5.Y4.Z11, A5.X5.Y4.Z12,
A5.X5.Y4.Z13, A5.X5.Y4.Z14, A5.X5.Y5.Z1, A5.X5.Y5.Z2, A5.X5.Y5.Z3,
A5.X5.Y5.Z4, A5.X5.Y5.Z5, A5.X5.Y5.Z6, A5.X5.Y5.Z7, A5.X5.Y5.Z8,
A5.X5.Y5.Z9, A5.X5.Y5.Z10, A5.X5.Y5.Z11, A5.X5.Y5.Z12,
A5.X5.Y5.Z13, A5.X5.Y5.Z14
Pharmaceutical Formulations
[0611] The compounds of this invention are formulated with
conventional carriers and excipients, which will be selected in
accord with ordinary practice. Tablets will contain excipients,
glidants, fillers, binders and the like. Aqueous formulations are
prepared in sterile form, and when intended for delivery by other
than oral administration generally will be isotonic. All
formulations will optionally contain excipients such as those set
forth in the Handbook of Pharmaceutical Excipients (1986), herein
incorporated by reference in its entirety. Excipients include
ascorbic acid and other antioxidants, chelating agents such as
EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,
hydroxyalkylmethylcellulose, stearic acid and the like. The pH of
the formulations ranges from about 3 to about 11, but is ordinarily
about 7 to 10.
[0612] While it is possible for the active ingredients to be
administered alone it may be preferable to present them as
pharmaceutical formulations. The formulations of the invention,
both for veterinary and for human use, comprise at least one active
ingredient, together with one or more acceptable carriers and
optionally other therapeutic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and physiologically innocuous to the
recipient thereof.
[0613] The formulations include those suitable for the foregoing
administration routes. The formulations may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Techniques and
formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by
reference in its entirety. Such methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0614] 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.
[0615] A tablet is made by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered active
ingredient moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and optionally are formulated so as
to provide slow or controlled release of the active ingredient.
[0616] For administration to the eye or other external tissues
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w
and most preferably 0.5 to 10% w/w. When formulated in an ointment,
the active ingredients may be employed with either a paraffinic or
a water-miscible ointment base. Alternatively, the active
ingredients may be formulated in a cream with an oil-in-water cream
base.
[0617] If desired, the aqueous phase of the cream base may include,
for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethyl sulphoxide and related
analogs.
[0618] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0619] Emulgents and emulsion stabilizers suitable for use in the
formulation of the invention include Tween.RTM. 60, Span.RTM. 80,
cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl
mono-stearate and sodium lauryl sulfate.
[0620] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties. The cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils are used.
[0621] Pharmaceutical formulations according to the present
invention comprise one or more compounds of the invention together
with one or more pharmaceutically acceptable carriers or excipients
and optionally other therapeutic agents. Pharmaceutical
formulations 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, lactose monohydrate, croscarmellose sodium, povidone,
calcium or sodium phosphate; granulating and disintegrating agents,
such as maize starch, or alginic acid; binding agents, such as
cellulose, microcrystalline cellulose, 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.
[0622] 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.
[0623] 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.
[0624] 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 herein, 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.
[0625] 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.
[0626] 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. 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.
[0627] 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 herein. 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.
[0628] 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 (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .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.
[0629] Formulations suitable for administration to the eye include
eye drops wherein the active ingredient is dissolved or suspended
in a suitable carrier, especially an aqueous solvent for the active
ingredient. The active ingredient is preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5
to 10% particularly about 1.5% w/w.
[0630] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0631] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0632] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 Mm (including particle sizes in a range between 0.1 and 500
.mu.m in increments such as 0.5 Mm, 1 Mm, 30 Mm, 35 Mm, etc.),
which is administered by rapid inhalation through the nasal passage
or by inhalation through the mouth so as to reach the alveolar
sacs. Suitable formulations include aqueous or oily solutions of
the active ingredient. Formulations suitable for aerosol or dry
powder administration may be prepared according to conventional
methods and may be delivered with other therapeutic agents such as
compounds heretofore used in the treatment or prophylaxis of
infections as described herein.
[0633] 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.
[0634] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0635] The formulations are presented in unit-dose or multi-dose
containers, for example sealed 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
injection, immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0636] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0637] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier.
[0638] Veterinary carriers are materials useful for the purpose of
administering the composition and may be solid, liquid or gaseous
materials which are otherwise inert or acceptable in the veterinary
art and are compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally or by any
other desired route.
[0639] Compounds of the invention can also be formulated to provide
controlled release of the active ingredient to allow less frequent
dosing or to improve the pharmacokinetic or toxicity profile of the
active ingredient. Accordingly, the invention also provided
compositions comprising one or more compounds of the invention
formulated for sustained or controlled release.
[0640] The effective dose of an active ingredient depends at least
on the nature of the condition being treated, toxicity, whether the
compound is being used prophylactically (lower doses) or against an
active disease or condition, the method of delivery, and the
pharmaceutical formulation, and will be determined by the clinician
using conventional dose escalation studies. The effective dose can
be expected to be from about 0.0001 to about 100 mg/kg body weight
per day. Typically, from about 0.01 to about 10 mg/kg body weight
per day. More typically, from about 0.01 to about 5 mg/kg body
weight per day. More typically, from about 0.05 to about 0.5 mg/kg
body weight per day. For example, the daily candidate dose for an
adult human of approximately 70 kg body weight will range from 1 mg
to 1000 mg, or between 5 mg and 500 mg, and may take the form of
single or multiple doses.
[0641] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of Formula I or
II, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, and a pharmaceutically acceptable carrier or
excipient.
[0642] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of Formula I or
II, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, in combination with at least one additional active agent,
and a pharmaceutically acceptable carrier or excipient.
[0643] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of Formula I or
II, or a pharmaceutically acceptable salt, solvate, and/or ester
thereof, in combination with at least one additional active agent,
and a pharmaceutically acceptable carrier or excipient, wherein the
additional active agent is selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
[0644] Examples of the interferons include, but are not limited to
pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b,
rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon,
intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with
DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon
alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated
IFN-beta;
[0645] Examples of the ribavirin analogs include, but are not
limited to rebetol, copegus, and viramidine (taribavirin);
[0646] Examples of the NS5b polymerase inhibitors include, but are
not limited to NM-283, valopicitabine, R1626, PSI-6130 (R1656),
HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048),
VCH-759, PF-868554, and GSK625433;
[0647] Examples of the HCV NS3 protease inhibitors include, but are
not limited to SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065,
BMS-605339, and ITMN-191;
[0648] Examples of the alpha-glucosidase 1 inhibitors include, but
are not limited to MX-3253 (celgosivir) and UT-231B;
[0649] Examples of the hepatoprotectants include, but are not
limited to IDN-6556, ME 3738, LB-84451, and MitoQ;
[0650] Examples of the non-nucleoside inhibitors of HCV include,
but are not limited to benzimidazole derivatives,
benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives,
GS-9190, A-831, and A-689; and
[0651] Examples of the other drugs for treating HCV include, but
are not limited to zadaxin, nitazoxanide (alinea), BIVN-401
(virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),
KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205,
tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065,
Bavituximab, Oglufanide, and VX-497 (merimepodib).
[0652] In yet another embodiment, the present application provides
a combination pharmaceutical agent comprising:
[0653] a) a first pharmaceutical composition comprising a compound
of Formula I or II, or a pharmaceutically acceptable salt, solvate,
or ester thereof; and
[0654] b) a second pharmaceutical composition comprising at least
one additional active agent selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
Routes of Administration
[0655] One or more compounds of the invention (herein referred to
as the active ingredients) are administered by any route
appropriate to the condition to be treated. Suitable routes include
oral, rectal, nasal, topical (including buccal and sublingual),
vaginal and parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), and the like.
It will be appreciated that the preferred route may vary with for
example the condition of the recipient. An advantage of the
compounds of this invention is that they are orally bioavailable
and can be dosed orally.
Combination Therapy
[0656] In one embodiment, the compounds of the present invention
are used in combination with other active therapeutic ingredients
or agents. Combinations of the compounds of Formula I or II and
additional active agents may be selected to treat patients with a
viral infection, e.g., HBV, HCV, or HIV infection.
[0657] Preferably, the other active therapeutic ingredients or
agents are interferons, ribavirin analogs, HCV NS3 protease
inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,
non-nucleoside inhibitors of HCV, and other drugs for treating HCV,
or mixtures thereof.
[0658] Combinations of the compounds of Formula I or II are
typically selected based on the condition to be treated,
cross-reactivities of ingredients and pharmaco-properties of the
combination. For example, when treating an infection (e.g., HCV),
the compositions of the invention are combined with other active
agents (such as those described herein).
[0659] Suitable active agents or ingredients which can be combined
with the compounds of Formula I or II can include interferons,
e.g., pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha
2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon,
intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with
DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon
alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated
IFN-beta; ribavirin analogs, e.g., rebetol, copegus, and viramidine
(taribavirin); NS5b polymerase inhibitors, e.g., NM-283,
valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941,
XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and
GSK625433; HCV NS3 protease inhibitors, e.g., SCH-503034 (SCH-7),
VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191;
alpha-glucosidase 1 inhibitors, e.g., MX-3253 (celgosivir) and
UT-231B; hepatoprotectants, e.g., IDN-6556, ME 3738, LB-84451, and
MitoQ; non-nucleoside inhibitors of HCV, e.g., benzimidazole
derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine
derivatives, GS-9190, A-831, and A-689; and other drugs for
treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-401
(virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),
KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205,
tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065,
Bavituximab, Oglufanide, and VX-497 (merimepodib).
[0660] In yet another embodiment, the present application discloses
pharmaceutical compositions comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, in combination with at least one additional active
agent, and a pharmaceutically acceptable carrier or excipient.
[0661] According to the present invention, the active agent used in
combination with the compound of the present invention can be any
agent having a therapeutic effect when used in combination with the
compound of the present invention. For example, the active agent
used in combination with the compound of the present invention can
be interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
[0662] In another embodiment, the present application provides
pharmaceutical compositions comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, and/or
ester thereof, in combination with at least one additional active
agent selected from the group consisting of interferons, e.g.,
pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b,
rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon,
intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with
DUROS, albuferon, locteron, Albuferon, Rebif, Oral interferon
alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated
IFN-beta; ribavirin analogs, e.g., rebetol, copegus, and viramidine
(taribavirin); NS5b polymerase inhibitors, e.g., NM-283,
valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941,
XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and
GSK625433; HCV NS3 protease inhibitors, e.g., SCH-503034 (SCH-7),
VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191;
alpha-glucosidase 1 inhibitors, e.g., MX-3253 (celgosivir) and
UT-231B; hepatoprotectants, e.g., IDN-6556, ME 3738, LB-84451, and
MitoQ; non-nucleoside inhibitors of HCV, e.g., benzimidazole
derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine
derivatives, GS-9190, A-831, and A-689; and other drugs for
treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-401
(virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),
KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205,
tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065,
Bavituximab, Oglufanide, and VX-497 (merimepodib).
[0663] In yet another embodiment, the present application provides
a combination pharmaceutical agent comprising:
[0664] a) a first pharmaceutical composition comprising a compound
of the present invention, or a pharmaceutically acceptable salt,
solvate, or ester thereof; and
[0665] b) a second pharmaceutical composition comprising at least
one additional active agent selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV, or mixtures
thereof.
[0666] More specifically, one or more compounds of the present
invention may be combined with one or more compounds selected from
the group consisting of interferons, e.g., pegylated rIFN-alpha 2b,
pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus
IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; ribavirin analogs, e.g.,
rebetol, copegus, and viramidine (taribavirin); NS5b polymerase
inhibitors, e.g., NM-283, valopicitabine, R1626, PSI-6130 (R1656),
HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048),
VCH-759, PF-868554, and GSK625433; HCV NS3 protease inhibitors,
e.g., SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065,
BMS-605339, and ITMN-191; alpha-glucosidase 1 inhibitors, e.g.,
MX-3253 (celgosivir) and UT-231B; hepatoprotectants, e.g.,
IDN-6556, ME 3738, LB-84451, and MitoQ; non-nucleoside inhibitors
of HCV, e.g., benzimidazole derivatives, benzo-1,2,4-thiadiazine
derivatives, phenylalanine derivatives, GS-9190, A-831, and A-689;
and other drugs for treating HCV, e.g., zadaxin, nitazoxanide
(alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002,
actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865,
ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C,
EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497
(merimepodib).
[0667] It is also possible to combine any compound of the invention
with one or more other active agents in a unitary dosage form for
simultaneous or sequential administration to a patient. The
combination therapy may be administered as a simultaneous or
sequential regimen. When administered sequentially, the combination
may be administered in two or more administrations.
[0668] Co-administration of a compound of the invention with one or
more other active agents generally refers to simultaneous or
sequential administration of a compound of the invention and one or
more other active agents, such that therapeutically effective
amounts of the compound of the invention and one or more other
active agents are both present in the body of the patient.
[0669] Co-administration includes administration of unit dosages of
the compounds of the invention before or after administration of
unit dosages of one or more other active agents, for example,
administration of the compounds of the invention within seconds,
minutes, or hours of the administration of one or more other active
agents. For example, a unit dose of a compound of the invention can
be administered first, followed within seconds or minutes by
administration of a unit dose of one or more other active agents.
Alternatively, a unit dose of one or more other active agents can
be administered first, followed by administration of a unit dose of
a compound of the invention within seconds or minutes. In some
cases, it may be desirable to administer a unit dose of a compound
of the invention first, followed, after a period of hours (e.g.,
1-12 hours), by administration of a unit dose of one or more other
active agents. In other cases, it may be desirable to administer a
unit dose of one or more other active agents first, followed, after
a period of hours (e.g., 1-12 hours), by administration of a unit
dose of a compound of the invention.
[0670] The combination therapy may provide "synergy" and
"synergistic effect", i.e. the effect achieved when the active
ingredients used together is greater than the sum of the effects
that results from using the compounds separately. A synergistic
effect may be attained when the active ingredients are: (1)
co-formulated and administered or delivered simultaneously in a
combined formulation; (2) delivered by alternation or in parallel
as separate formulations; or (3) by some other regimen. When
delivered in alternation therapy, a synergistic effect may be
attained when the compounds are administered or delivered
sequentially, e.g., in separate tablets, pills or capsules, or by
different injections in separate syringes. In general, during
alternation therapy, an effective dosage of each active ingredient
is administered sequentially, i.e. serially, whereas in combination
therapy, effective dosages of two or more active ingredients are
administered together.
[0671] In still yet another embodiment, the present application
provides for methods of inhibiting HCV polymerase in a cell,
comprising: contacting a cell infected with HCV with an effective
amount of a compound of Formula I or II, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, whereby HCV
polymerase is inhibited.
[0672] In still yet another embodiment, the present application
provides for methods of inhibiting HCV polymerase in a cell,
comprising: contacting a cell infected with HCV with an effective
amount of a compound of Formula I or II, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, and at least one
additional active agent, whereby HCV polymerase is inhibited.
[0673] In still yet another embodiment, the present application
provides for methods of inhibiting HCV polymerase in a cell,
comprising: contacting a cell infected with HCV with an effective
amount of a compound of Formula I or II, or a pharmaceutically
acceptable salt, solvate, and/or ester thereof, and at least one
additional active agent selected from the group consisting of
interferons, ribavirin analogs, HCV NS3 protease inhibitors,
alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside
inhibitors of HCV, and other drugs for treating HCV.
[0674] In still yet another embodiment, the present application
provides for methods of treating a viral infection in a patient,
comprising: administering to the patient a therapeutically
effective amount of a compound of Formula I or II, or a
pharmaceutically acceptable salt, solvate, and/or ester
thereof.
[0675] In still yet another embodiment, the present application
provides for methods of treating a viral infection in a patient,
comprising: administering to the patient a therapeutically
effective amount of a compound of Formula I or II, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
and at least one additional active agent.
[0676] In still yet another embodiment, the present application
provides for methods of treating HCV in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of Formula I or II, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof.
[0677] In still yet another embodiment, the present application
provides for methods of treating HCV in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of Formula I or II, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, and at least one additional
active agent, whereby HCV polymerase is inhibited.
[0678] In still yet another embodiment, the present application
provides for methods of treating HCV in a patient, comprising:
administering to the patient a therapeutically effective amount of
a compound of Formula I or II, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof, and at least one additional
active agent selected from the group consisting of interferons,
ribavirin analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1
inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV,
and other drugs for treating HCV, or mixtures thereof.
[0679] In still yet another embodiment, the present application
provides for the use of a compound of the present invention, or a
pharmaceutically acceptable salt, solvate, and/or ester thereof,
for the preparation of a medicament for treating a viral infection,
e.g., an HBV/HCV infection.
[0680] In yet another embodiment, the present application provides
a method for treating or preventing a viral infection comprising
co-administering, to a patient in need thereof, a therapeutically
effective amount of at least one compound of Formula I or II and at
least one additional active agent selected from the group
consisting of interferons, e.g., pegylated rIFN-alpha 2b, pegylated
rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha
(infergen), feron, reaferon, intermax alpha, r-IFN-beta,
infergen+actimmune, IFN-omega with DUROS, albuferon, locteron,
Albuferon, Rebif, Oral interferon alpha, IFNalpha-2b XL, AVI-005,
PEG-Infergen, and Pegylated IFN-beta; ribavirin analogs, e.g.,
rebetol, copegus, and viramidine (taribavirin); NS5b polymerase
inhibitors, e.g., NM-283, valopicitabine, R1626, PSI-6130 (R1656),
HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048),
VCH-759, PF-868554, and GSK625433; HCV NS3 protease inhibitors,
e.g., SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065,
BMS-605339, and ITMN-191; alpha-glucosidase 1 inhibitors, e.g.,
MX-3253 (celgosivir) and UT-231B; hepatoprotectants, e.g.,
IDN-6556, ME 3738, LB-84451, and MitoQ; non-nucleoside inhibitors
of HCV, e.g., benzimidazole derivatives, benzo-1,2,4-thiadiazine
derivatives, phenylalanine derivatives, GS-9190, A-831, and A-689;
and other drugs for treating HCV, e.g., zadaxin, nitazoxanide
(alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002,
actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865,
ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C,
EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497
(merimepodib).
[0681] In yet another embodiment, the present application provides
a method for antagonizing toll-like receptor 7, comprising
contacting a cell having a toll-like receptor 7 with an effective
amount of a compound of claim 1, or a pharmaceutically acceptable
salt, solvate, and/or ester thereof.
EXAMPLES
Example A
[0682] ##STR305## ##STR306##
Synthesis of Methyl
3-((6-amino-2-chloro-9H-purin-9-yl)methyl)benzoate (2)
[0683] To a solution of 2-chloro-6-aminopurine (1) (10 g, 58.97
mmol) and potassium carbonate (10 g, 744 mmol) in DMF (100 mL) was
added methyl 3-(bromomethyl)benzoate (13.5 g, 58.93 mmol). The
reaction mixture was heated to 60.degree. C. for 90 minutes at
which time the reaction was quenched by adding water. The quenched
reaction mixture was extracted with ethyl acetate (3.times.50 mL)
giving 16 g (86%) of Compound (2) as a white solid, which was used
in the next step without further purification. .sup.1H NMR (300
MHz, DMSO) .delta. 3.83 (s, 3H), 5.42 (s, 2H), 7.53 (m, 2H), 7.89
(m, 2H), 8.29 (s, 1H). LCMS: m/z for
C.sub.14H.sub.12ClN.sub.5O.sub.2.sup.++H observed 318.1 at 1.99
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O
(C18 column). ##STR307##
Synthesis of Methyl
3-((6-amino-2-chloro-9H-purin-9-yl)methyl)benzoate (3)
[0684] A suspension of Compound (2) (10.3 g, 31.64 mmol) in
2-methoxyethanol (50 mL) was treated with sodium hydride (759 mg,
31.64 mmol) and heated to reflux for 90 minutes. The remaining
hydride was quenched with 1N HCl, the solvent removed by rotary
evaporation to give 13.69 g (126%) of Compound (3) as a white
solid, which was used in the next step without further
purification. .sup.1H NMR (300 MHz, DMSO) .delta. 3.26 (s, 3H),
3.59 (t, J=5.1, 9.6 Hz, 2H), 4.32 (t, J=4.5, 9.3 Hz, 2H), 7.46 (t,
J=5.4, 9.5 Hz, 1H), 7.56 (d, J=9.3 Hz, 1H), 7.85 (d, J=9.3 Hz, 1H),
8.09 (s, 1H). LCMS: m/z for C.sub.17H.sub.19N.sub.5O.sub.4.sup.++H
observed 358.1 at 3.62 minutes of a 6 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O. LCMS: m/z for
C.sub.16H.sub.17N.sub.5O.sub.4.sup.++H observed 344.1 at 1.70
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O
(C18 column). ##STR308##
Synthesis of Methyl
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzoate
(4)
[0685] A solution of Compound (3) (13.69 g) and potassium carbonate
(8.75 g, 63.28 mmol) in DMF ("dimethylformamide") (20 mL) was
cooled to 0.degree. C. Iodomethane (6.74 g, 47.46 mmol) was added
to the solution and the mixture was allowed to warm to room
temperature. After 30 minutes, the reaction was complete and was
quenched with acetic acid. The quenched reaction mixture was
extracted with ethyl acetate to give Compound (4) (7.36 g, 65% over
two steps). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 3.43 (s, 3H),
3.77 (t, J=5.4, 10.2 Hz, 2H), 3.92 (s, 3H), 4.51 (t, J=4.8, 9.9 Hz,
2H), 5.32 (s, 2H), 7.45 (m, 3H), 7.65 (s, 1H), 8.03 (s, 1H). LCMS:
m/z for C.sub.17H.sub.19N.sub.5O.sub.4.sup.++H observed 358.1 at
3.62 minutes of a 6 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O. LCMS: m/z for C.sub.17H.sub.19N.sub.5O.sub.4.sup.++H
observed 358.1 at 1.93 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O (C18 column). ##STR309##
Synthesis of Methyl
3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzoate
(5)
[0686] A solution of Compound (4) (4.09 g, 11.45 mmol) and sodium
acetate (14.26 g, 171.84 mmol) in acetic acid (50 mL) was cooled to
0.degree. C. in an ice bath. Bromine (23.8 g, 148.93 mmol) was
added dropwise by syringe. The reaction mixture was allowed to warm
to room temperature and stirred overnight (16 hr), and subsequently
quenched with saturated sodium sulfite solution. The quenched
reaction mixture was extracted with dichloromethane (3.times.50
mL), dried over sodium sulfate and solvent evaporated to give
Compound (5) as a yellow solid (3.35 g, 67% yield). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 3.44 (s, 3H), 3.77 (t, J=5.1, 9.9 Hz,
2H), 3.92 (s, 3H), 4.52 (t, J=4.8, 9.9 Hz, 2H), 5.35 (s, 2H), 7.41
(t, J=7.5, 13.5, Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.8
Hz, 1H), 8.09 (s, 1H). LCMS: m/z for
C.sub.17H.sub.18BrN.sub.5O.sub.4.sup.++H observed 437.0 and 438.0
at 3.62 minutes of a 6 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O (C18 column). ##STR310##
Synthesis of
(3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)meth-
anol (6)
[0687] To a solution of Compound (5) (3.35 g, 7.67 mmol) in THF
("tetrahydrofuran") (20 mL) cooled to 0.degree. C. was added a 1 M
solution of DIBAL-H (34.5 mL, 34.52 mmol) in toluene. The reaction
temperature was maintained at 0.degree. C. for 2 h but little
progress in the reaction was observed. Additional equivalents (7.6
mL) of DIBAL-H were added at 2 and 4 hours respectively. The
DIBAL-H reagent was quenched with 1N HCl, and the quenched reaction
mixture was extracted with dichloromethane (3.times.50 mL) and
dried over Na.sub.2SO.sub.3. Evaporation of the solvent gave 38 g
(70%) of Compound (6) as a yellow solid. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 3.42 (s, 3H), 3.74 (t, J=5.1, 9.9 Hz, 2H), 4.49
(t, J=4.8, 10.2 Hz, 2H), 4.67 (s, 2H), 5.29 (s, 2H), 7.29 (m, 3H),
7.39 (s, 1H). LCMS: m/z for
C.sub.16H.sub.18BrN.sub.5O.sub.3.sup.++H observed 408.1 and 410.0
at 1.85 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O (C18 column). ##STR311##
Synthesis of
(3-((6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)me-
thanol (7)
[0688] To a solution of Compound (6) (1.53 g, 3.74 mmol) in
methanol (40 mL) was slowly added sodium methoxide (4.04 g, 74.85
mmol). The reaction mixture was heated to 70.degree. C. for 5
hours, at which time Dowex (H.sup.+) resin was added to quench any
remaining methoxide. The resin was filtered off and the solvent was
evaporated. Salts were removed by partition between water and
dichloromethane, and the combined organic layers were dried over
magnesium sulfate and evaporated to dryness giving 1.03 g (76%) of
Compound (7) as a white solid, which was used in the next step
without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 3.39 (s, 3H), 3.73 (t, J=4.8, 9.6 Hz, 2H), 4.12 (s, 3H),
4.45 (t, J=4.5, 9.3 Hz, 2H), 4.56 (s, 2H), 5.12 (s, 2H), 7.28 (m,
4H). LCMS: m/z for C.sub.17H.sub.21N.sub.5O.sub.4.sup.++H observed
360.1 at 1.87 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN
in H.sub.2O (C18 column). ##STR312##
Synthesis of
9-(3-(hydroxymethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-ol
(8)
[0689] A solution of Compound (7) (371.2 mg, 1.03 mmol) in a 1:1
p-dioxane:TFA ("trifluoroacetic acid") mixture, and a catalytic
amount of water was heated to 65.degree. C. for 24 hrs. Evaporation
of the solvent showed that a trifluoroacetyl adduct had formed. The
adduct was converted to the desired diol by stirring in a saturated
ammonia in methanol solution. Evaporation of the methanol gave
Compound (8) (757.3 mg, 213%) as a white solid. (The large excess
in recovery is most likely due to the presence of salts remaining
in the mixture.) .sup.1H NMR (300 MHz, DMSO) .delta. 3.26 (s, 3H),
3.57 (t, J=4.8, 9.3 Hz), 4.25 (t, J=4.8, 9.6 Hz, 2H), 4.43 (d,
J=5.1, 2H), 7.32 (m, 4H). LCMS: m/z for
C.sub.16H.sub.19N.sub.5O.sub.4.sup.++H observed 346.1 at 1.69
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O
(C18 column). ##STR313##
Synthesis of
9-(3-(bromomethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-ol
(9)
[0690] To a solution of Compound (8) (51.4 mg, 0.148 mmol) in THF
(2 mL) was added phosphorus tribromide (0.2 mL). The reaction
mixture was allowed to stir at room temperature for 5 minutes then
quenched with saturated sodium bicarbonate solution and extracted
with dichloromethane. The combined organic layers were dried over
Na.sub.2SO.sub.3 and evaporated to give Compound (9) as a white
solid. The crude mixture was used in the next step without further
purification. The identity of the product was verified by LCMS.
LCMS: m/z for C.sub.16H.sub.19N.sub.5O.sub.4.sup.++H observed 346.1
at 1.69 minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O. LCMS: m/z for C.sub.16H.sub.18BrN.sub.5O.sub.3.sup.++H
observed 408.0 and 410.1 at 2.03 minutes of a 3.5 minute run,
gradient 5-95% CH.sub.3CN in H.sub.2O (C18 column). ##STR314##
Synthesis of Ethyl
(3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)me-
thyl(methyl)phosphinate (10)
[0691] A solution of Compound (9) (0.148 mmol) and
diethylmethylphosphonite (1 mL) in dioxane (2.5 mL) was placed in
an oil bath preheated to 100.degree. C. for 30 minutes. The
progress of the reaction was monitored by LCMS at 10 minute
intervals. Once the reaction was observed to be complete, all of
the solvent and phosphonite reagent were evaporated under high
vacuum, and the remaining product was purified by HPLC.
Lyophylization of the crude product gave Compound (10) (8.9 mg,
14%) as a white powder. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.22 (t, J=6.9, 14.1 Hz, 2H), 1.36 (d, J=14.1 Hz, 3H), 3.20 (d,
J=17.7 Hz, 2H), 3.38 (s, 3H), 3.69 (t, J=4.8, 9.6 Hz, 2H), 3.95 (m,
3H), 4.39 (t, J=4.8, 9.6 Hz, 2H), 4.97 (s, 2H), 7.24 (s, 1H), 7.31
(m, 3H). LCMS: m/z for C.sub.19H.sub.26N.sub.9O.sub.5P.sup.++H
observed 436.1 at 1.29 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O (C18 column). ##STR315##
Synthesis of
(3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)me-
thyl(methyl)phosphinic acid (Example A)
[0692] A solution of Compound (10) (8.9 mg, 0.02 mmol) in 1N HCl (1
mL) was heated to 150.degree. C. in a microwave for 2 minute
periods. After 6 minutes of heating the reaction, was complete as
determined by LCMS. The solvent was evaporated and the product
purified by Prep-HPLC on a 50.times.21 mm C18 column (mobile phase
gradient 2-40% CH.sub.3CN in H.sub.2O) giving Example A (1.1 mg) as
a white solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.33 (d,
J=14.1 Hz, 3H), 3.13 (d, J=17.7 Hz, 2H), 3.39 (s, 3H), 3.75 (m,
2H), 4.65 (m, 2H), 5.05 (s, 2H), 7.31 (m, 4H). LCMS: m/z for
C.sub.17H.sub.22N.sub.5O.sub.5P.sup.++H observed 408.1 at 1.13
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O
(C18 column).
Example B
[0693] ##STR316## ##STR317##
Synthesis of
9-(3-(bromomethyl)benzyl)-8-methoxy-2-(2-methoxyethoxy)-9H-purin-6-amine
(11)
[0694] A solution of Compound 7 (65 mg, 0.18 mmol) in
dichloromethane (2 mL) was cooled to 0.degree. C. and phosphorus
tribromide (17 .mu.L, 48.9 mg, 0.18 mmol) was added by syringe. The
reaction mixture was stirred at 0.degree. C. and the progress of
the reaction was monitored by TLC (silica gel, eluting 10% methanol
in ethyl acetate). After 20 minutes, the reaction mixture was
quenched with saturated sodium bicarbonate solution, washed with
water, and the combined organic layers were dried over sodium
sulfate and evaporated to dryness. The crude mixture containing
Compound (11) was used in the next step without further
purification. LCMS: m/z for
C.sub.17H.sub.20BrN.sub.5O.sub.3.sup.++H observed 423 and 424.1 at
1.42 minutes of a 3.0 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O (C18 column). ##STR318##
Synthesis of Methyl
(3-((6-amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)me-
thyl(phenyl)phosphinate (12)
[0695] A suspension of Compound (11) (73.4 mg, 0.18 mmol) was
combined with dimethyl phenylphosphonite (0.57 mL, 621.5 mg, 3.6
mmol) in a round bottom flask, which was placed in an oil bath
preheated to 100.degree. C. The progress of the reaction was
monitored by TLC (silica gel, eluting 10% methanol in ethyl
acetate). After 15 minutes, the reaction was observed to be
complete and the solvent was evaporated. The resulting residue was
purified by column chromatography (silica gel, eluting a gradient
of 0-25% methanol in ethyl acetate), giving 4.7 mg (5%) of Example
(B) as a white solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
3.35 (s, 3H), 3.39 (q, J=4.2, 7.8, 11.4, 3H), 3.58 (dd, J=3.4,
11.4, 2H), 3.72 (m, 2H), 4.10 (s, 3H), 4.42 (m, 2H), 4.99 (d,
J=5.4, 2H), 7.20 (m, 2H), 7.31 (m, 5H), 7.46 (m, 2H). LCMS: m/z for
C23H.sub.26N.sub.5O.sub.5P.sup.++H observed 484.1 at 1.84 minutes
of a 3.5 minute run, eluting 5-95% CH.sub.3CN in H.sub.2O (C18
column). ##STR319##
Synthesis of
(3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)me-
thyl(phenyl)phosphinic acid (Example B)
[0696] A solution of Compound (12) (4.7 mg, 0.01 mmol) in
acetonitrile (1 mL) was cooled to 0.degree. C. under nitrogen in an
ice bath. Bromotrimethylsilane (100 .mu.L) was added via syringe.
The reaction was stirred at 0.degree. C. for 50 minutes, then
warmed to room temperature for 1 hr. No reaction was observed, so
an additional 200 .mu.L bromotrimethylsilane was added along with
an additional 2 mL of acetonitrile. The reaction was observed to be
complete 1 hour after the addition of the bromotrimethylsilane. The
crude reaction mixture was purified by HPLC on a 50.times.21 mm C18
column (eluting 15-80% CH.sub.3CN in H.sub.2O) and lyophilized to
give 1.1 mg of Example (B) as a white powder. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 3.31 (m, 2H), 3.40 (s, 3H), 3.73 (m, 2H), 4.44
(m, 2H), 4.86 (s, 2H), 6.97 (m, 1H), 7.72-7.58 (m, 8H). (LCMS: m/z
for C.sub.22H.sub.24N.sub.5O.sub.5P.sup.++H observed 470.2 at 1.62
minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in H.sub.2O
(C18 column).
Example C
[0697] ##STR320##
[0698] Compound (8) (18 mg, 0.05 mmol) and 100 .mu.l of thionyl
chloride in 5 ml of CHCl.sub.3 was heated to 80.degree. C. for 5
minutes in a Emzys optimizer. The reaction solution was
concentrated and purified using a Gilson HPLC on a C18 column
(eluting 2-98% CH.sub.3CN in H.sub.2O) to afford Compound (13)
(18.3 mg, 97%) as a white solid. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 7.77 (s, 1H), 7.42 (s, 1H), 7.27 (m, 2H), 4.96 (s, 2H),
4.55 (s, 2H), 4.42 (m, 2H), 3.67 (m, 2H), 3.27 (s, 3H).
(M.sup.++1): 364.1 ##STR321##
[0699] NaH (40 mg, 0.85 mmol) was added to a solution of
dimethylphosphite (92 ml, 1.00 mmol) in 2 ml of DMF at 0.degree. C.
The reaction solution was stirred for 1 hour and then a solution of
Compound (13) (18.3 mg, 0.05 mmol) in 1 ml of DMF was added at
0.degree. C. The reaction solution was stirred for 1 hour at room
temperature and was quenched with 1N HCl and concentrated. The
concentrated material was purified using a Gilson HPLC on a C18
column (eluting 3-95% CH.sub.3CN in H.sub.2O) to afford Compound
(14) (6.5 mg, 31%) as a white solid. .sup.1H NMR (300 MHz, DMSO):
.delta. 7.19 (m, 4H), 4.82 (s, 2H), 4.25 (m, 3H), 3.58 (m, 2H),
3.55 (s, 3H), 3.52 (s, 3H), 3.25 (s, 3H). (M.sup.++1): 438.0
##STR322##
[0700] Compound (13) (36 mg, 0.08 mmol) was dissolved in 1 ml of
CH.sub.3CN and TMSBr ("bromotrimethylsilane") (106 .mu.L, 0.80
mmol) was added. The reaction mixture was stirred at room
temperature for one hour. The reaction mixture was quenched with
MeOH and concentrated. The resulting crude material was purified
using a Gilson HPLC on a C18 column (eluting 5-95% CH.sub.3CN in
H.sub.2O) to afford Example (C) (32 mg, 100%) as a white solid.
.sup.1H NMR (300 MHz, DMSO+CD.sub.3OD): .delta. 7.32 (s, 1H), 7.21
(s, 3H), 4.94 (s, 2H), 4.40 (m, 2H), 3.67 (m, 2H), 3.26 (s, 3H),
3.09 (s, 1H), 3.01 (s, 1H). (M.sup.++1): 410.0
Example D
[0701] ##STR323##
[0702] Example (C) (28 mg, 0.68 mmol), triethylamine (114 .mu.L,
0.82 mmol), L-Ala-OEt.HCl (21 mg, 0.14 mmol), phenol (32 mg, 0.34
mmol), aldrithiol (105 mg, 0.47 mmol) and triphenylphosphine (126
mg, 0.47 mmol) was heated at 60.degree. C. in 1 ml of pyridine for
7 hours. The solution was concentrated and purified by HPLC to
afford Example (D) (10.5 mg, 26%) as a white solid. .sup.1H NMR
(300 MHz, DMSO+CD.sub.3OD): .delta. 7.32 (m, 6H), 7.10 (m, 3H),
5.58 (m, 1H), 4.83 (s, 2H), 4.23 (m, 2H), 3.98 (m, 2H), 3.58 (m,
2H), 3.22 (s, 5H), 1.15 (m, 3H), 0.98 (m, 3H). (M.sup.++1):
585.2
Example E
[0703] ##STR324## ##STR325##
Step 1: Preparation of 2-(2-methoxyethoxy)adenine (15)
[0704] To a flask with 150 ml 2-methoxyethanol, was added NaH (13
g, 60% dispersion in mineral oil). The mixture was allowed to stir
at room temperature for 10 min. Then 6-amino-2-chloroadenine
(Compound (1)) (25 g, 0.15 mol) was added. The reaction was
refluxed for 2 days while monitoring by LC/MS. Additional NaH (5 g,
60% dispersion in mineral oil) was added and refluxing was
continued for another day. After the starting material was
consumed, the reaction mixture was cooled to rt ("room
temperature") and the solvent was removed under vacuum. Water was
added, and the mixture was neutralized with acetic acid until a
solid precipitated. The solid Compound (15) was collected and dried
under high vacuum. .sup.1H NMR (DMSO-d.sub.6) .delta. 3.28 (s, 3H),
.delta. 3.61 (t, 2H), .delta. 4.28 (t, 2H), .delta. 7.08 (bs, 2H),
.delta. 7.88 (s, 1H), .delta. 145 (bs, 1H); MS: 210.0 (M+H).sup.+,
208.1 (M-1).
Step 2: Preparation of
(2-(6-amino-2-(2-methoxyethoxy)-purin-9-yl)-ethoxymethyl)phosphonic
acid diisopropyl ester (16)
[0705] To a solution of diisopropyl (2-hydroxyethoxy)phosphonate
(413 mg, 1.71 mmol) in DMF (10 ml) was added
2-(2-methoxyethoxy)adenine (15), prepared in Step 1 (300 mg, 1.43
mmol). Triphenylphosphine (830 mg, 3.15 mmol) and diisopropyl
azodicarboxylate (420 .mu.l, 34 mmol) were then added. The reaction
mixture was stirred at rt for 1 h, after which the solvent was
removed under vacuum and the residue was dissolved in DCM
("dichloromethane"). The organic layer was washed with brine, and
the water layer was extracted with DCM. The organic layers were
combined and dried over Na.sub.2SO.sub.4, filtered, and
concentrated, then purified by silica gel chromatography (eluting a
linear gradient of 0-10% methanol in dichloromethane) to obtain 320
mg of Compound (16). .sup.1H NMR (CDCl.sub.3) .delta.1.26-1.32 (m,
12H), .delta. 3.43 (s, 3H), .delta. 3.71-3.77 (m, 4H), .delta. 3.91
(t, 2H), .delta. 4.31 (t, 2H), .delta. 4.48 (t, 2H), .delta.
4.67-4.74 (m, 2H), .delta. 5.62 (bs, 2H), .delta. 7.77 (s, 1H); MS:
432.0 (M+H).sup.+, 430.2 (M-1).
Step 3: Preparation of
(2-(6-amino-8-bromo-2-(2-methoxyethoxy)purin-9-yl)-ethoxymethyl)phosphoni-
c acid diisopropyl ester (17)
[0706] To a solution of the phosphonate Compound (16) prepared in
Step 2 (295 mg, 0.68 mmol) in acetonitrile (5 ml) was added NBS
("N-bromosuccinamide") (182 mg, 1.0 mmol). The reaction mixture was
stirred at rt for 20 min. The solvent was removed under vacuum and
the residue was washed with saturated aq. Na.sub.2SO.sub.3. The
aqueous phase was extracted with DCM. The organic layers were
combined and dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude material was purified using silica gel
chromatography (eluting a linear gradient of 0-10% methanol in
dichloromethane) to obtain 280 mg of Compound (17). .sup.1H NMR
(CDCl.sub.3) .delta. 1.22-1.28 (m, 12H), .delta. 3.42 (s, 3H),
.delta. 3.71-3.75 (m, 4H), .delta. 3.94 (t, 2H), .delta. 4.32 (t,
2H), .delta. 4.50 (t, 2H), .delta. 4.62-4.70 (m, 2H), .delta. 5.85
(bs, 2H); MS: 510.0 (M+H).sup.+.
Step 4: Preparation of
(2-(6-amino-8-hydroxy-2-(2-methoxyethoxy)-purin-9-yl)ethoxymethyl)phospho-
nic acid (Example E)
[0707] A mixture of bromide Compound (17) prepared in Step 3 (21
mg) in 1 N HCl (1.5 ml) was reacted at 150.degree. C. in a
microwave for 15 min. The solvent was removed under vacuum and the
residue was dissolved in water, and purified by prep HPLC on a C18
column (eluting 5-95% CH.sub.3CN in H.sub.2O) on a C18 column to
give Example (E). .sup.1H NMR (D.sub.2O) .delta. 3.31 (s, 3H),
.delta. 3.56 (d, 2H), .delta. 3.70-3.73 (m, 2H), .delta. 3.80 (t,
2H), .delta. 3.97 (t, 2 h), .delta. 4.45-4.48 (m, 2H); MS 364.1
(M+H).sup.+, 362.0 (M-1).
Example F
[0708] ##STR326##
(2-(6-amino-8-hydroxy-2-(2-methoxyethoxy)-purin-9-yl)ethoxymethyl)phosphon-
ic acid monoethyl ester (Example F)
[0709] A mixture of bromide Compound (17) (10 mg) in 50% KOH (1 ml)
and t-BuOH (1 ml) was refluxed at 105.degree. C. overnight. The
mixture was cooled to rt and neutralized with acetic acid. The
NaOAc ("sodium acetate") was removed by filtration, and the product
was purified by prep HPLC on a C18 column (eluting 5-95% CH.sub.3CN
in H.sub.2O) to give Example (F). .sup.1H NMR (CD.sub.3OD) .delta.
1.11 (d, 6H), .delta. 3.405 (s, 3H), .delta. 3.61 (d, 2H), .delta.
3.71-3.74 (m, 2H), .delta. 3.84 (t, 2H), .delta. 4.04 (t, 2H),
.delta. 4.30-4.40 (m, 1H), .delta. 4.11-4.43 (m, 2H); MS: 406.1
(M+H).sup.+, 404.0 (M-1).
Examples G and H
[0710] ##STR327##
Example H
Step 1: Preparation of
(3-(6-amino-2-(2-methoxyethoxy)purin-9-yl)propyl)phosphonic acid
diethyl ester (19)
[0711] To a suspension of 2-(2-methoxyethoxy)adenine Compound (15)
(200 mg, 0.96 mmol) in DMF (5 ml) was added K.sub.2CO.sub.3 (132 mg
0.96 mmol). Then diethyl (3-bromopropyl)phosphonate (265 .mu.l,
1.44 mmol) was added. The reaction mixture was stirred at
70.degree. C. for 1 h, and the solvent was removed under vacuum.
The residue was dissolved in DCM and washed with brine. The aqueous
phase was extracted again with DCM. The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum. The residue was purified by silica gel chromatography
(eluting using a linear gradient of 0-10% MeOH in DCM) to give 293
mg of Compound (19). .sup.1H NMR (CDCl.sub.3) .delta. 1.10-1.16 (m,
6H), .delta. 1.52-1.59 (m, 2H), .delta. 1.90-2.09 (m, 2H), .delta.
3.25 (s, 3H), .delta. 3.51-3.57 (m, 2H), .delta. 3.89-3.92 (m, 4H),
.delta. 4.04 (t, 2H), .delta. 4.28 (t, 2H), .delta. 6.60 (M, 2H),
.delta. 7.53 (s, 1H); MS: 388.1 (M+H).sup.+, 386.0 (M-1).
Step 2: Preparation of
(3-(6-amino-8-bromo-2-(2-methoxyethoxy)purin-9-yl)propyl)phosphonic
acid diethyl ester (21)
[0712] To a solution of the phosphonate Compound (19) prepared in
Step 1 (293 mg, 0.76 mmol) in CH.sub.3CN (5 ml) was added NBS (200
mg, 1.14 mmol). The reaction mixture was stirred at room
temperature for 30 min. The solvent was removed under vacuum, and
the residue was washed with saturated aq. Na.sub.2SO.sub.3
solution. The aqueous phase was extracted again with DCM. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
concentrated and purified by silica gel chromatography (eluting a
linear gradient of 0-10% MeOH in DCM) to give 308 mg of Compound
(21). .sup.1H NMR (CDCl.sub.3) .delta. 1.31 (t, 6H), .delta.
1.76-1.83 (m, 2H), .delta. 2.09-38 (m, 2H), .delta. 3.43 (s, 3H),
.delta. 3.76 (t, 2H), .delta. 4.04-4.14 (M, 4H), .delta. 4.20 (t,
2H), .delta. 4.46 (t, 2H), .delta. 5.66 (bs, 2H). MS: 466.1
(M+H).sup.+.
Step 3: Preparation of
(3-(6-Amino-8-hydroxy-2-(2-methoxyethoxy)purin-9-yl)propyl)phosphonic
acid (Example H)
[0713] A mixture of bromide Compound (21) prepared in Step 2 (37
mg) in 1 N HCl (3 ml) was reacted at 150.degree. C. in a microwave
for 12 min. The solvent was removed under vacuum, and the residue
was purified by HPLC on a C18 column (eluting a linear gradient of
0-10% MeOH in DCM) to give Example (H). .sup.1H NMR (D.sub.2O)
61.44-1.56 (m, 2H), .delta. 1.80-1.90 (m, 2H), .delta. 3.30 (s,
3H), .delta. 3.70-3.72 (m, 2H), .delta. 3.79 (t, 2H), .delta. 4.46
(t, 2H); MS 348.1 (M+H).sup.+, 345.9 (M-1).
Example G
[0714] Example (G) with a two carbon linker (n=2) was prepared
using procedures similar to those used to prepare Example (H),
except that diethyl (2-bromoethyl)phosphonate was used instead of
diethyl (3-bromopropyl)phosphonate in step 1.
(2-(6-amino-2-(2-methoxyethoxy)purin-9-yl)ethyl)phosphonic acid
diethyl ester (18)
[0715] .sup.1H NMR (CDCl.sub.3) .delta. 1.22 (t, 6H), .delta.
51-2.42 (m, 2H), .delta. 3.40 (s, 3H), .delta. 3.72 (t, 2H),
.delta. 3.98-4.06 (m, 4H), .delta. 4.30-4.4.40 (m, 2H), .delta.
4.44 (t, 2H), .delta. 6.20 (bs, 2H), .delta. 7.65 (s, 1H); MS:
374.1 (M+H).sup.+.
(2-(6-amino-8-bromo-2-(2-methoxyethoxy)-purin-9-yl)ethyl)phosphonic
acid diethyl ester (20)
[0716] .sup.1H NMR (CDCl.sub.3) .delta.1.33 (t, 6H), .delta.
49-2.40 (m, 2H), .delta. 3.44 (s, 3H), .delta. 3.76 (t, 2H),
.delta. 4.07-4.18 (m, 4H), .delta. 4.36-4.44 (m, 2H), .delta. 4.48
(t, 2H), .delta. 5.69 (bs, 2H); MS: 452.0 (M+H).sup.+.
(2-(6-Amino-8-hydroxy-2-(2-methoxyethoxy)-purin-9-yl)ethyl)phosphonic
acid (G)
[0717] .sup.1H NMR (CD.sub.3OD) .delta. 2.05-38 (m, 2H), .delta.
3.42 (s, 3H), .delta. 3.76 (t, 2H), .delta. 4.05-4.14 (m, 2H),
.delta. 4.43-4.49 (m, 2H); MS: 334.1 (M+H).sup.+, 331.9 (M-1).
Examples I and J
[0718] ##STR328##
Step 1: Preparation of
1-(6-Amino-2-(2-methoxyethoxy)purin-9-yl)-3-phenylpropan-2-ol
(22)
[0719] To a suspension of 6-amino-2-(2-methoxyethoxy)adenine
Compound (15) (300 mg, 1.43 mmol) in DMF (3 ml) was added
K.sub.2CO.sub.3. Then (2,3-epoxypropyl)benzene (285 .mu.l, 34 mmol)
was added and the reaction mixture was stirred at 70.degree. C. for
5 h. The solvent was removed under vacuum and the residue was
washed with brine. The aqueous phase was extracted with DCM and the
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
concentrated, and purified by silica gel chromatography (eluting a
linear gradient of 0-10% MeOH in DCM) to give 170 mg of Compound
(22). .sup.1H NMR (CDCl.sub.3) .delta. 2.82-2.85 (dd, 2H), .delta.
3.43 (s, 3H), .delta. 3.74 (t, 2H), .delta. 4.00-4.10 (m, 1H),
.delta. 4.25-4.29 (m, 2H), .delta. 4.42 (t, 2H), .delta. 5.76 (bs,
2H), .delta. 7.21-7.34 (m, 5H), .delta. 7.50 (s, 1H); MS: 494.2
(M+H).sup.+.
Step 2: Preparation of
(2-(6-Amino-2-(2-methoxyethoxy)-purin-9-yl)-1-benzyl-ethoxymethyl)phospho-
nic acid diethyl ester (24)
[0720] To a solution of the adenine derivative Compound (22)
prepared in Step 1 (190 mg, 0.55 mmol) in DMF (2 ml) was added
magnesium di-tert-butoxide (68 mg, 0.72 mmol) at room temperature.
The temperature was raised to 75.degree. C. and the tosylate
reagent (28) (242 mg) was added. After stirring at 75.degree. C.,
approximately 50% of the starting material was converted to
product. The reaction mixture was quenched with water and extracted
with DCM. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, concentrated, and purified by silica gel chromatography
diethyl (eluting a linear gradient of 0-10% MeOH in DCM). The
starting material (Compound (22)) and product (Compound (24)) were
not separable, so the mixture was used in the next step without
further purification. MS: 494.2 (M+H).sup.+.
Step 3: Preparation of
(2-(6-Amino-8-bromo-2-(2-methoxyethoxy)purin-9-yl)-1-benzyl-ethoxymethyl)-
phosphonic acid diethyl ester (26)
[0721] To a solution of the phosphonate Compound (24) prepared in
Step 2 (210 mg) in CH.sub.3CN (3 ml) was added NBS (115 mg) at room
temperature. The reaction mixture was stirred at room temperature
for 20 min. The solvent was removed and the residue was taken up in
DCM and washed with saturated aq. Na.sub.2SO.sub.3. The aqueous
phase was extracted again with DCM. The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, concentrated and
purified by prep HPLC on a C18 column (eluting a using a gradient
of 5-95% CH.sub.3CN in H.sub.2O) to give Compound (26). .sup.1H NMR
(CDCl.sub.3) .delta. 1.19-1.28 (m, 6H), .delta. 2.81-2.87 (dd, 1H),
.delta. 3.00-3.06 (dd, 1H), .delta. 3.43 (s, 3H), .delta. 3.52-3.60
(m, 1H), .delta. 3.69-3.76 (m, 4H), .delta. 3.90-4.03 (m, 4H),
.delta. 4.12-4.23 (m, 4H), .delta. 4.39 (t, 2H), .delta. 5.52 (bs,
2H), .delta. 7.24-7.31 (m, 5H); MS: 574 (M+H).sup.+.
Step 4: preparation of
(2-(6-Amino-8-hydroxy-2-(2-methoxyethoxy)purin-9-yl)-1-benzyl-ethoxymethy-
l)phosphonic acid (Example I)
[0722] A mixture of bromide Compound (26) prepared in Step 3 (20
mg) in 1 N HCl (1.5 ml) was stirred at 150.degree. C. in a
microwave for 12 min. The solvent was removed under vacuum and the
residue was purified by prep HPLC on a C18 column (eluting a using
a gradient of 5-95% CH.sub.3CN in H.sub.2O) to give Example (I).
.sup.1H NMR (CD.sub.3OD) .delta. 2.80-2.86 (dd, 1H), .delta.
3.00-3.06 (dd, 1H), .delta. 3.40 (s, 3H), .delta. 3.56-3.72 (m,
4H), .delta. 3.85-3.4.02 (m, 2H), .delta. 4.15-4.22 (m, 1H),
.delta. 4.37 (t, 2H), .delta. 7.14-7.32 (m, 5H); MS: 454.2
(M+H).sup.+.
Example (J)
[0723] Example (J) with R.dbd.H was prepared using procedures
similar to those used to prepare a compound (1), except that
propylene carbonate was used instead of the epoxide in Step 1.
1-(6-Amino-2-(2-methoxyethoxy)purin-9-yl)-propan-2-ol (23)
[0724] .sup.1H NMR (CDCl.sub.3) .delta. 1.24 (d, 3H), .delta. 3.43
(s, 3H), 3.72 .delta. (t, 2H), 3.92 .delta. (q, 1H), .delta.
4.14-4.25 (m, 2H), .delta. 4.07 (t, 2H), .delta. 6.10 (bs, 2H),
.delta. 7.56 (s, 1H); MS: 268.1 (M+H).sup.+.
(2-(6-Amino-2-(2-methoxyethoxy)purin-9-yl)-1-methyl-ethoxymethyl)phosphoni-
c acid diethyl ester (25)
[0725] .sup.1H NMR (CDCl.sub.3) .delta. 1.20-1.34 (m, 9H), .delta.
3.43 (s, 3H), .delta. 3.56-3.64 (m, 1H), .delta. 3.74-3.3.92 (m,
4H), .delta. 4.01-4.13 (m, 6H), .delta. 4.47 (t, 2H), .delta. 5.67
(bs, 2H), .delta. 7.78 (s, 1H); MS: 418.2 (M+H).sup.+.
(2-(6-Amino-8-bromo-2-(2-methoxyethoxy)purin-9-yl)-1-methyl-ethoxymethyl)p-
hosphonic acid diethyl ester (27)
[0726] .sup.1H NMR (CDCl.sub.3) .delta. 1.16-1.26 (m, 9H), .delta.
3.38 (s, 3H), .delta. 3.55-3.82 (m, 4H), .delta. 3.90-4.16 (m, 7H),
.delta. 4.38-4.40 (m, 2H), .delta. 6.27 (bs, 2H); MS: 496.1
(M+H).sup.+.
(2-(6-Amino-8-hydroxy-2-(2-methoxyethoxy)purin-9-yl)-1-methyl-ethoxymethyl-
)phosphonic acid (Example J)
[0727] .sup.1H NMR (CD.sub.3OD) .delta. 1.22 (d, 3H), .delta. 3.40
(s, 3H), .delta. 3.67-3.83 (m, 6H), .delta. 3.93-4.01 (m, 2H),
.delta. 4.43 9 (t, 2H); MS: 378.1 (M+H).sup.+, 376.0 (M-1).
Example K
[0728] ##STR329##
Synthesis of 9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine
(29)
[0729] 2-(2-methoxyethoxy)-9H-purin-6-amine (15) (1.0 g, 4.78
mmol), 3-bromobenzyl bromide (1.5 g, 6.00 mmol) and anhydrous
potassium carbonate (0.85 g, 6.15 mmol) were combined in DMF (15
mL) and stirred at room temperature for 16 h. The mixture was
diluted with ethyl acetate (150 mL) and washed with water and
brine. The organic phase was dried with sodium sulfate and the
solvent was removed under vacuum. The resulting residue was
triturated with a mixture of diethylether and ethyl acetate (4:1)
and filtered.
9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine, Compound
(39) (0.77 g, 43%) was obtained as a yellowish solid. .sup.1H-NMR
(DMSO) .delta.: 8.07 (s, 1H), 7.57 (s, 1H), 7.52-7.46 (m, 1H),
7.34-7.22 (m, 4H), 5.26 (s, 2H), 4.32 (t, J=4.5 Hz, 2H), 3.60 (t,
J=4.5 Hz, 2H), 3.27 (s, 3H). MS: 378/380 (MH.sup.+)
Synthesis of Diethyl
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate
(30)
[0730] 9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine (29)
(500 mg, 1.32 mmol) was suspended in DMF (5 mL). Diethylphosphite
(0.26 mL, 2.0 mmol), triethylamine (0.28 mL, 2.0 mmol) and
(1,1'-Bis(diphenylphosphino)ferrocene)dichloropalladium(II),
complex with CH.sub.2Cl.sub.2 (106 mg, 0.13 mmol) was added and the
mixture was heated at 130.degree. C. for 5 min in a microwave
reactor. Then the reaction mixture was diluted with ethyl acetate
(150 mL) and washed with water and brine. The organic solution was
dried with sodium sulfate and the solvent was removed under vacuum.
The residue was redissolved in ethyl acetate (10 mL) and adsorbed
on a short column of silica gel. The product was eluted with
dichloromethane/methanol 1:0 to 1:1 giving diethyl
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate
(30) (400 mg, 70%) as a dark brown oil after evaporation of the
solvent. MS: 436 (MH.sup.+).
Synthesis of Diethyl
3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosph-
onate
[0731] Diethyl
3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate
(30) (400 mg, 0.92 mmol) was dissolved in acetonitrile and
N-bromosuccinimide (500 mg, 2.8 mmol) was added in one portion.
After stirring at room temperature for 2 h, the reaction mixture
was diluted with ethyl acetate (150 mL) and washed with water, 0.2
M sodium thiosulfate solution and brine. The organic phase was
dried with sodium sulfate and the solvent was removed under vacuum.
The crude diethyl
3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosph-
onate (450 mg, 95%) was used in the next step without further
purification.
Synthesis of Ethyl hydrogen
3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonate (Example K)
[0732] Diethyl
3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosph-
onate (100 mg, 0.194 mmol) was dissolved in methanol (5 mL) and 1 N
aqueous NaOH solution was added. The reaction mixture was heated at
reflux and progress was monitored by HPLC. As soon as all the
starting material had been consumed, the reaction mixture was
acidified with conc. HCL. After heating at reflux for 1 h, the
mixture was evaporated to dryness under vacuum. The product was
purified by preparative reverse phase HPLC, yielding ethyl hydrogen
3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonate Example (K) (18 mg, 22%) as a white powder. .sup.1H-NMR
(DMSO) .delta.: 10.0 (s, 1H), 7.65-7.42 (m, 5H), 6.51 (br, 2H),
4.90 (s, 2H), 4.25 (t, J=4.5 Hz, 2H), 3.84 (quint, J=7 Hz, 2H),
3.57 (t, J=4.5 Hz, 2H), 3.26 (s, 3H), 1.13 (t, J=7 Hz, 3H).
.sup.31P-NMR (DMSO) .delta.: 13.04. MS: 424 (MH.sup.+).
Example L
[0733] ##STR330##
Synthesis of
3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonic acid (L)
[0734] Ethyl hydrogen
3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonate (K) (10 mg, 0.0236 mmol) was suspended in anhydrous
acetonitrile (3 mL). Bromotrimethylsilane (0.2 mL) was added. After
stirring at room temperature overnight, the mixture was
concentrated under vacuum and treated with water (2 mL).
Acetonitrile (1 mL) was added and the product was purified by
preparative reverse phase HPLC, yielding
3-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonic acid (L) (1.5 mg) as a white solid. .sup.1H-NMR (DMSO)
.delta.: 10.0 (s, 1H), 7.64-7.35 (m, 5H), 6.48 (br, 2H), 4.86 (s,
2H), 4.25 (t, J=4.5 Hz, 2H), 3.57 (t, J=4.5 Hz, 2H), 3.25 (s, 3H).
MS: 396 (MH.sup.+).
Examples M and N
[0735] Examples M and N were prepared using procedures similar to
those shown in Scheme 22, except that 4-bromobenzyl bromide was
used instead of 3-bromobenzyl bromide in step 1: ##STR331##
Synthesis of Ethyl hydrogen
4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonate (M)
[0736] .sup.1H-NMR (DMSO) .delta.: 10.0 (s, 1H), 7.63 (dd, J=7.8
Hz, J=12.6 Hz, 2H), 7.37 (dd, J=3.3 Hz, J=7.8 Hz, 2H), 6.50 (br,
2H), 4.90 (s, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.84 (quint, J=7 Hz,
2H), 3.56 (t, J=4.5 Hz, 2H), 3.25 (s, 3H), 1.15 (t, J=7 Hz, 3H).
.sup.31P-NMR (DMSO) .delta.: 14.97. MS: 424 (MH.sup.+).
Synthesis of
4-((6-amino-8-hydroxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphos-
phonic acid (N)
[0737] .sup.1H-NMR (DMSO) .delta.: 10.0 (s, 1H), 7.63 (dd, J=7.5
Hz, J=12.6 Hz, 2H), 7.38 (dd, J=3.3 Hz, J=7.5 Hz, 2H), 6.49 (br,
2H), 4.90 (s, 2H), 4.24 (t, J=4.5 Hz, 2H), 3.56 (t, J=4.5 Hz, 2H),
3.25 (s, 3H). .sup.31P-NMR (DMSO) .delta.: 16.34. MS: 396
(MH.sup.+).
Example O
[0738] ##STR332## ##STR333##
Step 1: Preparation of
1-(6-amino-2-(2-methoxyethoxy)purin-9-yl)-3-phenoxy-propan-2-ol.
(31)
[0739] To a suspension of 6-amino-2-(2-methoxyethoxy)adenine (300
mg, 1.43 mmol) in DMF (3 ml) was added K.sub.2CO.sub.3 (200 mg,
1.43 mmol). Then 1,2-epoxy-3-phenoxy-propane (321 mg, 2.14 mmol)
was added. The reaction mixture was stirred at 70.degree. C.
overnight. The solvent was removed and the residue was taken up in
CH.sub.2Cl.sub.2 and washed with water. The aqueous phase was
extracted with DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, concentrated, and purified by silica
gel chromatography, using linear gradient of MeOH in DCM as eluent
to give 350 mg product. .sup.1H NMR (CDCl.sub.3): .delta. 3.43 (s,
3H), .delta. 3.74 (t, 2H), .delta. 3.90-4.06 (m, 2H), .delta.
4.30-4.35 (m, 1H), .delta. 4.30-4.50 (m, 4H), .delta. 6.00 (bs,
2H), .delta. 6.88-7.01 (m, 3H), .delta. 7.27-7.32 (m, 2H), .delta.
7.70-7.73 (m, 1H); MS: 360.2 (M+1).
Step 2: Preparation of
(2-(6-amino-2-(2-methoxyethoxy)purin-9-yl)-1-phenoxymethylethoxymethyl)-p-
hosphonic acid diethyl ester. (32)
[0740] To a solution of the purine analog prepared in step 1 (350
mg, 0.97 mmol) in DMF (3 ml) was added magnesium di-tert-butoxide
(165 mg, 0.97 mmol) at room temperature. The mixture was heated to
75.degree. C. and the tosylate reagent (468 mg) was added, followed
by stirring at that temperature. LC/MS after 3 h indicated that the
reaction was finished. The reaction was quenched with ether and
extracted with DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, concentrated, and purified by silica
gel chromatography, using linear gradient of MeOH in DCM as eluent.
.sup.1H NMR (CDCl.sub.3) .delta. 1.17-1.23 (m, 6H), .delta. 3.35
(s, 3H), .delta. 3.64 (t, 2H), .delta. 3.78-3.86 (m, 1H), .delta.
3.91-3.4.15 (m, 8H), .delta. 4.22-4.44 (m, 4H), .delta. 6.54 (bs,
2H), .delta. 6.79-6.92 (m, 3H), .delta. 7.18-7.24 (m, 2H), .delta.
7.72 (s, 1H); MS: 510.3 (M+1).
Step 3: Preparation of
(2-(6-amino-8-bromo-2-(2-methoxy-ethoxy)purin-9-yl)-1-(phenoxymethyl)etho-
xymethyl)phosphonic acid diethyl ester. (33)
[0741] To a solution of the phosphonate prepared in step 2 (300 mg,
0.59 mmol) in CH.sub.3CN (5 ml) was added NBS (157 mg, 0.88 mmol)
at room temperature. The reaction mixture was stirred at room
temperature for 1 h. The solvent was removed and the residue was
washed with sat. aq Na.sub.2SO.sub.3 solution. The aqueous phase
was extracted again with DCM. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, concentrated, and purified by prep HPLC
on a C18 column, eluting with a gradient of 5-95% CH.sub.3CN in
H.sub.2O as solvent. .sup.1H NMR (CDCl.sub.3) .delta. 1.19-1.27 (m,
6H), .delta. 3.40 (s, 3H), .delta. 3.68 (t, 2H), .delta.
3.84-3.3.88 (m, 1H), .delta. 3.93-4.10 (m, 8H), .delta. 4.30-4.36
(m, 4H), .delta. 6.30 (bs, 2H), .delta. 6.83-6.97 (m, 3H), .delta.
7.23-7.28 (m, 2H); MS: 588.2 (M+1).
Step 4: preparation of
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-1-(phenoxymethyl)e-
thoxymethyl)phosphonic acid. (Example O)
[0742] A mixture of bromide prepared in step 3 (50 mg) in 1 N HCl
(2.5 ml) was heated at 150.degree. C. in a microwave reactor for 12
min. The solvent was removed under vacuum and the product was
purified by prep HPLC on a C18 column, eluting with a gradient of
5-95% CH.sub.3CN in H.sub.2O. .sup.1H NMR (CDCl.sub.3) .delta. 3.37
(s, 3H), .delta. 3.65 (t, 2H), .delta. 3.91-3.96 (m, 2H), .delta.
3.10-3.20 (m, 4H), .delta. 4.23-4.4.27 (m, 1H), .delta. 4.32 (t,
2H), .delta. 6.85-6.94 (m, 3H), .delta. 7.21-7.27 (M, 1H); MS:
470.2 (M+1), 468.1 (M-1).
Example P
[0743] ##STR334## ##STR335##
Step 1: Preparation of
2-(6-amino-2-(2-methoxyethoxy)purin-9-yl)-1-phenylethanone.
(34)
[0744] To a suspension of 6-amino-2-(2-methoxyethoxy)adenine (500
mg, 2.39 mmol) in DMF (5 ml) was added K.sub.2CO.sub.3 (330 mg,
2.39 mmol). Then 2-bromoacetophenone was added and the reaction
mixture was heated to 70.degree. C. with stirring for 30 min. The
solvent was removed under vacuum and the residue was washed with
brine. The aqueous phase was extracted with DCM and the organic
layer was dried over Na.sub.2SO.sub.4, filtered, concentrated, and
purified by silica gel chromatography using linear gradient of MeOH
in DCM as eluent. .sup.1H NMR (CDCl.sub.3) .delta. 3.40 (s, 3H),
.delta. 3.72 (t, 2H), .delta. 4.45 (t, 2H), .delta. 5.58 (s, 2H),
.delta. 5.67 (bs, 2H), .delta. 7.53-7.74 (m, 4H), .delta. 8.03 (s,
1H), .delta. 8.06 (s, 1H); MS: 328.2 (M+1), 326.0 (M-1).
Step 2: 2-(6-amino-2-(2-methoxyethoxy)purin-9-yl)-1-phenylethanol.
(35)
[0745] To a suspension of ethanone prepared in step 1 (60 mg, 0.18
mmol) in THF, was added NaBH.sub.4 at room temperature. The
reaction was complete after stirring at room temperature for 1 h.
The solvent was removed under vacuum and the residue was washed
with sat. aq. NaHCO.sub.3 solution. The aqueous phase was extracted
with DCM. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, concentrated, and purified by silica gel chromatography
using a liner gradient of MeOH in DCM as eluent. .sup.1H NMR
(CDCl.sub.3) .delta. 3.36 (s, 3H), .delta. 3.68 (t, 2H), .delta.
4.07-4.38 (m, 4H), .delta. 5.12-5.14 (m, 1H), .delta. 6.36 (bs,
2H), .delta. 7.26-7.38 (m, 5H), .delta. 7.51 (s, 1H); MS: 330.1
(M+1).
[0746] The other steps were carried out according to the procedures
used in preparing Example O.
[0747]
(2-(6-Amino-2-(2-methoxyethoxy)purin-9-yl)-1-phenylethoxymethyl)ph-
osphonic acid diethyl ester. (36) .sup.1H NMR (CDCl.sub.3): .delta.
1.09-1.16 (m, 6H), 3.30 .delta. (s, 3H), .delta. 3.38-3.63 (m, 4H),
.delta. 3.84-3.98 (m, 4H), .delta. 4.14-4.34 (m, 4H), .delta.
4.65-4.71 (m, 1H), .delta. 6.57 (bs, 2H), .delta. 7.20-7.24 (m,
5H), .delta. 7.60 (s, 1H); MS: 480.2 (M+1).
[0748]
(2-(6-Amino-8-bromo-2-(2-methoxyethoxy)purin-9-yl)-1-phenylethoxym-
ethyl)phosphonic acid diethyl ester. (37) .sup.1H NMR (CDCl.sub.3):
.delta. 1.20-1.31 (m, 6H), .delta. 3.42-3.77 (m, 5H), .delta. 3.78
(t, 2H), .delta. 3.91-4.06 (m, 4H), .delta. 4.16-4.51 (m, 4H),
.delta. 4.96-5.00 (m, 1H), .delta. 5.73 (bs, 2H), .delta. 7.30-7.40
(m, 5H); MS: 480.2 (M+1).
[0749]
(2-(6-Amino-8-hydroxy-2-(2-methoxyethoxy)purin-9-yl)-1-phenylethox-
ymethyl)phosphonic acid. (Example P) .sup.1H NMR (CD.sub.3OD):
.delta. 3.42 (s, 3H), .delta. 3.45-3.59 (m, 2H), .delta. 3.74 (t,
2H), .delta. 3.92-4.22 (m, 2H), .delta. 4.41 (t, 2H), .delta.
4.93-4.98 (m, 1H), .delta. 7.30-7.43 (m, 5H); MS: 440.1 (M+1),
438.2 (M-1).
Example Q
[0750] ##STR336##
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-1-(R)-phenoxymethyl-
ethoxymethyl)-phosphonic acid (Example Q)
[0751] Example Q were prepared using procedures similar to those
used to prepare Example O, except that R-2-epoxy-3-phenoxy-propane
was used instead of racemic 2-epoxy-3-phenoxy-propane in step a).
Enantiomerically pure 2-epoxy-3-phenoxy-propane was made from
chiral glycidyl tosylate according to the procedure described in
Journal of Organic Chemistry, 1989, 54, 1295-1304. .sup.1H NMR
(CD.sub.3OD) .delta. 3.37 (s, 3H), .delta. 3.64 (t, 2H), .delta.
3.91-3.96 (m, 2H), .delta. 4.12-4.25 (m, 5H), .delta. 4.32 (t, 2H),
.delta. 6.85-6.94 (m, 3H), .delta. 7.21-7.27 (m, 2H); .sup.31P NMR
(CD.sub.3OD) 18.48 (s); MS: 470.2 (M+H).sup.+, 468.1 (M-1).
Example R
[0752] ##STR337##
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-1-(S)-phenoxymethyl-
ethoxymethyl)-phosphonic acid (Example R)
[0753] Example R was prepared using procedures similar to those
used to prepare Example O, except that S-2-epoxy-3-phenoxy-propane
was used instead of racemic 2-epoxy-3-phenoxy-propane in step a).
Enantiomerically pure 2-epoxy-3-phenoxy-propane was made from
chiral glycidyl tosylate according to the procedure described in
Journal of Organic Chemistry, 1989, 54, 1295-1304. .sup.1H NMR
(CD.sub.3OD) .delta. 3.37 (s, 3H), .delta. 3.65 (t, 2H), .delta.
3.91-3.96 (m, 2H), .delta. 4.12-4.25 (m, 5H), .delta. 4.32 (t, 2H),
.delta. 6.85-6.94 (m, 3H), .delta. 7.21-7.27 (m, 2H); .sup.31P NMR
(CD.sub.3OD) .delta. 18.62 (s); MS: 470.1 (M+H).sup.+, 468.1
(M-1).
Examples S and T
[0754] Examples S and T were prepared using procedures similar to
those used to prepare Example O except cis-stilbene oxide or
cyclopentene oxide were used in the step 1, respectively. The
spectral data of the two compounds (Example S and T) and
intermediates are listed below. ##STR338##
2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-1,2-diphenyl-ethanol
(38)
[0755] .sup.1H NMR (CDCl.sub.3): .delta. 3.42 (s, 3H), .delta. 3.73
(t, 2H), .delta. 4.41-4.44 (m, 1H), .delta. 5.75 (s, 2H), .delta.
5.88 (bs, 2H), .delta. 7.18-7.28 (m, 10H), .delta. 7.75 (s, 1H);
MS: 406.1 (M+H).sup.+.
(2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-1,2-diphenyl-ethoxymethyl)-ph-
osphonic acid diethyl ester (39)
[0756] .sup.1H NMR (CDCl.sub.3): .delta. 1.21-1.29 (m, 6H), .delta.
3.42 (s, 3H), .delta. 3.57-3.74 (m, 5H), .delta. 3.95-4.04 (m, 4H),
.delta. 4.37-4.42 (m, 2H), .delta. 5.56 (d, 1H), .delta. 5.76 (d,
1H), .delta. 5.93 (bs, 2H), .delta. 7.12-7.31 (m, 10H), .delta.
8.21 (s, 1H); MS: 554.1 (M-1).
(2-(6-Amino-8-bromo-2-(2-methoxy-ethoxy)-purin-9-yl)-1,2-diphenyl-ethoxyme-
thyl)-phosphonic acid diethyl ester (40)
[0757] .sup.1H NMR (CDCl.sub.3): .delta. 1.11-1.19 (m, 6H), .delta.
3.50 (s, 3H), .delta. 3.61 (d, 2H), .delta. 3.76-3.96 (m, 6H),
.delta. 4.59-4.68 (m, 2H), .delta. 6.59 (d, 1H), .delta. 5.80 (bs,
2H), .delta. 6.15 (d, 1H), .delta. 7.14-7.37 (m, 10H); MS: 634.0
(M+H).sup.+.
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-1,2-diphenyl-ethoxy-
methyl)-phosphonic acid (Example S)
[0758] .sup.1H NMR (CD.sub.3OD): .delta. 3.45 (s, 3H), .delta.
3.48-3.57 (m, 2H), .delta. 3.82 (t, 2H), .delta. 4.60 (t, 3H),
.delta. 5.56 (d, 1H), .delta. 5.92 (d, 1H), .delta. 7.16-7.41 (m,
10H); MS: 516.1 (M+H).sup.+, 514.1 (M-1).
Example T
[0759] ##STR339##
2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-cyclopentanol (41)
[0760] .sup.1H NMR (CDCl.sub.3): .delta.1.82-2.27 (m, 6H), .delta.
2.46-2.49 (m, 1H), .delta. 3.44 (s, 3H), 83.77 (t, 2H), .delta.
4.37-4.41 (m, 1H), .delta. 4.44 (t, 2H), .delta. 4.48-4.53 (m, 1H),
.delta. 5.80 (bs, 2H), .delta. 7.63 (s, 1H); MS: 294.1
(M+H).sup.+.
(2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-cyclopentyloxymethyl)-phospho-
nic acid diethyl ester (42)
[0761] .sup.1H NMR (CDCl.sub.3): .delta. 1.25-1.30 (M, 4H), .delta.
1.84-2.34 (m, 6H), .delta. 3.45 (s, 3H), .delta. 3.73-3.80 (m, 4H),
.delta. 4.05-4.11 (m, 2H), .delta. 4.44-4.49 (m, 3H), .delta.
4.68-4.69 (m, 1H), .delta. 5.78 (bs, 2H), .delta. 7.70 (s, 1H); MS:
444.1 (M+H).sup.+.
(2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-cyclopentyloxymethyl)-phospho-
nic phosphonic acid diethyl ester (43)
[0762] .sup.1H NMR (CDCl.sub.3): .delta. 1.23-1.30 (m, 4H), .delta.
1.82-2.36 (m, 6H), .delta. 3.45 (s, 3H), .delta. 3.64-3.76 (m, 2H),
.delta. 3.77 (t, 2H), .delta. 4.04-4.13 (m, 2H), .delta. 4.45 (t,
2H), .delta. 4.73-4.78 (m, 2H), .delta. 5.77 (bs, 2H); MS: 522.0
(M+H).sup.+.
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-cyclopentyloxymethy-
l) phosphonic acid (Example T)
[0763] .sup.1H NMR (CD.sub.3OD): .delta.1.81-1.87 (m, 2H),
61.95-2.13 (m, 2H), .delta. 2.18-2.28 (m, 2H), .delta. 3.41 (s,
3H), .delta. 3.60-3.71 (m, 2H), .delta. 3.74 (t, 2H), .delta. 4.43
(t, 2H), .delta. 4.59-4.68 (m, 2H); MS: 404.0 (M+H).sup.+, 403.1
(M-1).
Example U
[0764] ##STR340## ##STR341##
Step 1: synthesis of
(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-phenyl-acetic acid ethyl
ester (44)
[0765] To a suspension of 2-methoxylethoxyadenine (500 mg, 2.39
mmol) in DMF (5 ml), was added K.sub.2CO.sub.3 (329 mg, 2.39 mmol)
and ethyl .alpha.-bromophenylacetate (460 .mu.l, 2.68 mmol). The
reaction mixture was allowed to react at 70.degree. C. for 2 h. The
reaction mixture was washed with water and extracted by DCM. The
organic later was dried over Na.sub.2SO.sub.4. The organic layer
then was filtered, concentrated and purified by silica gel column,
using dichlormethane and MeOH as the solvent in a linear gradient.
.sup.1H NMR (CDCl.sub.3): .delta. 1.31 (t, 3H), .delta. 3.45 (s,
3H), .delta. 3.78 (t, 2H), .delta. 4.29-4.33 (m, 2H), .delta. 4.51
(t, 2H), .delta. 5.83 (bs, 2H), .delta. 7.41-7.42 (m, 5H), .delta.
7.78 (s, 1H); MS: 372.1 (M+H).sup.+, 370.1 (M-1).
Step 2: synthesis of
2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-2-phenylethanol
(45)
[0766] To a solution of ester made above (360 mg, 0.89 mmol) in THF
(5 ml), was added LAH (101 mg, 2.67 mmol) in one portion at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for
1/2 h, until reaction finished. The reaction was quenched with a
few drops of 1N HCl, then washed with water and extracted with
dichlormethane. The organic was dried over Na.sub.2SO.sub.4,
filtered, concentrated and purified by silica gel chromatography,
using dichloromethane and MeOH as the solvent in a linear gradient
to give 260 mg product. .sup.1H NMR (CDCl.sub.3): .delta. 3.42 (s,
3H), .delta. 3.76 (t, 2H), .delta. 4.32 (d, 2H), .delta. 4.52-4.59
(m, 3H), .delta. 7.37-7.43 (m, 5H); MS: 372.1 (M+H).sup.+.
(2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-yl)-2-phenyl-ethoxymethyl)-phosph-
onic acid diethyl ester (46)
[0767] .sup.1H NMR (CDCl.sub.3): .delta. 1.24-1.28 (m, 6H), .delta.
3.43 (s, 3H), .delta. 3.75 (t, 2H), .delta. 3.81-3.87 (m, 2H),
.delta. 4.03-4.09 (m, 4H), .delta. 4.20-4.23 (M, 1H), .delta. 4.17
(t, 2H), .delta. 4.56-4.60 (m, 1H), .delta. 5.84-5.87 (m, 1H),
.delta. 5.88 (bs, 2H), .delta. 7.34-7.36 (m, 5H), .delta. 7.92 (s,
1H); MS: 480.1 (M+H).sup.+.
(2-(6-Amino-8-bromo-2-(2-methoxy-ethoxy)-purin-9-yl)-2-phenyl-ethoxymethyl-
)-phosphonic acid diethyl ester (47)
[0768] .sup.1H NMR (CDCl.sub.3): .delta. 1.22-1.27 (m, 6H), .delta.
3.45 (s, 3H), .delta. 3.82-3.85 (m, 2H), .delta. 3.99-4.07 (m, 4H),
.delta. 4.30-4.34 (m, 1H), .delta. 4.48 (t, 2H), .delta. 5.11 (t,
1H), .delta. 5.82-5.85 (m, 3H), .delta. 7.28-7.36 (m, 3H), .delta.
7.47-7.49 (m, 2H); MS: 558.0 (M+H).sup.+.
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-2-phenyl-ethoxymeth-
yl)-phosphonic acid (Example U)
[0769] .sup.1H NMR (CD.sub.3OD) .delta. 3.40 (s, 3H), .delta. 3.72
(t, 2H), .delta. 3.77-3.79 (q, 2H), .delta. 4.20-4.23 (q, 1H),
.delta. 4.42 (t, 3H), .delta. 4.90-4.94 (m, 2H), .delta. 5.70-5.74
(q, 1H), .delta. 7.30-7.36 (m, 3H), .delta. 7.52 (d, 2H); MS: 440.1
(M+H).sup.+, 438.1 (M-1).
Example V
[0770] ##STR342## ##STR343##
(2-(6-Amino-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-allyloxymethyl)-phospho-
nic acid diethyl ester (48)
[0771] Compound 48 was prepared by alkylating Compound 15 with the
corresponding bromide, using the procedures similar to those shown
in Scheme 28.
[0772] .sup.1H NMR (CDCl.sub.3): .delta. 1.35 (t, 3H), .delta. 3.42
(s, 3H), .delta. 3.73 (s, 2H), .delta. 3.76 (s, 2H), .delta. 4.06
(s, 2H), .delta. 4.13-4.23 (m, 4H), .delta. 4.45 (t, 2H), .delta.
4.75 (t, 2H), .delta. 4.75 (s, 2H), .delta. 5.02 (s, 1H), .delta.
5.24 (s, 1H), .delta. 5.94 (bs, 2H), .delta. 7.71 (s, 1H).
(2-(6-Amino-8-bromo-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-allyloxymethyl--
phosphonic acid diethyl ester (49)
[0773] .sup.1H NMR (CDCl.sub.3): .delta. 1.34 (t, 6H), .delta. 3.41
(s, 3H), .delta. 3.70-3.79 (m, 4H), .delta. 4.13-4.23 (m, 6H),
.delta. 4.43 (t, 2H), .delta. 4.72 (s, 3H), .delta. 5.21 (s, 1H),
.delta. 6.04 (s, 2H); MS: 508.2 (M+H).sup.+.
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-allyloxymethy-
l)-phosphonic acid (Example V)
[0774] .sup.1H NMR (CD.sub.3OD) .delta. 3.39 (s, 3H), .delta.
3.67-3.73 (m, 4H), .delta. 4.17 (s, 2H), .delta. 4.40 (t, 2H),
.delta. 4.47 (s, 2H), .delta. 4.88 (s, 1H, which is cover by the
H.sub.2O peak in CD.sub.3OD), .delta. 5.21 (s, 1H); MS: 390.1
(M+H).sup.+, 388.0 (M-1).
Example W
[0775] ##STR344##
Synthesis of 2,2-Dimethyl-propionic acid
(3-(6-amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-(2,2-
-dimethyl-propionyloxymethoxy)-phosphinoyloxymethyl ester (Example
W)
[0776] To a suspension of
(3-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phos-
phonic acid (Example C) (50 mg, 0.12 mmol) in DMF (2 ml) was added
N,N'-dicyclohexyl-4-morpholine-carboxamidine (71 mg, 0.24 mmol) and
chloromethyl pivalate (90 .mu.l, 0.60 mmol). The reaction mixture
was stirred at 60.degree. C. overnight. The reaction mixture was
purified by Prep-HPLC on a C18 column, eluting with a gradient of
5-95% acetonitrile in water as solvent. .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.19 (s, 18H), .delta. 3.21 (d, 2H), .delta. 3.41
(s, 3H), .delta. 3.72 (t, 3H), .delta. 4.44 (s, 2H), .delta. 5.01
(s, 2H), .delta. 5.59 (d, 4H), .delta. 5.77 (bs, 2H), .delta.
7.18-7.34 (m, 4H), .delta. 10.43 (bs, 1H); .sup.31P NMR
(CDCl.sub.3, 300 MHz): .delta. 27.18 (s); MS: 638.2
(M+H).sup.+.
Example X
[0777] ##STR345##
Synthesis of 2,2-Dimethyl-propionic acid
(3-(6-amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-hydr-
oxy-phosphinoyloxymethyl ester (X)
[0778] To a solution of
(3-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phos-
phonic acid (Example C) (50 mg, 0.12 mmol) in DMF, was added
diisopropylethylamine (110 .mu.l, 0.60 mmol), and chloromethyl
pivalate. The reaction mixture stirred at 60.degree. C. After
checking the reaction after 6 h by LC/MS, about 60% starting
material was converted to desired product. The product was isolated
by prep-HPLC on a C 18 column, eluting with a gradient of 5-95%
acetonitrile in water as solvent. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.21 (s, 9H), .delta. 3.01 (d, 2H), .delta. 3.39 (s, 3H),
.delta. 3.17 (t, 3H), .delta. 4.42 (t, 3H), .delta. 4.92 (s, 2H),
.delta. 5.60 (d, 2H), .delta. 7.17-7.37 (m, 4H), .delta. 10.64 (s,
1H); MS: 524.1 (M+H).sup.+, 531.9 (M-1).
Example Y
[0779] ##STR346##
Synthesis of Example Y
[0780] To a solution of L-alanine ethyl ester hydrochloride (56 mg,
0.36 mmol) in pyridine, was added triphenyl phosphate (190 mg, 0.72
mmol), aldrithiol-2 (160 mg, 0.72 mmol), and
(3-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phos-
phonic acid (30 mg, 0.073 mmol). The reaction mixture was stirred
at 60.degree. C. for 4 h. After the reaction was finished,
NaHCO.sub.3 (60 mg) was added and the mixture was stirred at RT for
10 min. The solvent was removed, and the residue was dissolved in
DCM and purified by 4 g silica gel column. The column was eluted
with 50% EtOAc/hexane to wash out all yellow color. Then the
product was eluted with 20% EtOH/EtOAc. The fraction with product
(Example Y) was concentrated and purified again by prep HPLC using
5-100% acetonitrile in water. .sup.1H NMR (CDCl.sub.3, 300 MHz):
.delta. 1.20 (t, 6H), .delta. 1.27-1.34 (m, 6H), .delta. 3.14 (d,
2H), .delta. 3.28-3.44 (m, 5H), .delta. 3.71 (t, 2H), .delta.
3.87-3.98 (M, 2 h), .delta. 4.08-4.14 (M, 4H), .delta. 4.43 (t,
2H), .delta. 4.97 (s, 2H), .delta. 5.99 (bs, 2H), .delta. 7.16-7.40
(m, 4H), .delta. 10.54 (s, 1H); .sup.31P NMR (CDCl.sub.3, 300 MHz):
.delta. 25.65 (s); MS: 608.2 (M+H).sup.+, 606.2 (M-1).
[0781] Example Z was isolated from the reaction above.
##STR347##
[0782] .sup.1H NMR (CDCl.sub.3) .delta.1.33 (t, 3H), .delta. 1.50
(d, 3H), .delta. 3.01 (d, 2H), .delta. 3.39 (s, 3H), .delta. 3.70
(t, 2H), .delta. 3.92 (m, 1H), .delta. 4.05-4.29 (m, 4 h), .delta.
4.46 (s, 2H), .delta. 4.90 (s, 2H), .delta. 7.16-7.40 (m, 4H); MS:
509.1 (M+H).sup.+, 507.0 (M-1).
Examples AA and AB
[0783] Examples AA and AB were prepared using procedures similar to
those used to prepare Example Y, except that different amino acids
were used during the reaction. ##STR348##
[0784] .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 1.11-1.19 (q,
6H), .delta. 2.62-2.99 (m, 6H), .delta. 3.38 (s, 3H), .delta. 3.69
(t, 2H), .delta. 3.80-4.19 (m, 6H), .delta. 4.38 (t, 2H), .delta.
4.95 (s, 2H), .delta. 6.88-7.36 (m, 14H); .sup.31P NMR (CD.sub.3OD,
300 MHz): .delta. 25.25 (s); MS: 760.2 (M+H).sup.+, 758.2 (M-1).
##STR349##
[0785] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 1.15-1.28 (m,
18H), .delta. 3.15 (d, 2H), .delta. 3.39 (s, 3H), .delta. 3.70-3.76
(m, 3H), .delta. 3.82-3.88 (m, 1), .delta. 4.44 (t, 2H), .delta.
4.88-4.96 (m, 2H), .delta. 4.98 (s, 2H), .delta. 7.27-7.39 (m, 4H);
.sup.31P NMR (CD.sub.3OD, 300 MHz): 27.14 (s); MS: 636.1
(M+H).sup.+, 634.2 (M-1).
Example AC
[0786] ##STR350##
Synthesis of Example AC
[0787] To a solution of L-alanine ethyl ester hydrochloride (37 mg,
0.24 mmol) in pyridine (2 ml) was added triphenylphosphate (256 mg,
0.98 mmol), aldrithiol-2 (440 mg, 0.98 mmol) and
(2-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-yl)-1-phenoxymethyl-et-
hoxymethyl)-phosphonic acid (Example O) (23 mg, 0.049 mmol). The
reaction mixture stirred at 60.degree. C. for 4 h and cooled to rt.
NaHCO.sub.3 (50 mg) was added to the reaction mixture and it was
stirred at rt for 10 min. The solvent was evaporated and the
residue was dissolve in dichloromethane. The mixture was purified
by 4 g silica gel chromatography. The column was eluted with 50%
EtOAc/hexane to get rid of yellow impurities. Then the desired
product was eluted with 20% EtOH/EtOAc. The fraction with product
(Example AC) was concentrated and purified by prep-HPLC by 5-100%
acetonitrile in water. .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta.
1.19-1.22 (m, 6H), .delta. 1.35-1.38 (m, 6H), .delta. 3.38 (s, 3H),
.delta. 3.54-3.64 (m, 2H), .delta. 3.87-4.30 (m, 18H), .delta. 5.99
(s, 2H), .delta. 6.87-7.26 (m, 5H), .delta. 10.52 (d, 1H); .sup.31P
NMR (CDCl.sub.3, 300 MHz): .delta. 22.26 (s), .delta. 22.33 (s);
MS: 668.2 (M+H).sup.+, 666.2 (M-1).
Examples AD, AE, and AF
[0788] Examples AD, AE, and AF were prepared using procedures
similar to shown in Scheme 32 except that different amino acid
esters were used in the reaction. ##STR351##
[0789] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 1.10-1.21 (m, 6H),
(2.72-3.05 (m, 4H), .delta. 3.36 (d, 3H), .delta. 3.43-3.74 (m,
4H), .delta. 3.93-4.14 (m, 11H), .delta. 4.27-4.31 (m, 2H),
(6.84-7.28 (m, 15H); 31P NMR (CD3OD, 300 MHz): (23.17 (s), (23.25
(s); MS: 820.3 (M+H).sup.+, 818.3 (M-1). ##STR352##
[0790] .sup.1H NMR (CD.sub.3OD, 300 MHz): (1.30 (s, 3H), (1.32 (s,
3H), (1.42 (s, 9H), (1.45 (s, 9H), (3.37 (s, 3H), (3.65 (t, 3H),
(3.78-3.87 (m, 2H), (3.95-3.98 (m, 2H), (4.12-4.16 (m, 2H),
(4.20-4.24 (m, 2H), (4.21-4.33 (m, 2H), (6.90-6.95 (m, 3H),
(7.23-7.28 (m, 2H); .sup.31P NMR (CD.sub.3OD, 300 MHz): (23.55 (s),
(23.75 (s); MS: 724.2 (M+H).sup.+, 722.2 (M-1). ##STR353##
[0791] .sup.1H NMR (CD.sub.3OD, 300 MHz) (1.19-1.24 (m, 12H),
(1.31-1.34 (m, 6H), (3.37 (d, 3H), (3.63-3.67 (m, 2H), (3.90-4.00
(m, 4H), (4.12-4.15 (m, 3H), (4.32-4.34 (m, 2H), (4.90-4.97 (m,
2H), (6.90-6.96 (m, 3H), (7.23-7.28 (m, 2H); .sup.31P NMR
(CD.sub.3OD, 300 MHz): (23.52 (s), (23.74 (s); MS: 696.2
(M+H).sup.+, 694.1 (M-1).
Example AG
[0792] ##STR354##
Synthesis of Example AG
[0793] To a solution of
(3-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phos-
phonic acid (40 mg, 0.098 mmol) in pyridine (2 ml), was added
L-alanine isopropyl ester hydrochloride (33 mg, 0.19 mmol),
triethyl amine (170 .mu.l, 1.16 mmol), phenol (46 mg, 4.85 mmol),
triphenylphosphate (180 mg, 0.69 mmol), aldrithiol-2 (150 mg, 0.69
mmol). The reaction mixture was stirred at 60.degree. C. overnight.
The solvent was removed, and the residue was dissolved in
dichloromethane and purified using 4 g silica gel chromatography.
The column was eluted with 50% EtOAc/hexane to wash out the yellow
impurities and then the product was eluted with 20% EtOH/EtOAc. The
organic fraction with product (Example AG) was concentrated and
purified again by prep-HPLC using 5-100% acetonitrile in water.
.sup.1H NMR (CDCl.sub.3, 300 MHz): (1.12-1.17 (m, 9H), (3.38 (s,
3H), (3.49-3.53 (m, 1H), (3.70 (t, 2H), (3.88-3.92 (m, 1H), (4.45
(t, 2H), (4.89-4.94 (m, 1H), (4.99 (s, 2H), (6.26 (bs, 1H),
(7.00-7.46 (m, 9H), (10.41 (s, 1H); .sup.1H NMR (CD.sub.3OD):
(1.00-1.20 (m, 9H), (3.34-3.38 (m, 5H), (3.69 (t, 2H), (3.72-3.81
(m, 1H), (4.41 (t, 3H), (4.86 (m, 1H), (5.00 (s, 2H), (6.98-7.41
(m, 9H); .sup.31P NMR (CDCl.sub.3, 300 MHz): (27.06 (s), (27.11
(s); .sup.31P NMR (CD.sub.3OD): (28.36 (s), (28.76 (s); MS: 599.2
(M+H).sup.+, 597.2 (M-1);
Example AH
[0794] ##STR355##
Synthesis of Example AH
[0795] To a solution of compound AH (5.7 mg, 0.0096 mmol) in
dichloromethane (0.5 ml) was added triethylamine (30 .mu.l) and
ethyl chloroformate (20 .mu.l). The reaction mixture was stirred at
rt for 10 min. The solvent was removed, and the residue was
dissolved in DMF and purified by prep-HPLC using 5-100%
acetonitrile in water. .sup.1H NMR (CDCl.sub.3): (1.10-1.20 (m,
9H), (1.22-1.46 (m, 3H), (3.13-3.36 (m, 4H), (3.41 (s, 3H), (3.71
(t, 2H), (3.92-4.00 (m, 1H), (4.42-4.50 (m, 4H), (4.86-4.99 (m,
3H), (7.01-7.52 (m, 9H); .sup.31P NMR (CDCl.sub.3): (25.61 (s),
(25.86 (s); MS: 671.2 (M+H).sup.+.
Examples AI, AJ, AK, AL, AM, AN, AO, and AP
[0796] Examples AI, AJ, AK, AL, AM, AN, AO, and AP were prepared
from chiral phosphonic acid example Q and R using procedures
similar to those used to prepare Example AC. ##STR356##
[0797] .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 1.19-1.27 (m,
6H), (1.32-1.36 (m, 6H), (3.37 (s, 3H), (3.65 (t, 2H), (3.90-4.00
(m, 4H), (4.03-4.23 (m, 9H), (4.32 (t, 2H), (6.89-6.96 (m, 3H),
(7.23-7.29 (m, 2H); .sup.31P NMR (CD.sub.3OD, 300 MHz): (23.58; MS:
668.2 (M+H).sup.+; 666.2 (M-1). ##STR357##
[0798] 1H NMR (CD.sub.3OD, 300 MHz): (1.20-1.27 (m, 6H), (1.33-1.36
(m, 6H), (3.38 (s, 3H), (3.65 (t, 2H), (3.93-4.01 (m, 4H),
(4.07-4.16 (m, 7H), (4.20-4.28 (m, 2H), (4.32 (t, 2H), (6.89-6.96
(m, 3H), (7.26 (t, 2H); .sup.31P NMR (CD.sub.3OD, 300 MHz): (23.84;
MS: 668.1 (M+H).sup.+, 666.1 (M-1). ##STR358##
[0799] 1H NMR (CD.sub.3OD, 300 Hz): (1.19-1.22 (m, 12H), (1.24-1.34
(m, 6H), (3.37 (s, 3H), (3.65 (t, 2H), (3.85-4.00 (m, 4H),
(4.12-4.15 (m, 3H), (4.20-4.24 (m, 2H), (4.31 (t, 2H), (4.88-4.99
(M, 2H), (6.90-6.95 (m, 3H), (7.26 (t, 2H); .sup.31P NMR
(CD.sub.3OD, 300 MHz): (23.54; MS: 696.1 (M+H).sup.+, 694.2 (M-1).
##STR359##
[0800] .sup.1H NMR (CD.sub.3OD, 300 MHz): (1.20-1.24 (m, 12H),
(1.32-1.35 (m, 6H), (3.38 (s, 3H), (3.66 (t, 2H), (3.90-4.01 (m,
4H), (4.09-4.15 (m, 3H), (4.20-4.25 (m, 2H), (4.32 (t, 2H),
(4.90-4.99 (m, 2H), (6.90-6.96 (m, 3H), (7.26 (t, 2H); .sup.31P NMR
(CD3OD, 300 MHz): (23.77; MS: 696.1 (M+H).sup.+, 694.1 (M-1).
##STR360##
[0801] 1H NMR (CD.sub.3OD, 300 MHz): (1.11-1.22 (m, 6H), (2.73-3.04
(m, 4H), (3.36 (s, 3H), (3.49-3.55 (m, 2H), (3.64 (t, 2H),
(3.98-4.17 (m, 11H), (4.29 (t, 2H), (6.84-6.93 (m, 3H), (7.10-7.28
(m, 12H); .sup.31P NMR (CD.sub.3OD, 300 MHz): (23.16; MS: 820.2
(M+H).sup.+, 818.2 (M-1). ##STR361##
[0802] 1H NMR (CD.sub.3OD, 300 MHz): (1.14-1.20 (m, 6H), (2.72-3.07
(m, 4H), (3.36 (s, 3H), (3.43-3.74 (m, 4H), (3.95-4.15 (m, 11H),
(4.27-4.29 (m, 2H), (6.86-6.96 (m, 3H), (7.09-7.29 (m, 12H);
.sup.31P NMR (CD.sub.3OD, 300 MHz): (23.24; MS: 820.1 (M+H).sup.+,
818.2 (M-1). ##STR362##
[0803] .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 1.16 (d, 6H),
.delta. 1.25 (d, 3H), .delta. 3.37 (s, 3H), .delta. 3.96-4.33 (m,
10H), .delta. 4.90-4.91 (m, partly covered by water peak, 1H),
.delta. 6.92-7.32 (m, 10H); .sup.31P NMR (CD.sub.3OD, 300 MHz):
.delta. 24.26; MS: 659.2 (M+H).sup.+, 657.1 (M-1). ##STR363##
[0804] .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 1.16-1.20 (m,
6H), .delta. 1.25 (d, 3H), .delta. 3.37 (s, 3H), .delta. 3.65 (t,
2H), .delta. 3.94-4.25 (m, 7H), .delta. 4.30-4.33 (m, 3H), .delta.
4.90-4.91 (m, partly covered by water peak, 1H), .delta. 6.92-7.29
(m, 10H); .sup.31P NMR (CD.sub.3OD, 300 MHz): .delta. 23.36 (s),
.delta. 24.55 (s); MS: 659.2 (M+H).sup.+, 657.1 (M-1).
Examples AQ and AR
[0805] ##STR364##
Step 1: Synthesis of
(3-(6-Amino-8-mercapto-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-pho-
sphonic acid monoethyl ester (51)
[0806] To a solution of
(3-(6-Amino-8-bromo-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phosph-
onic acid diethyl ester (50) (180 mg, 0.34 mmol) in DMF (2 ml) was
added potassium thioacetate (778 mg, 6.8 mmol). The reaction
mixture stirred at 100.degree. C. for 24 h. After cooling to rt,
the reaction mixture was filtered and purified by reversed phase
prep-HPLC using a linear gradient of acetronitrile in water from 5%
to 95%. .sup.1H NMR (DMSO, 300 MHz): (1.08 (t, 3H), (3.00 (d, 2H),
(3.25 (s, 3H), (3.58 (t, 2H), (3.77-3.84 (m, 2H), (4.29 (t, 2H),
(5.23 (s, 2H), (6.87 (bs, 2H), (7.16-7.28 (m, 4H); .sup.31P NMR
(DMSO, 300 MHz): (23.20; MS: 454.1 (M+H).sup.+, 452.0 (M-1).
(3-(6-Amino-8-mercapto-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phos-
phonic acid (Example AQ)
[0807] .sup.1H NMR (CD.sub.3OD, 300 MHz): (3.07 (d, 2H), (3.38 (s,
3H), (3.71 (t, 2H), (4.44 (t, 2H), (5.36 (s, 2H), (7.21-7.47 (m,
4H); .sup.31P NMR (CD.sub.3OD, 300 MHz): (23.48; MS: 426.1
(M+H).sup.+, 424.0 (M-1).
Example AR
[0808] .sup.1H NMR (CD.sub.3OD, 300 MHz): .delta. 1.14-1.29 (m,
18H), .delta. 3.15 (d, 2H), .delta. 3.38 (s, 3H), .delta. 3.69-3.89
(m, 4H), .delta. 4.44 (t, 2H), (4.90-4.96 (m, 2H), (5.37 (s, 2H),
(7.24-7.48 (m, 4H); .sup.31P NMR (CD.sub.3OD, 300 MHz): (27.23. MS:
652.0 (M+H).sup.+, 650.2 (M-1).
Examples AS, AT, and AU
[0809] Example AS, AT, and AU were prepared from Example C using
procedures as shown in Scheme 17, except that phenol was replaced
with cyclic amines or oxime. ##STR365##
[0810] .sup.1H NMR (CDCl.sub.3, 300 MHz): (1.18-1.33 (m, 9H),
(1.85-1.95 (m, 6H), (3.25-3.35 (m, 2H), (3.39 (s, 3H), (3.49-3.67 9
m, 1H), (3.72 (t, 2H), (3.95-3.98 (m, 1H), (4.46 (t, 2H),
(4.96-5.00 (m, 3H), (6.25 (bs, 2H), (7.15-7.35 (m, 4H), (10.40 (bs,
1H); .sup.31P NMR (CDCl.sub.3, 300 MHz): (33.51 (s), (33.38 (s);
MS: 578.2 (M+H).sup.+, 576.1 (M-1). ##STR366##
[0811] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.16-1.35 (m,
9H), .delta. 2.90-3.17 (m, 4H), .delta. 3.40 9 s, 3H), .delta.
3.46-3.50 (m, 4H), .delta. 3.73 (t, 2H), .delta. 3.86-3.89 (m, 1H),
.delta. 4.52 (t, 2H), .delta. 4.96-5.03 (m, 3H), .delta. 7.14-7.37
(m, 4H), .delta. 10.63 (s, 1H); .sup.31P NMR (CDCl.sub.3, 300 MHz):
.delta. 27.07 (s), .delta. 28.11 (s); MS: 592.1 (M+H).sup.+, 590.2
(M-1). ##STR367##
Synthesis of Example AU
[0812] To a solution of
(3-(6-Amino-8-hydroxy-2-(2-methoxy-ethoxy)-purin-9-ylmethyl)-benzyl)-phos-
phonic acid (Example C) (100 mg, 0.24 mmol) in pyridine (1 ml) was
added (s)-2-(methoxymethyl)pyrrolidine (28 mg, 0.24 mmol),
triphenylphosphane (314 mg, 1.2 mmol) and aldrithiol-2 (264 mg, 1.2
mmol). The reaction mixture was reacted at 65.degree. C. for 2 h.
After starting material was consumed, L-alanine isopropyl ester
hydrogen chloride (80 mg, 0.48 mmol), triphenylphosphine (314 mg,
1.2 mmol), adrithiol-2 (264 mg, 1.2 mmol) and molecular sieves (50
mg) were added to the reaction mixture. The mixture was stirred at
65.degree. C. until LC/MC indicated that the reaction was complete,
and then the mixture was cooled and the solvent was removed. The
residue was loaded on silica gel column, eluted with EtOAc/Hexane
(1/1) to remove a yellow impurity and then with 20% EtOH/EtOAC to
elute the product. The fractions containing product were
concentrated and purified by reversed phase HPLC, using 5-85%
acetonitrile in water as solvent. .sup.1H NMR (CDCl.sub.3, 300
MHz): .delta. 1.19-1.33 (m, 12H), .delta. 1.72-1.75 (m, 3H),
.delta. 2.90-3.01 (m, 2H), .delta. 3.03-3.20 (m, 6H), .delta. 3.38
(s, 3H), .delta. 3.71-3.82 (m, 4H), .delta. 4.08-4.10 (m, 1H),
.delta. 4.46 (t, 2H), .delta. 4.94-5.00 (m, 3H), .delta. 6.55 (bs,
2H), .delta. 7.16-7.33 (m, 4H), .delta. 10.72 (b, 1H); .sup.31P NMR
(CDCl.sub.3, 300 MHz): .delta. 26.65 (s), .delta. 28.78 (s); MS:
620.2 (M+H).sup.+, 618.2 (M-1).
Example AV
[0813] ##STR368##
Synthesis of Example AV
[0814] Example C (95 mg, 0.232 mmol) was suspended in NMP (0.5 mL).
Triethylamine (0.22 mL) was added and the mixture was heated to
62.degree. C. A solution of chloromethyl isopropyl carbonate (0.22
mL) in NMP (1.5 mL) was added with a syringe pump over 90 minutes.
The mixture was heated at 62.degree. C. for 5 more hours, and then
diluted with ethyl acetate, washed with water and brine, dried with
Na.sub.2SO.sub.4 and evaporated under vacuum. The crude product was
purified by flash chromatography on silica gel (Eluent 50% to 100%
hexane/ethyl acetate) giving AV (20 mg) as colorless oil. MS: 758.2
(M+H).sup.+.
Example AW
[0815] ##STR369##
Synthesis of Example AW
[0816] Diethyl
(3-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenyl)meth-
ylphosphonate 50 from the synthesis of Example C (40 mg, 0.076
mmol), n-butylamine (0.1 mL) and n-butanol (1 mL) were combined and
heated in the microwave at 200.degree. C. for 10 minutes. The
solvent was evaporated under vacuum and the residue was partitioned
between brine and dichloromethane. The aqueous layer was extracted
with dichloromethane (4.times.). The combined organic layers were
dried with Na.sub.2SO.sub.4 and evaporated under vacuum. The crude
product 56 was dissolved in acetonitrile (1 mL) and
bromotrimethylsilane (1 mL) was added. The mixture was stirred at
ambient temperature overnight. After evaporation to dryness the
crude product was purified by preparative reverse phase HPLC giving
Example AW (6 mg) was white powder. MS: 465.2 (M+H).
Example AX
[0817] ##STR370##
[0818] Example AX was prepared using procedures similar to those
used to prepare Example AW except that n-butylamine was replaced
with 2-morpholinoethanamine. MS: 522.2 (M+H).
Example AY
[0819] ##STR371## ##STR372##
Synthesis of 9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (53)
[0820] 2-Chloroadenine (1.53 g, 9.0 mmol), 3-bromobenzyl bromide
(2.48 g, 9.92 mmol), potassium carbonate (1.38 g, 10 mmol) were
combined in DMF (10 mL) and stirred at ambient temperature
overnight. The mixture was diluted with ethyl acetate (200 mL) and
washed with water and brine. The organic layer was dried with
Na.sub.2SO.sub.4 and evaporated to dryness. The residue was
triturated with diethyl ether/ethyl acetate 4:1 and filtered giving
9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (Compound 53) (2.3 g)
as off-white solid.
Synthesis of 9-(3-bromobenzyl)-N.sup.2-butyl-9H-purine-2,6-diamine
(54)
[0821] 9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (2.3 g) (100 mg,
0.295 mmol), n-butylamine (0.5 mL) and n-butanol (1 mL) were
combined and heated in the microwave at 170.degree. C. for 15
minutes. The solvent was evaporated under vacuum and the residue
was partitioned between water and ethylacetate. The organic layer
was washed with brine, dried with Na.sub.2SO.sub.4 and evaporated
under vacuum. The crude product was triturated with diethylether
and filtered giving
9-(3-bromobenzyl)-N.sup.2-butyl-9H-purine-2,6-diamine (Compound 54)
(60.9 mg) as off-white solid.
Synthesis of Example AY
[0822] 9-(3-Bromobenzyl)-N.sup.2-butyl-9H-purine-2,6-diamine (50
mg, 0.133 mmol), diethylphosphite (0.026 mL, 0.2 mmol),
triethylamine (0.028 mL, 0.2 mmol), Pd(dppf)Cl.sub.2.DCM (15 mg,
0.018 mmol) were combined in DMF (1 mL) and heated in the microwave
at 130.degree. C. for 5 minutes. The mixture was diluted with ethyl
acetate (50 mL) and washed with water and brine, dried with
Na.sub.2SO.sub.4 and evaporated. The crude product (Compound 55)
was dissolved in chloroform (2 mL) and a 10% solution of bromine in
chloroform was added dropwise until the bromine color remained.
After stirring for additional 10 minutes the mixture was diluted
with ethyl acetate (50 mL) and washed with 0.1N sodium thiosulfate
solution, water, sodium bicarbonate solution and brine, dried with
Na.sub.2SO.sub.4 and evaporated under vacuum to dryness. The crude
product (Compound 56) was dissolved in methanol (10 mL) and 50%
aqu. KOH solution (2 mL) was added. The mixture was heated under
reflux until HPLC analysis showed complete disappearance of the
bromide. Then the mixture was acidified with conc. HCl and heated
under reflux for 2 hours. All solvents were removed under vacuum
and the solid residue was extracted with methanol three times. The
combined methanol extracts were evaporated under vacuum. The crude
monoester was dissolved in acetonitrile (2 mL),
bromotrimethylsilane (2 mL) was added and the mixture was stirred
at ambient temperature overnight. After evaporation to dryness the
crude product was dissolved in 1N HCl/acetonitrile and precipitated
by slowly neutralizing with 1N NaOH to pH-5. The precipitate was
filtered and dried giving Example AY (11.3 mg) as tan solid. MS:
393.2 (M+H).sup.+.
[0823] Examples AZ and BA were prepared using procedures similar to
those as shown in Schemes 39 and 40 except that n-butylamine was
replaced with benzylamine or sodium n-butoxide.
Example AZ
427.3 (M+H).sup.+
[0824] ##STR373##
Example BA
394.2 (M+H).sup.+
[0825] ##STR374##
Example BB
[0826] ##STR375##
Synthesis of Example BB
[0827] 9-(3-Bromobenzyl)-N.sup.2-butyl-9H-purine-2,6-diamine (200
mg, 0.532 mmol), diethylmethylphosphonite (0.1 mL), triethylamine
(0.12), Pd(dppf)Cl.sub.2.DCM (50 mg) were combined in DMF (2 mL)
and heated in the microwave at 130.degree. C. for 5 minutes. The
mixture was diluted with ethyl acetate (150 mL) and washed with
water and brine, dried with Na.sub.2SO.sub.4 and evaporated. The
crude product was dissolved in ethyl acetate and filtered through a
pad of silica gel (3 g), eluting with 25% methanol in ethyl
acetate. After evaporation to dryness the product was dissolved in
chloroform (10 mL) and a 5% solution of bromine in chloroform was
added dropwise until the bromine color remained. After stirring for
additional 10 minutes the mixture was diluted with ethyl acetate
(50 mL) and washed with 0.1N sodium thiosulfate solution, water,
sodium bicarbonate solution and brine, dried with Na.sub.2SO.sub.4
and evaporated under vacuum to dryness. The crude product was
dissolved in methanol (5 mL) and 50% aqu. KOH solution (1 mL) was
added. The mixture was heated under reflux for 2 hours. Then the
mixture was acidified with conc. HCl and heated under reflux
overnight. All solvents were removed under vacuum and the solid
residue was extracted with methanol. The methanol extract was
evaporated under vacuum and the residue was purified by preparative
reverse phase HPLC giving Example BB (87 mg) as white powder. MS:
391.2 (M+H).
Example BC
[0828] ##STR376##
[0829] Example BC was prepared using procedures similar to those
shown in Scheme 40 expect that diethylmethylphosphonite was
replaced with ethyl benzylphosphinate. MS: 467.3 (M+H).
Example BD
[0830] ##STR377## ##STR378##
Synthesis of 2-butoxy-9H-purin-6-amine (59)
[0831] 2-chloroadenine (1) (1.53 g, 9.03 mmol) was divided among
three microwave vials (10-20 mL), each containing 1-butanol (10 mL)
and t-BuOK (5 mL, 1M in THF). Each vial was heated to 170.degree.
C. for 40 minutes. After reaction completion the solvent was
removed by rotary evaporation and the product was purified on flash
column eluting 10% methanol in ethylacetate. Evaporation of solvent
gave 1.33 g (70%) of 59 as an off white solid. .sup.1H NMR (300
MHz, DMSO) .delta. 0.919 (t, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 4.09
(t, 2H), 6.00 (s, 2H), 7.44 (s, 1H). LCMS: m/z for
C.sub.9H.sub.13N.sub.5O.sup.++H observed 208.1 at 1.34 minutes of a
3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O.
##STR379##
Synthesis of diethyl 3-(bromomethyl)benzylphosphonate (60)
[0832] To a solution of .alpha.,.alpha.'-Bisbromo-m-xylene (10.02
g, 37.95 mmol) in DMF (20 mL) was added triethyl phosphite (3.15 g,
3.3 mL, 19.98 mmol) via syringe. The mixture was heated to
150.degree. C. for 2 minutes in a microwave. The reaction mixture
was poured into water and product extracted with diethyl ether
(3.times.25 mL). The combined organics were washed with water
(2.times.50 mL) and brine (50 mL), and dried over Na.sub.2SO.sub.4.
Reduced volume in vacuo and purified product by flash column
eluting 30-100% ethyl acetate in hexanes to give 4.64 g (76%) 60 as
a colorless oil. LCMS: m/z for C.sub.12H.sub.18BrO.sub.3P.sup.++H
observed 321.0 and 323.0 at 2.29 minutes of a 3.5 minute run,
gradient 5-95% CH.sub.3CN in H.sub.2O. ##STR380##
Synthesis of diethyl
(3-((6-amino-2-butoxy-9H-purin-9-yl)methyl)phenyl)methylphosphonate
(61)
[0833] A mixture of 59 (348.7 mg, 1.68 mmol) and K.sub.2CO.sub.3
(232.56 mg, 1.68) was dissolved in DMF (5 mL) and to it was added
60 (540.4 mg, 1.68 mmol). The mixture was left to stir over night
at room temperature, solvent was evaporated by rotary evaporation.
The remaining solid was taken up in water and the product extracted
with DCM (3.times.50 mL). Combined organic layers were washed with
water (1.times.50 mL) and brine (2.times.50 mL) and dried over
Na.sub.2SO.sub.4. Product was purified by flash column eluting
0-15% methanol in ethyl acetate to give 165.8 mg (22%) 61 as a
solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.969 (t, 3H),
1.21 (m, 6H), 1.51 (m, 2H), 1.80 (m, 2H), 3.11 (d, 2H), 3.98 (m,
4H), 4.36 (t, 2H), 5.27 (s, 2H), 7.26 (m, 4H), 7.67 (s, 1H). LCMS:
m/z for C.sub.21H.sub.30N.sub.5O.sub.4P.sup.++H observed 448.1 at
2.28 minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O. ##STR381##
Synthesis of diethyl
(3-((6-amino-8-bromo-2-butoxy-9H-purin-9-yl)methyl)phenyl)methylphosphona-
te (62)
[0834] To a solution of 61 (134.9 mg, 0.30 mmol) in CHCl.sub.3 (5
mL) was added a 10% (v) solution of Br.sub.2 in chloroform. The
reaction was stopped when starting material was consumed, monitored
by HPLC. Bromine was quenched with a saturated Na.sub.2SO.sub.3
solution and product extracted with DCM (2.times.10 mL). Organics
were washed with water (2.times.10 mL) and brine (1.times.10 mL)
and dried over Na.sub.2SO.sub.4. Purified by flash column eluting
100% ethyl acetate. Evaporation of solvent gave 76.0 mg (49%) of 62
as a yellow solid. LCMS: m/z for
C.sub.21H.sub.29BrN.sub.5O.sub.4P.sup.++H observed 526.1 and 528.1
at 2.37 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O. ##STR382##
Synthesis of methyl
(3-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)methyl(methyl-
)phosphinate (63)
[0835] To a solution of 62 (76.0 mg, 0.144 mmol) in methanol (10
mL) was slowly added sodium methoxide (155.9 mg, 2.88 mmol). The
mixture was heated to 70.degree. C. for 5.5 hours at which time
Dowex resin was added to quench any remaining methoxide. The resin
was filtered off and the solvent evaporated. The product was
stirred in 6N HCl over night after which time the solvent was
evaporated to give 61 mg (93%) 63 as a white solid, the crude
product was carried through to the next step. LCMS: m/z for
C21H.sub.30N.sub.5O.sub.5P.sup.++H observed 464.1 at 2.10 minutes
of a 3.5 minute run, eluting 5-95% CH.sub.3CN in H.sub.2O.
##STR383##
Synthesis of
(3-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)methylphospho-
nic acid (BD)
[0836] TMS-Br was added to a solution of 63 (61 mg, 0.13 mmol) in
CH.sub.3CN was cooled to 0.degree. C. The mixture was stirred at
0.degree. C. for 30 minutes, then heated to 70.degree. C. for 6.5
hours. The solvent and TMS-Br were removed by rotary evaporation,
and the resulting product was purified by prep. HPLC giving 1.6 mg
of BD as a white solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
0.972 (t, 3H), 1.49 (m, 2H), 1.74 (m, 2H), 2.97 (d, 2H), 4.28 (t,
2H), 4.98 (s, 2H), 7.18 (m, 2H), 7.29 (d, 1H), 7.36 (s, 1H). LCMS:
m/z for C.sub.17H.sub.22N.sub.5O.sub.5P.sup.++H observed 408.2 at
1.70 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O.
Example BE
[0837] ##STR384## ##STR385##
Synthesis of N.sup.2-butyl-9H-purine-2,6-diamine (64)
[0838] 2-chloroadenine (1) (1.60 g, 9.44 mmol) was divided among
three microwave vials (10-20 mL), each containing Butylamine (4
mL), 1-Butanol (10 mL,), and DMSO (1 mL). Each vial was heated to
170.degree. C. for 90 minutes. After reaction completion the
solvent was removed by rotary evaporation and the product was
purified on flash column eluting 10% methanol in ethylacetate.
Evaporation of solvent gave 1.62 g (83%) of 64 as an off white
solid. .sup.1H NMR (300 MHz, DMSO) .delta. 0.877 (t, 3H), 1.29 (m,
2H), 1.45 (m, 2H), 3.17 (t, 2H), 6.49 (s, 2H), 7.61 (s, 1H), 12.1
(s, 1H). LCMS: m/z for C.sub.9H.sub.14N.sub.6.sup.++H observed
207.2 at 1.40 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O. ##STR386##
Synthesis of ethyl 3-(bromomethyl)benzyl(methyl)phosphinate
(65)
[0839] To a solution of .alpha.,.alpha.'-Bisbromo-m-xylene (7.75 g,
29.38 mmol) in DMF (10 mL) was added diethyl methylphosphonite (2.0
g, 14.69 mmol) via syringe. The mixture was heated to 150.degree.
C. for 2 minutes in a microwave. The reaction mixture was poured
into water and product extracted with ethyl acetate (3.times.25
mL). The combined organics were washed with water (2.times.50 mL)
and brine (50 mL), and dried over Na.sub.2SO.sub.4. Reduced volume
in vacuo and purified product by flash column eluting 20-100% ethyl
acetate in hexanes to give 1.89 g mg (44%) 65 as a colorless oil.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.24 (t, 3H), 1.33 (d,
3H), 3.08 (d, 2H), 3.97 (dt, 2H), 4.44 (s, 2H), 7.25 (m, 4H). LCMS:
m/z for C.sub.11H.sub.16BrO.sub.2P.sup.++H observed 291.0 and 293.0
at 2.09 minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O. ##STR387##
Synthesis of ethyl
(3-((6-amino-2-(butylamino)-9H-purin-9-yl)methyl)phenyl)methyl(methyl)pho-
sphinate (66)
[0840] A mixture of 64 (300.0 mg, 1.45 mmol) and K.sub.2CO.sub.3
(200.0 mg, 1.45 mmol) was dissolved in DMF (5 mL) and to it was
added 65 (420.0 mg, 1.45 mmol). The mixture was left to stir over
night at room temperature, solvent was evaporated by rotary
evaporation. The remaining solid was taken up in water and the
product extracted with DCM (3.times.50 mL). Combined organic layers
were washed with water (1.times.50 mL) and brine (2.times.50 mL)
and dried over Na.sub.2SO.sub.4. Product was purified by flash
column eluting 0-20% methanol in ethyl acetate to give 299.4 mg
(50%) 66 as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.818 (t, 3H), 1.15 (t, 3H), 1.24 (d, 3H), 1.27 (m, 2H), 1.43 (m,
2H), 2.99 (d, 2H), 3.28 (m, 2H), 3.87 (m, 2H), 4.01 (m, 2H), 5.09
(s, 2H), 7.11 (m, 4H), 7.36 (s, 1H). LCMS: m/z for
C.sub.20H.sub.29N.sub.6O.sub.2P.sup.++H observed 417.3 at 1.76
minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O.
##STR388##
Synthesis of ethyl
(3-((6-amino-8-bromo-2-(butylamino)-9H-purin-9-yl)methyl)phenyl)methyl(me-
thyl)phosphinate (67)
[0841] To a solution of 66 (299.4 mg, 0.72 mmol) in CHCl.sub.3 (5
mL) was added a 10% (v) solution of Br.sub.2 in chloroform. The
reaction was stopped when starting material was consumed, monitored
by HPLC. Bromine was quenched with a saturated Na.sub.2SO.sub.3
solution and product extracted with DCM (2.times.10 mL). Organics
were washed with water (2.times.10 mL) and brine (1.times.10 mL)
and dried over Na.sub.2SO.sub.4. Purified by flash column eluting
10% methanol in ethyl acetate. Evaporation of solvent gave 223.6 mg
(63%) of 67 as a yellow solid. LCMS: m/z for
C.sub.20H.sub.28BrN.sub.6O.sub.2P.sup.++H observed 495.2 and 497.2
at 1.98 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O. ##STR389##
Synthesis of methyl
(3-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)methyl(methyl-
)phosphinate (Example BE)
[0842] To a solution of 67 (223.6, 0.45 mmol) in methanol (10 mL)
was slowly added sodium methoxide (487.7 mg, 5.25 mmol). The
mixture was heated to 70.degree. C. for 7 hours at which time Dowex
resin was added to quench any remaining methoxide. The resin was
filtered off and the solvent evaporated. The product was stirred in
6N HCl over night (16 hr) after which time the solution was heated
to reflux for 2 hr. The pH was adjusted to 4, 90.6 mg (50%) of BE
was collected by filtration as a white solid. .sup.1H NMR (300 MHz,
DMSO) .delta. 0.86 (t, 3H), 1.15 (d, 3H), 1.25 (m, 2H), 1.43 (m,
2H), 2.96 (d, 2H), 3.19 (s, 2H), 4.78 (s, 2H), 7.19 (m, 4H). LCMS:
m/z for C.sub.18H.sub.25N.sub.6O.sub.3P.sup.++H observed 405.3 at
1.65 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O.
Example BF
[0843] ##STR390##
[0844] Example BF was prepared using procedures similar to those
shown in Schemes 39 and 40 except that n-butylamine was replaced
with sodium n-butoxide.
[0845] .sup.1H NMR (300 MHz, DMSO) .delta. 0.88 (t, 3H), 1.32 (m,
2H), 1.47 (m, 2H), 2.87 (d, 2H), 3.27 (t, 2H), 4.80 (s, 2H), 7.13
(m, 4H). LCMS: m/z for C.sub.17H.sub.23N.sub.6O.sub.4P.sup.++H
observed 407.2 at 1.57 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O
Example BG
[0846] ##STR391## ##STR392##
Synthesis of ethyl
(3-((6-amino-2-butoxy-9H-purin-9-yl)methyl)phenyl)methyl(methyl)phosphina-
te (68)
[0847] A mixture of 59 (300.0 mg, 1.45 mmol) and K.sub.2CO.sub.3
(200.0 mg, 1.45 mmol) was dissolved in DMF (5 mL) and to it was
added 65 (421.0 mg, 1.45 mmol). The mixture was left to stir over
night at room temperature, solvent was evaporated by rotary
evaporation. The remaining solid was taken up in water and the
product extracted with DCM (3.times.50 mL). Combined organic layers
were washed with water (1.times.50 mL) and brine (2.times.50 mL)
and dried over Na.sub.2SO.sub.4. Product was purified by flash
column eluting 0-10% methanol in ethyl acetate to give 204.0 mg
(34%) 68 as a solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
0.923 (t, 3H), 1.19 (t, 3H), 1.31 (d, 3H), 1.44 (m, 2H), 1.73 (m,
2H), 3.07 (dd, 2H), 3.94 (m, 2H), 4.28 (t, 2H), 5.24 (s, 2H), 7.17
(m, 4H), 7.59 (s, 1H). LCMS: m/z for
C.sub.20H.sub.28NO.sub.3P.sup.++H observed 418.2 at 2.03 minutes of
a 3.5 minute run, gradient 5-95% CH.sub.3CN in H.sub.2O.
##STR393##
Synthesis of ethyl
(3-((6-amino-8-bromo-2-butoxy-9H-purin-9-yl)methyl)phenyl)methyl(methyl)p-
hosphinate (69)
[0848] To a solution of 68 (204.0 mg, 0.488 mmol) in CHCl.sub.3 (5
mL) was added a 10% (v) solution of Br.sub.2 in chloroform. The
reaction was stopped when starting material was consumed, monitored
by HPLC. Bromine was quenched with a saturated Na.sub.2SO.sub.3
solution and product extracted with DCM (2.times.10 mL). Organics
were washed with water (2.times.10 mL) and brine (1.times.10 mL)
and dried over Na.sub.2SO.sub.4. Purified by flash column eluting
10% methanol in ethyl acetate. Evaporation of solvent gave 130.4 mg
(54%) of 69 as a yellow solid. LCMS: m/z for
C.sub.20H.sub.27BrN.sub.5O.sub.3P.sup.++H observed 496.2 and 498.1
at 2.18 minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O. ##STR394##
Synthesis of methyl
(3-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)methyl(methyl-
)phosphinate (70)
[0849] To a solution of 69 (130.4, 0.26 mmol) in methanol (10 mL)
was slowly added sodium methoxide (283.8 mg, 5.25 mmol). The
mixture was heated to 70.degree. C. for 3 hours at which time Dowex
resin was added to quench any remaining methoxide. The resin was
filtered off and the solvent evaporated. The product was stirred in
6N HCl over night (16 hr) after which time the solvent was
evaporated to give 70 as a white solid, the crude product was
carried through to the next step. LCMS: m/z for
C.sub.20H.sub.28N.sub.5O.sub.4P.sup.++H observed 420.2 at 1.92
minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in H.sub.2O.
##STR395##
Synthesis of
(3-((6-amino-2-butoxy-8-hydroxy-9H-purin-9-yl)methyl)phenyl)methyl(methyl-
)phosphinic acid (Example BF)
[0850] TMS-Br was added to a solution of 70 in CH.sub.3CN was
cooled to 0.degree. C. The mixture was stirred at 0.degree. C. for
30 minutes, then heated to 70.degree. C. for 2.5 hours. The solvent
and TMS-Br were removed by rotary evaporation, and the resulting
product was purified by prep. HPLC giving 13.2 mg (13%) of BF as a
white solid. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 0.973 (t,
3H), 1.35 (d, 3H), 1.49 (m, 2H), 1.79 (m, 2H), 3.14 (d, 2H), 4.53
(t, 2H), 5.04 (s, 2H), 7.26 (m, 4H). LCMS: m/z for
C.sub.18H.sub.24N.sub.5O.sub.4P.sup.++H observed 406.1 at 1.76
minutes of a 3.5 minute run, eluting 5-95% CH.sub.3CN in
H.sub.2O.
Example BG
[0851] ##STR396## ##STR397##
Synthesis of N.sup.2-benzyl-9H-purine-2,6-diamine (71)
[0852] 2-chloroadenine (1) (2.81 g, 16.67 mmol) was divided among
three microwave vials (10-20 mL), each containing Benzylamine (6
mL), 1-Butanol (8 mL,), and DMSO (1 mL). Each vial was heated to
170.degree. C. for 90 minutes. After reaction completion the
solvent was removed by rotary evaporation and triteration with
diethylether gave 5.85 g of 71 as an off white solid pure enough
for the next step. LCMS: m/z for C.sub.12H.sub.12N.sub.6.sup.++H
observed 241.2 at 1.45 minutes of a 3.5 minute run, gradient 5-95%
CH.sub.3CN in H.sub.2O.
[0853] Example BG was prepared from 71 using procedures similar to
those used to prepare Example BD.
[0854] .sup.1H NMR (300 MHz, DMSO) .delta. 2.85 (d, 2H), 4.39 (s,
2H), 4.75 (s, 2H), 6.44 (s, 2H), 7.13 (m, 9H), 10.2 (s, 1H). LCMS:
m/z for C.sub.20H.sub.21N.sub.6O.sub.4P.sup.++H observed 441.2 at
1.61 minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O.
Example BH
[0855] ##STR398##
[0856] Example BH was prepared using procedures similar to those
used to prepare BG except that 71 was replaced with 59.
[0857] .sup.1H NMR (300 MHz, DMSO) .delta. 1.15 (d, 3H), 2.94 (d,
2H), 4.41 (s, 2H), 4.76 (s, 2H), 7.03 (m, 9H), 9.72 (s, 1H). LCMS:
m/z for C.sub.21H.sub.23N.sub.6O.sub.3P.sup.++H observed 439.2 at
1.67 minutes of a 3.5 minute run, gradient 5-95% CH.sub.3CN in
H.sub.2O.
TLR7 Reporter Assay protocol
A. HEK293 Assay
1. Cell Culture:
[0858] HEK293 cells stably transfected with the human TLR7 gene and
a pNiFty.TM. NF-.kappa.B inducible luciferase reporter plasmid were
obtained from Invivogen (San Diego, Calif.). DMEM/F12 medium, fetal
bovine serum (FBS), Penicillin-Streptomycin (Pen-Strep),
Blasticidin and Zeocine were from Invitrogen (Carlsbad, Calif.).
The HEK293/TLR7/Luciferase cell line was constructed by
transfecting stably the HEK293/TLR7 cells with the pNiFty plasmid.
Cells were grown in the DMEM/F12 medium with 10% heat-inactivated
FBS, supplemented with 1.times. Pen-Strep, 10 .mu.g/mL Blasticidin
and 5 .mu.g/mL Zeocin.
2. Assay Procedure:
[0859] For the determination of the EC50 and Emax values of TLR7
agonists in the reporter assay, 20 .mu.L of 2.times. test
concentration of serial diluted compound in cell culture medium was
added to each well of a white, clear-bottomed 384-well cell culture
plate from Corning (Corning, N.Y.). To this plate, 20 .mu.L of cell
culture medium containing 12,000 HEK293/TLR7/Luciferase cells was
dispensed to each well. The plate was then placed in incubator
(37.degree. C. and 5% CO.sub.2) and incubated for 2 days. After the
incubation, 40 .mu.L of the pre-mixed lysis buffer/luciferase
substrate solution was dispensed into each well. The lysis buffer
(5.times.) and luciferase substrate was obtained from Promega
(Madison, Wis.) and they were mixed at 2:3 (v/v) ratio immediately
prior to use. After 10 minutes of incubation at room temperature,
the luminescence signal was measured using a VictorLight plate
reader (Perkin Elmer, Wellesley, Mass.) with an integration time of
0.1 seconds per sample.
[0860] Data analysis was performed with Prism software from
GraphPad (San Diego, Calif.) using a single site binding algorithm.
The maximum signal for each test compound (E.sub.max) was
normalized with the maximum signal for the positive control,
Resiquimod, on each plate. The concentration of a compound that
corresponds to 50% of the maximum signal is defined as the
EC.sub.50.
[0861] The compounds of the present invention have HCV EC50 values
(.mu.M) in the range of about 0.01 to about 1000, or about 0.1 to
about 500, or about 0.1 to about 300, or about 0.1 to about 200, or
about 0.1 to about 100, or about 0.1 to about 50, or less than
about 500, or less than about 400, or less than about 300, or less
than about 200, or less than about 100, or less than about 50, or
less than about 20, or less than about 10.
B. PBMC Assay
[0862] Assays were conducted to determine cytokine stimulation at
24 hours from human Peripheral Blood Mononuclear Cell (PMBC) using
the compounds of the present invention. The assays were run in
duplicate, with 8-point, half-log dilution curves. The compounds of
the present invention were diluted from 10 .mu.M DMSO solution.
Cell supernatants are assayed directly for IFN.alpha. and 1:10
dilution for TNF.alpha.. The assays were performed in a similar
fashion as described in Bioorg. Med. Chem. Lett. 16, 4559, (2006).
Specifically, cryo-preserved PBMCs were thawed and seeded 96 well
plates with 750,000 cells/well in 190 .mu.L/well cell media. The
PBMCs were then incubated for 1 hour at 37.degree. C. at 5%
CO.sub.2. Then, the compounds of the present invention were added
in 10 .mu.L cell media at 8 point, half-log dilution titration. The
plates were incubated at 37.degree. C. and 5% CO.sub.2 for 24 hours
and then spinned at 1200 rpm for 10 min, which was followed by
collecting supernatant and storing the same at -80.degree. C.
Cytokine secretion was assayed with Luminex and Upstate multi-plex
kits, using a Luminex analysis instrument.
[0863] The compounds of the present invention have IFN ECmax values
(.mu.M) in the range of about 0.01 to about 1000, or about 0.1 to
about 500, or about 0.1 to about 300, or about 0.1 to about 200, or
about 0.1 to about 100, or about 0.1 to about 50, or less than
about 500, or less than about 400, or less than about 300, or less
than about 200, or less than about 100, or less than about 50, or
less than about 20, or less than about 10.
* * * * *