U.S. patent application number 09/740267 was filed with the patent office on 2002-08-01 for novel heterocycles.
Invention is credited to Bohacek, Regine, Dalgarno, David C., Kawahata, Noriyuki H., Luke, George P., Metcalf, Chester A. III, Sawyer, Tomi K., Shakespeare, William C., Sundaramoorthi, Rajeswari, Vu, Chi B., Wang, Yihan, Weigele, Manfred.
Application Number | 20020103161 09/740267 |
Document ID | / |
Family ID | 27390089 |
Filed Date | 2002-08-01 |
United States Patent
Application |
20020103161 |
Kind Code |
A1 |
Weigele, Manfred ; et
al. |
August 1, 2002 |
Novel heterocycles
Abstract
The present invention relates to bone-targeting compounds useful
for treating a variety of disorders and conditions, e.g., of bone
tissue.
Inventors: |
Weigele, Manfred;
(Cambridge, MA) ; Luke, George P.; (Clinton,
CT) ; Sawyer, Tomi K.; (Southborough, MA) ;
Bohacek, Regine; (Boston, MA) ; Shakespeare, William
C.; (Framingham, MA) ; Sundaramoorthi, Rajeswari;
(Watertown, MA) ; Wang, Yihan; (Newton, MA)
; Dalgarno, David C.; (Brookline, MA) ; Metcalf,
Chester A. III; (Boston, MA) ; Vu, Chi B.;
(Arlington, MA) ; Kawahata, Noriyuki H.; (Medford,
MA) |
Correspondence
Address: |
Karoline K.M. Shair, Ph.D.
Choate, Hall & Stewart
53 State Street
Exchange Place
Boston
MA
02109
US
|
Family ID: |
27390089 |
Appl. No.: |
09/740267 |
Filed: |
December 18, 2000 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60172510 |
Dec 17, 1999 |
|
|
|
60172161 |
Dec 17, 1999 |
|
|
|
60240788 |
Oct 16, 2000 |
|
|
|
Current U.S.
Class: |
514/79 ;
544/232 |
Current CPC
Class: |
C07F 9/6561 20130101;
C07F 9/65583 20130101; A61K 47/548 20170801; C07D 487/04 20130101;
C07F 9/4012 20130101; C07F 9/65616 20130101; A61K 47/54 20170801;
C07F 9/58 20130101; C07D 471/04 20130101; C07F 9/405 20130101 |
Class at
Publication: |
514/79 ;
544/232 |
International
Class: |
A61K 031/675 |
Claims
We claim:
1. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb (I)
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; Tb represents a bone-targeting group selected from:
139 and R.sub.4, independently for each occurrence, represents H or
lower alkyl, wherein Hc-X--K-Cy-L is free of hydrolyzable
linkages.
2. A compound having the general formula (II): Hc-X--K-Z-Tb,
wherein K is absent or represents -M.sub.n-Y-M.sub.p-; X, Y, and Z,
independently, are absent or represent NR, O, or S; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethylene or ethyne; p and n, independently, represent
integers from 0-10. R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl. Hc represents a
heterocycle; Tb represents a bone-targeting group selected from:
140 and R.sub.4, independently for each occurrence, represents H or
lower alkyl, wherein Hc-X--K is free of hydrolyzable linkages.
3. The compound of claim 1 or 2, wherein the compound selectively
targets osteoclasts.
4. The compound of claim 1 or 2, wherein R.sub.4 represents H for
all occurrences.
5. The compound of claim 1, wherein Cy represents an uncharged
carbocycle or nitrogen-bearing heterocycle.
6. The compound of claim 1, wherein Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system
having between 8 and 11 atoms.
7. The compound of claim 1, wherein Cy represents phenyl.
8. The compound of claim 1, wherein Cy represents a bicyclic ring
system, whereof L is attached to a first ring and K is attached to
a second ring.
9. The compound of claim 1 or 2, wherein Hc represents a bicyclic
structure.
10. The compound of claim 9, wherein the two rings of the bicyclic
structure consist of carbon and nitrogen atoms.
11. The compound of claim 1 or 2, wherein K is directly attached to
a heteroatom of Hc.
12. The compound of claim 1 or 2, wherein Hc is selected from:
141wherein one of R.sub.1, R.sub.2, and R.sub.3 represents a bond
to K, the others represent, independently, hydrogen, halogen,
alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl,
cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, or alkanoyl,
or taken together with the nitrogen to which it is attached,
represent amidine, amide, carbamate, urea, or guanidine; and W
represents O or S.
13. The compound of claim 1, wherein Tb is represented by i and Z
is absent.
14. The compound of claim 13, wherein L is absent.
15. The compound of claim 1 or 2, wherein Tb is selected from xi,
xii, xiv, and xv.
16. The compound of claim 1 or 2, wherein Tb is selected from v,
vii, and viii.
17. The compound of claim 1 or 2, wherein Tb is selected from ii,
iii, or iv.
18. The compound of claim 1 or 2, wherein Tb is represented by
x.
19. The compound of claim 1 or 2, wherein Tb is represented by
ix.
20. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound having the general formula (I):
Hc-X--K-Cy-L-Z-Tb, wherein L and K, independently, are absent or
represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; Tb represents a bone-targeting group selected from:
142 and R.sub.4, independently for each occurrence, represents H or
lower alkyl, wherein Hc-X--K is free of hydrolyzable linkages.
21. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound having the general formula (II):
Hc-X--K-Z-Tb, wherein K is absent or represents
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethylene or
ethyne; p and n, independently, represent integers from 0-10. R
represents, independently for each occurrence, H or substituted or
unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or
alkyl. Hc represents a heterocycle; Tb represents a bone-targeting
group selected from: 143 and R.sub.4, independently for each
occurrence, represents H or lower alkyl, wherein Hc-X--K-Cy-L is
free of hydrolyzable linkages.
22. The pharmaceutical composition of claim 20 or 21, wherein the
compound selectively targets osteoclasts.
23. The pharmaceutical composition of claim 20 or 21, wherein
R.sub.4 represents H for all occurrences.
24. The pharmaceutical composition of claim 20, wherein Cy
represents an uncharged carbocycle or nitrogen-bearing
heterocycle.
25. The pharmaceutical composition of claim 20, wherein Cy
represents a phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused
bicyclic ring system having between 8 and 11 atoms.
26. The pharmaceutical composition of claim 20, wherein Cy
represents phenyl.
27. The pharmaceutical composition of claim 20, wherein Cy
represents a bicyclic ring system, whereof L is attached to a first
ring and K is attached to a second ring.
28. The pharmaceutical composition of claim 20 or 21, wherein Hc
represents a bicyclic structure.
29. The pharmaceutical composition of claim 20 or 21, wherein the
two rings of the bicyclic structure consist of carbon and nitrogen
atoms.
30. The pharmaceutical composition of claim 20 or 21, wherein K is
directly attached to a heteroatom of Hc.
31. The pharmaceutical composition of claim 20 or 21, wherein Hc is
selected from: 144wherein one of R.sub.1, R.sub.2, and R.sub.3
represents a bond to K, the others represent, independently,
hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl,
heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl,
or alkanoyl, or taken together with the nitrogen to which it is
attached, represent amidine, amide, carbamate, urea, or guanidine;
and W represents O or S.
32. The compound of claim 20, wherein Tb is represented by i and Z
is absent.
33. The compound of claim 32, wherein L is absent.
34. The pharmaceutical composition of claim 20 or 21, wherein Tb is
selected from xi, xii, xiv, and xv.
35. The pharmaceutical composition of claim 20 or 21, wherein Tb is
selected from v, vii, and viii.
36. The pharmaceutical composition of claim 20 or 21, wherein Tb is
selected from ii, iii, or iv.
37. The pharmaceutical composition of claim 20 or 21, wherein Tb is
represented by x.
38. The pharmaceutical composition of claim 20 or 21, wherein Tb is
represented by ix.
39. A method for the treatment or prevention of a bone disorder
comprising treating a patient with a compound having the general
formula (I): Hc-X--K-Cy-L-Z-Tb, wherein L and K, independently, are
absent or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z,
independently, are absent or represent NR, O, or S; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene or ethyne; R represents, independently for
each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; Cy represents a
substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or
cycloalkyl; Hc represents a heterocycle; Tb represents a
bone-targeting group selected from: 145 and R.sub.4, independently
for each occurrence, represents H or lower alkyl.
40. A method for the treatment or prevention of a bone disorder
comprising treating a patient with a compound having the general
formula (II): Hc-X--K-Z-Tb, wherein K is absent or represents
-M.sub.n-Y-M.sub.p; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethylene or
ethyne; p and n, independently, represent integers from 0-10. R
represents, independently for each occurrence, H or substituted or
unsubstituted aryl, heterocyclyl, heteroaryl, aralkyl, alkenyl, or
alkyl. Hc represents a heterocycle; Tb represents a bone-targeting
group selected from: and R.sub.4, independently for each
occurrence, represents H or lower alkyl.
41. The method of claim 39 or 40, wherein the compound selectively
targets osteoclasts.
42. The method of claim 39 or 40, wherein R.sub.4 represents H for
all occurrences.
43. The method of claim 39, wherein Cy represents an uncharged
carbocycle or nitrogen-bearing heterocycle.
44. The method of claim 39, wherein Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system
having between 8 and 11 atoms.
45. The method of claim 39, wherein Cy represents phenyl.
46. The method of claim 39, wherein Cy represents a bicyclic ring
system, whereof L is attached to a first ring and K is attached to
a second ring.
47. The method of claim 39 or 40, wherein Hc represents a bicyclic
structure.
48. The method of claim 39 or 40, wherein the two rings of the
bicyclic structure consist of carbon and nitrogen atoms.
49. The method of claim 39 or 40, wherein K is directly attached to
a heteroatom of Hc.
50. The method of claim 39 or 40, wherein Hc is selected from:
146wherein one of R.sub.1, R.sub.2, and R.sub.3 represents a bond
to K, the others represent, independently, hydrogen, halogen,
alkyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl,
cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl, or alkanoyl,
or taken together with the nitrogen to which it is attached,
represent amidine, amide, carbamate, urea, or guanidine; and W
represents O or S.
51. The method of claim 39, wherein Tb is represented by i and Z is
absent.
52. The method of claim 51, wherein L is absent.
53. The method of claim 39 or 40, wherein Tb is selected from xi,
xii, xiv, and xv.
54. The method of claim 39 or 40, wherein Tb is selected from v,
vii, and viii.
55. The method of claim 39 or 40, wherein Tb is selected from ii,
iii, or iv.
56. The method of claim 39 or 40, wherein Tb is represented by
x.
57. The method of claim 39 or 40, wherein Tb is represented by
ix.
58. A compound having the structure: Tb-L-V, wherein L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; Tb represents a bone-targeting group
selected from: 147R.sub.4, independently for each occurrence,
represents H or lower alkyl, and V represents OR, NR.sub.2, or
SR.
59. The compound of claim 58, wherein Tb is selected from xi, xii,
xiv, and xv.
60. The compound of claim 58, wherein Tb is x.
61. The compound of claim 58, wherein Tb is xiii.
62. The compound of claim 58, wherein V represents NR.sub.2.
63. A compound having the structure: Tb-Cy-L-V, wherein L is absent
or represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; Cy represents a substituted or
unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Tb
represents a bone-targeting group selected from: 148R.sub.4,
independently for each occurrence, represents H or lower alkyl, and
V represents OR, NR.sub.2, or SR.
64. The compound of claim 63, wherein Cy represents a phenyl
ring.
65. The compound of claim 63, wherein V represents NR.sub.2.
66. A compound having the structure: Tb-L-U, wherein L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; Tb represents a bone-targeting group
selected from: 149R.sub.4, independently for each occurrence,
represents H or lower alkyl, and U represents a sulfonate ester,
halogen, formyl, or a suitable leaving group.
67. The compound of claim 66, wherein Tb is selected from xi, xii,
xiv, and xv.
68. The compound of claim 66, wherein Tb is x.
69. The compound of claim 66, wherein Tb is xiii.
70. A compound having the structure: Tb-Cy-L-U, wherein L is absent
or represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; Cy represents a substituted or
unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl; Tb
represents a bone-targeting group selected from: 150R.sub.4,
independently for each occurrence, represents H or lower alkyl, and
U represents a sulfonate ester, halogen, formyl, or a suitable
leaving group.
71. A compound of claim 70, wherein Cy represents a phenyl
ring.
72. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb,
or (II): Hc-X--K-Z-Tb, wherein L and K, independently, are absent
or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents one of: 151
73. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb,
or (II): Hc-X--K-Z-Tb, wherein L and K, independently, are absent
or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents a group selected from: 152x
represents 1, 2, 3, 4, 5, or 6; each occurrence of Y is
independently a covalent bond, --O--, --S--, or --N(R.sub.J).sub.2,
wherein R.sub.J, for each occurrence, is independently hydrogen,
aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or
alkylheteroaryl; R.sub.6 represents from 0-3 substituents selected
from halogen, lower alkyl, lower alkenyl, aryl, heteroaryl,
carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido,
amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate,
sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate,
phosphinate, --(CH.sub.2).sub.palkyl, --(CH.sub.2).sub.palkenyl,
--(CH.sub.2).sub.palkynyl, --(CH.sub.2).sub.paryl,
--(CH.sub.2).sub.paralkyl, --(CH.sub.2).sub.pOH,
--(CH.sub.2).sub.pO-lowe- r alkyl, --(CH.sub.2).sub.pO-lower
alkenyl, --O(CH.sub.2).sub.nR, --(CH.sub.2).sub.pSH,
--(CH.sub.2).sub.pS-lower alkyl, --(CH.sub.2).sub.pS-lower alkenyl,
--S(CH.sub.2).sub.nR, --(CH.sub.2).sub.pN(R).sub.2,
--(CH.sub.2).sub.pNR-lower alkyl, --(CH.sub.2).sub.pNR-lower
alkenyl, --NR(CH.sub.2).sub.nR, or protected forms of the above and
wherein p is 1-10; and each occurrence of R.sub.4 is independently
hydrogen or a lower alkyl.
74. The compound of claim 73, wherein M, where it occurs in Tb, is
selected from CH.sub.2, CHJ, CHOH, and CJ.sub.2, wherein J
represents a halogen.
75. The compound of claim 73, wherein R.sub.6 is selected from
lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl,
sulfonate, phosphonate, and salts thereof, and lower alkyl
substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl,
sulfonate, phosphonate, and salts thereof.
76. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb,
or (aI): Hc-X--K-Z-Tb, wherein L and K, independently, are absent
or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents a group having the structure:
153A represents a group selected from GPO.sub.3(R.sub.4).sub.- 2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B represents a group
selected from NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; and G is absent or
represents a linkage of one or two atoms.
77. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb,
or (II): Hc-X--K-Z-Tb, wherein L and K, independently, are absent
or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb has the structure xxxxiii: 154B represents
a group selected from NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; and G is absent or
represents a linkage of one or two atoms.
78. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb,
or (II): Hc-X--K-Z-Tb, wherein L and K, ind ependently, are absent
or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb has the structure xxxxiv or xxxxv: 155A
represents a group selected from GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B represents a group
selected from NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; G is absent or represents a
linkage of one or two atoms; C represents H, R.sub.6, NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, or GSO.sub.3R.sub.4,
such that in xxxxiv, any one occurrence of A or B is present, and
the other occurrences may represent a bond to Z, H, or R.sub.6 as
desired.
79. A compound having the general formula (I): Hc-X--K-Cy-L-Z-Tb,
or (II): Hc-X--K-Z-Tb, wherein L and K, independently, are absent
or represent -M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are
absent or represent NR, O, or S; M represents, independently for
each occurrence, a substituted or unsubstituted methylene group, or
two M taken together represent substituted or unsubstituted ethene
or ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents a heteroaryl bearing one or two
B substituents, and 0-4 R.sub.6 substituents; A represents a group
selected from GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and
GSO.sub.3R.sub.4; B represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
80. The compound of any of claims 72-79, wherein Hc is selected
from: 156
81. The compound of any of claims 72-79, wherein, except in Tb, the
compound is free of hydrolyzable linkages.
82. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or
U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or
a suitable leaving group; V represents OR, NR.sub.2, or SR; L is
absent or represents -M.sub.n-Y-M.sub.p-; Y is absent; M
represents, independently for each occurrence, a substituted or
unsubstituted methylene group, or two M taken together represent
substituted or unsubstituted ethene; R represents, independently
for each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; R.sub.4, independently
for each occurrence, represents H or lower alkyl; and Tb represents
one of: 157
83. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or
U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or
a suitable leaving group; V represents OR, NR.sub.2, or SR; L is
absent or represents -M.sub.n-Y-M.sub.p-; Y is absent; M
represents, independently for each occurrence, a substituted or
unsubstituted methylene group, or two M taken together represent
substituted or unsubstituted ethene; R represents, independently
for each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; R.sub.4, independently
for each occurrence, represents H or lower alkyl; and Tb represents
a group selected from: 158x represents 1 or 2, and R.sub.6
represents from 0-3 substituents selected from halogen, lower
alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl,
ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro,
azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl,
sulfonamido, phosphoryl, phosphonate, phosphinate,
--(CH.sub.2).sub.palkyl, --(CH.sub.2).sub.palkenyl,
--(CH.sub.2).sub.palkynyl, --(CH.sub.2).sub.paryl,
--(CH.sub.2).sub.paralkyl, --(CH.sub.2).sub.pOH,
--(CH.sub.2).sub.pO-lower alkyl, --(CH.sub.2)pO-lower alkenyl,
--O(CH.sub.2).sub.nR, --(CH.sub.2).sub.pSH,
--(CH.sub.2).sub.pS-lower alkyl, --(CH.sub.2).sub.pS-lower alkenyl,
--S(CH.sub.2).sub.nR, --(CH.sub.2).sub.pN(R).sub.2,
--(CH.sub.2).sub.pNR-lower alkyl, --(CH.sub.2).sub.pNR-lower
alkenyl, --NR(CH.sub.2).sub.nR, or protected forms of the
above.
84. The compound of claim 83, wherein M, where it occurs in Tb, is
selected from CH.sub.2, CHJ, CHOH, and CJ.sub.2, wherein J
represents a halogen.
85. The compound of claim 83, wherein R.sub.6 is selected from
lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl,
sulfonate, phosphonate, and salts thereof, and lower alkyl
substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl,
sulfonate, phosphonate, and salts thereof.
86. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or
U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or
a suitable leaving group; V represents OR, NR.sub.2, or SR; L is
absent or represents -M.sub.n-Y-M.sub.p-; Y is absent; M
represents, independently for each occurrence, a substituted or
unsubstituted methylene group, or two M taken together represent
substituted or unsubstituted ethene; R represents, independently
for each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; R.sub.4, independently
for each occurrence, represents H or lower alkyl; and Tb represents
a group having the structure: 159A represents a group selected from
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B
represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
87. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or
U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or
a suitable leaving group; V represents OR, NR.sub.2, or SR; L is
absent or represents -M.sub.n-Y-M.sub.p-; Y is absent; M
represents, independently for each occurrence, a substituted or
unsubstituted methylene group, or two M taken together represent
substituted or unsubstituted ethene; R represents, independently
for each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; R.sub.4, independently
for each occurrence, represents H or lower alkyl; and Tb has the
structure xxxxiii: 160B represents a group selected from NH.sub.2,
OH, GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and
GSO.sub.3R.sub.4; and G is absent or represents a linkage of one or
two atoms.
88. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or
U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or
a suitable leaving group; V represents OR, NR.sub.2, or SR; L is
absent or represents -M.sub.n-Y-M.sub.p-; Y is absent; M
represents, independently for each occurrence, a substituted or
unsubstituted methylene group, or two M taken together represent
substituted or unsubstituted ethene; R represents, independently
for each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; R.sub.4, independently
for each occurrence, represents H or lower alkyl; and Tb has the
structure xxxxiv or xxxxv: 161A represents a group selected from
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B
represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; G
is absent or represents a linkage of one or two atoms; C represents
H, R.sub.6, NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, or GSO.sub.3R.sub.4, such that in xxxxiv, any one
occurrence of A or B is present, and the other occurrences may
represent a bond to Z, H, or R.sub.6 as desired.
89. A compound having the formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or
U-L-Tb, wherein U represents a sulfonate ester, halogen, formyl, or
a suitable leaving group; V represents OR, NR.sub.2, or SR; L is
absent or represents -M.sub.n-Y-M.sub.p-; Y is absent; M
represents, independently for each occurrence, a substituted or
unsubstituted methylene group, or two M taken together represent
substituted or unsubstituted ethene; R represents, independently
for each occurrence, H or substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, aralkyl, alkenyl, or alkyl; p and n,
independently, represent integers from 0-10; R.sub.4, independently
for each occurrence, represents H or lower alkyl; and Tb represents
a heteroaryl bearing one or two B substituents, and 0-4 R.sub.6
substituents; A represents a group selected from
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B
represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
90. The compound of any of claims 82-89, wherein Hc is selected
from: 162
91. The compound of any of claims 82-89, wherein L represents
alkyl.
92. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
general formula (I): Hc-X--K-Cy-L-Z-Tb, or (II): Hc-X--K-Z-Tb,
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents one of: 163
93. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
general formula (I): Hc-X--K-Cy-L-Z-Tb, or (II): Hc-X--K-Z-Tb,
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents a group selected from: 164x
represents 1 or 2, and R.sub.6 represents from 0-3 substituents
selected from halogen, lower alkyl, lower alkenyl, aryl,
heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino,
acylamino, amido, amidino, cyano, nitro, azido, sulfonyl,
sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl,
phosphonate, phosphinate, --(CH.sub.2).sub.palkyl,
--(CH.sub.2).sub.palkenyl, --(CH.sub.2).sub.palkynyl,
--(CH.sub.2).sub.paryl, --(CH.sub.2).sub.paralkyl,
--(CH.sub.2).sub.pOH, --(CH.sub.2).sub.pO-lower alkyl,
--(CH.sub.2).sub.pO-lower alkenyl, --O(CH.sub.2).sub.nR,
--(CH.sub.2).sub.pSH, --(CH.sub.2).sub.pS-lower alkyl,
--(CH.sub.2).sub.pS-lower alkenyl, --S(CH.sub.2).sub.nR,
--(CH.sub.2).sub.pN(R).sub.2, --(CH.sub.2).sub.pNR-lower alkyl,
--(CH.sub.2).sub.pNR-lower alkenyl, --NR(CH.sub.2).sub.nR, or
protected forms of the above.
94. The compound of claim 92, wherein M, where it occurs in Tb, is
selected from CH.sub.2, CHJ, CHOH, and CJ.sub.2, wherein J
represents a halogen.
95. The compound of claim 92, wherein R.sub.6 is selected from
lower alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl,
sulfonate, phosphonate, and salts thereof, and lower alkyl
substituted with hydroxyl, sulfhydryl, amino, amido, carboxyl,
sulfonate, phosphonate, and salts thereof.
96. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
general formula (I): Hc-X--K-Cy-L-Z-Tb, or (II): Hc-X--K-Z-Tb,
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents a group having the structure:
165A represents a group selected from GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B represents a group
selected from NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; and G is absent or
represents a linkage of one or two atoms.
97. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
general formula (I): Hc-X--K-Cy-L-Z-Tb, or (II): Hc-X--K-Z-Tb,
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb has the structure xxxxiii: 166B represents
a group selected from NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; and G is absent or
represents a linkage of one or two atoms.
98. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
general formula (I): Hc-X--K-Cy-L-Z-Tb, or (II): Hc-X--K-Z-Tb,
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb has the structure xxxxiv or xxxxv: 167A
represents a group selected from GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B represents a group
selected from NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; G is absent or represents a
linkage of one or two atoms; C represents H, R.sub.6, NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, or GSO.sub.3R.sub.4,
such that in xxxxiv, any one occurrence of A or B is present, and
the other occurrences may represent a bond to Z, H, or R.sub.6 as
desired.
99. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
general formula (I): Hc-X--K-Cy-L-Z-Tb, or (II): Hc-X--K-Z-Tb,
wherein L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-; X, Y, and Z, independently, are absent or
represent NR, O, or S; M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, or two
M taken together represent substituted or unsubstituted ethene or
ethyne; R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl, or alkyl; p and n, independently, represent
integers from 0-10; Cy represents a substituted or unsubstituted
aryl, heterocyclyl, heteroaryl, or cycloalkyl; Hc represents a
heterocycle; R.sub.4, independently for each occurrence, represents
H or lower alkyl; and Tb represents a heteroaryl bearing one or two
B substituents, and 0-4 R.sub.6 substituents; A represents a group
selected from GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and
GSO.sub.3R.sub.4; B represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
100. The method of any of claims 92-99, wherein Hc is selected
from: 168
101. The method of any of claims 92-99, wherein, except in Tb, the
compound is free of hydrolyzable linkages.
102. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U
represents a sulfonate ester, halogen, formyl, or a suitable
leaving group; V represents OR, NR.sub.2, or SR; L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; R.sub.4, independently for each
occurrence, represents H or lower alkyl; and Tb represents one of:
169
103. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U
represents a sulfonate ester, halogen, formyl, or a suitable
leaving group; V represents OR, NR.sub.2, or SR; L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; R.sub.4, independently for each
occurrence, represents H or lower alkyl; and Tb represents a group
selected from: 170x represents 1, 2, 3, 4, 5, or 6; each occurrence
of Y is independently a covalent bond, --O--, --S--, or
--N(R.sub.J).sub.2, wherein R.sub.J, for each occurrence, is
independently hydrogen, aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl, or alkylheteroaryl; R.sub.6 represents from
0-3 substituents selected from halogen, lower alkyl, lower alkenyl,
aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino,
acylamino, amido, amidino, cyano, nitro, azido, sulfonyl,
sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl,
phosphonate, phosphinate, --(CH.sub.2).sub.palkyl,
--(CH.sub.2).sub.palkenyl, --(CH.sub.2).sub.palkynyl,
--(CH.sub.2).sub.paryl, --(CH.sub.2).sub.paralkyl,
--(CH.sub.2).sub.pOH, --(CH.sub.2).sub.pO-lowe- r alkyl,
--(CH.sub.2).sub.pO-lower alkenyl, --O(CH.sub.2).sub.nR,
--(CH.sub.2).sub.pSH, --(CH.sub.2).sub.pS-lower alkyl,
--(CH.sub.2).sub.pS-lower alkenyl, --S(CH.sub.2).sub.nR,
--(CH.sub.2).sub.pN(R).sub.2, --(CH.sub.2).sub.pNR-lower alkyl,
--(CH.sub.2).sub.pNR-lower alkenyl, --NR(CH.sub.2).sub.nR, or
protected forms of the above; and each occurrence of R.sub.4 is
independently hydrogen or a lower alkyl.
104. The method of claim 103, wherein M, where it occurs in Tb, is
selected from CH.sub.2, CHJ, CHOH, and CJ.sub.2, wherein J
represents a halogen.
105. The method of claim 103, wherein R is selected from lower
alkyl, hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate,
phosphonate, and salts thereof, and lower alkyl substituted with
hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate,
phosphonate, and salts thereof.
106. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U
represents a sulfonate ester, halogen, formyl, or a suitable
leaving group; V represents OR, NR.sub.2, or SR; L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; R.sub.4, independently for each
occurrence, represents H or lower alkyl; and Tb represents a group
having the structure: 171A represents a group selected from
GPO.sub.3(R.sub.4).sub.- 2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
B represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
107. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U
represents a sulfonate ester, halogen, formyl, or a suitable
leaving group; V represents OR, NR.sub.2, or SR; L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; R.sub.4, independently for each
occurrence, represents H or lower alkyl; and Tb has the structure
xxxxiii: 172B represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
108. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U
represents a sulfonate ester, halogen, formyl, or a suitable
leaving group; V represents OR, NR.sub.2, or SR; L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; R.sub.4, independently for each
occurrence, represents H or lower alkyl; and Tb has the structure
xxxxiv or xxxxv: 173A represents a group selected from
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B
represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; G
is absent or represents a linkage of one or two atoms; C represents
H, R.sub.6, NH.sub.2, OH, GPO.sub.3(R.sub.4).sub.2,
GCO.sub.2R.sub.4, or GSO.sub.3R.sub.4, such that in xxxxiv, any one
occurrence of A or B is present, and the other occurrences may
represent a bond to Z, H, or R.sub.6 as desired.
109. A method for treating or preventing a bone disorder comprising
a pharmaceutically acceptable excipient and a compound having the
formula: V-L-Cy-Tb, V-L-Tb, U-L-Cy-Tb, or U-L-Tb, wherein U
represents a sulfonate ester, halogen, formyl, or a suitable
leaving group; V represents OR, NR.sub.2, or SR; L is absent or
represents -M.sub.n-Y-M.sub.p-; Y is absent; M represents,
independently for each occurrence, a substituted or unsubstituted
methylene group, or two M taken together represent substituted or
unsubstituted ethene; R represents, independently for each
occurrence, H or substituted or unsubstituted aryl, heterocyclyl,
heteroaryl, aralkyl, alkenyl, or alkyl; p and n, independently,
represent integers from 0-10; R.sub.4, independently for each
occurrence, represents H or lower alkyl; and Tb represents a
heteroaryl bearing one or two B substituents, and 0-4 R.sub.6
substituents; A represents a group selected from
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4; B
represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms.
110. The method of any of claims 102-109, wherein Hc is selected
from: 174
111. The method of any of claims 102-109, wherein L represents
alkyl.
Description
PRIORITY INFORMATION
[0001] The present application claims priority under 35 U.S.C.
.sctn. 119(e) to U.S. Provisional Patent Application No.
60/172,510, filed Dec. 17, 1999, entitled "Bone Targeting Agents",
U.S. Provisional Patent Application No. 60/172,161, filed Dec. 17,
1999, entitled "Proton Pump Inhibitors", and U.S. Provisional
Patent Application No. 60/240,788, filed Oct. 16, 2000 entitled
"Bone Targeting Agents", and the entire contents of each of these
applications are hereby incorporated by reference.
[0002] The application further claims priority to U.S. National
patent application Ser. No. ______, entitled "Proton Pump
Inhibitors", and U.S. National patent application Ser. No. ______,
entitled "Novel Purines", each of which is filed on even date
herewith and is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0003] The need to treat debilitating bone disorders, such as
osteoporosis, has led to extensive research on the mechanism and
regulation of continuous bone formation and resorption. In
particular, an appropriate balance of osteoblasts, which function
to form bone tissue, and osteoclasts, which function to resorb bone
tissue, is required to maintain the structural integrity and proper
functioning of the skeleton in spite of continuous metabolism. Any
changes in this balance of metabolism, such as an increased bone
resorption (either absolute, or an increase via decreased bone
formation relative to bone resorption) can lead bone diseases or
disorders. One of the most common diseases resulting from this
imbalance is osteoporosis, which is characterized by a decrease in
bone mass and deterioration in skeletal micro-architecture leading
to an increased fragility and susceptibility to fractures. Other
diseases which result from alterations in bone resorption include,
but are not limited to, Paget's Disease, primary and secondary
hyperparathyroidism, humoral hypercalcemia of malignancy, various
cancers where resorption is increased, and rheumatoid
arthritis.
[0004] Because of the serious disorders that may result from a
metabolic imbalance, researchers have been interested in studying
bone metabolism, and the mechanism by which bone resorption and
formation occurs, to ultimately develop a strategy for inhibiting
resorption, and/or for improving bone mass and/or bone
micro-architecture by stimulating osteoblast activity. However, the
action of both osteoclasts and osteoblasts is controlled by a
number of complex factors, and thus developing selective
therapeutics has proven to be a difficult task.
[0005] One approach that has been taken for the development of
novel therapeutics for bone disorders is inhibition of the
osteoclast proton pump. Baron and coworkers have previously
demonstrated that this proton pump is a vacuolar H.sup.+-ATPase
(see, Blair et al., Science 1989, 245, 855-857; Finbow et al.,
Biochem. J. 1997, 324, 697-712; Forgac, M. Soc. Gen. Physiol. Ser.
1996, 51, 121-132). It has been shown that osteoclasts, to effect
bone resorption, ultimately lower the pH in the sealed
microcompartment which underlies their site of attachment to the
bone surface (see, Baron et al., J. Cell. Biol. 1985, 101,
2210-2222), thus resulting in the acidic environment required to
dissolve the bone mineral and to allow degradation of the bone
matrix by proteases. The osteoclast uses a proton pump (an
ATP-dependent transport of protons) to achieve this acidification
and thus any therapeutic inhibition of the osteoclast proton pump
should lead to a decrease in bone loss or turnover. As a result,
many novel therapeutics developed to reduce bone resorption have
focused on the inhibition of the proton pump to prevent osteoclast
activity and excessive bone resorption. For a discussion of the
vacuolar H.sup.+-ATPase and inhibitors of vacuolar H.sup.+-ATPase
see Farina et al., Exp. Opin. Ther. Patents 1999, 9, 157-168 and
David, P. and Baron, R. "The Vacuolar H.sup.+-ATPase: A Potential
Target for Drug Development in Bone Diseases" Exp. Opin. Invest.
Drugs 1995, 4, 725-740.
[0006] In addition to the inhibition of the proton pump, studies
have also been directed towards the control of signal transduction
to ultimately affect osteoclast or osteoblast function. For
example, studies have provided evidence that Src protein kinases
play a cruical role in osteoclastic function, and it has been shown
in different cell types that phosphorylation by Src, and related
kinases, of proteins proposed to participate or regulate the
cytoskeletal architecture is one important requirement for their
proper function (see, for example, Missbach et al., "A Novel
Inhibitor of the Tyrosine Kinase Src Suppresses Phosphorylation of
Its Major Cellular Substrates and Reduces Bone Resorption In Vitro
and in Rodent Models In Vivo," Bone 1999, 24, 437-449). Because the
cytoskeleton plays an important role in osteoclast motility,
attachment, and formation of the sealing zone, it is likely that
these cytoskeletal proteins may influence osteoclast function.
Thus, agents which inhibit or promote interactions with Src or
related kinases, are likely to affect cyctoskeletal proteins and
ultimately affect osteoclast function. Several compounds have been
reported as inhibitors of tyrosine Src kinase and thus are useful
in the inhibition of osteoclast-mediated bone resorption (see, for
example, Missbach et al., Bone 1999, 24, 437-449; Connolly et al.,
Bioorg. & Med. Chem. Lett. 1997, 7, 2415-2420; Trump-Kallmeyer
et al., J. Med. Chem. 1998, 41, 1752-1763; Klutchko et al., J. Med.
Chem. 1998, 41, 3276-3292; Legraverend et al., Bioorg. & Med.
Chem. 1999, 7, 1281-1293; Chang et al., Chem. & Biol. 1999, 6,
361-375; Lev et al. Nature 1995, 376, 737-784; Palmer et al., J.
Med. Chem. 1997, 40, 1519-1529.
[0007] As described above, many of the existing therapeutics that
have been developed for the treatment of bone disorders such as
osteoporosis are thought to act by inhibiting osteoclast activity.
For example, estrogens, bisphosphonates, calcitonin, flavonoids,
and selective estrogen receptor modulators are believed to act by
the inhibition of osteoclast activity. Additionally, more recently,
novel therapeutics have been developed to promote a fast increase
in bone mineral content by promoting osteoblast activity. Such
examples include peptides from the parathyroid hormone family,
strontium ranelate, and growth hormone and insulin-like growth
response (see, for example, Reginster et al. "Promising New Agents
in Osteoporosis," Drugs R & D 1999, 3, 195-201). Unfortunately,
a significant problem of many of these therapetic agents, however,
is that they are not specific enough for bone tissue and thus may
lead to unwanted adverse side effects.
[0008] Clearly, as evidenced by the number of different approaches
to the available therapeutic agents, bone metabolism is controlled
by a variety of factors. A common theme, however, is the desire to
develop selective inhibitors or promoters of osteoclast or
osteoblast activity, respectively. Although progress has been made
towards developing therapeutic agents for osteoporosis and other
bone disorders, there remains a need to develop potent and
selective agents having minimal side effects.
SUMMARY OF THE INVENTION
[0009] In general, the present invention provides compounds
comprising a bone targeting moiety and a payload for the treatment
or prevention of bone disorders and/or other conditions. In other
embodiments, certain novel bone targeting moieties themselves, as
described herein, also act as therapeutic agents for use in the
treatment of bone disorders and/or other conditions. In certain
other embodiments, the present invention provides compounds
comprising a bone targeting moiety and a kinase inhibitor.
[0010] Thus, the present invention provides, in certain
embodiments, compounds of Formula I, or pharmaceutically acceptable
derivatives thereof.
[0011] In certain embodiments, a subject compound has the structure
of Formula (I):
Hc-X--K-Cy-L-Z-Tb (I)
[0012] wherein
[0013] L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-;
[0014] X, Y, and Z, independently, are absent or represent NR, O,
or S;
[0015] M represents, independently for each occurrence, a
substituted or unsubstituted methylene group, such as --CH.sub.2--,
--CHF--, --CHOH--, --CH(Me)-, --C(.dbd.O)--, etc., or two M taken
together represent substituted or unsubstituted ethene or
ethyne;
[0016] R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl or alkyl.
[0017] Cy represents a substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, or cycloalkyl, including polycyclic
groups;
[0018] p and n, independently, represent integers from 0-10,
preferably from 0-5, even more preferably, from 0-3.
[0019] Hc represents a heterocycle, preferably a
nitrogen-containing heterocycle; and
[0020] Tb represents a bone-targeting moiety preferably selected
from: 1
[0021] wherein R.sub.4 independently for each occurrence represents
H or lower alkyl, preferably H or C.sub.1--C.sub.3 lower alkyl.
[0022] In embodiments wherein Tb is selected from i, v, vi, vii,
viii, and ix, Z is preferably absent. In embodiments wherein Tb is
selected from ii, iii, and iv, Z may be absent or represent O or
NR. In embodiments wherein Tb is selected from x, xi, xii, xiii,
xiv, and xv, Z may be absent or represent O or NR, preferably being
absent.
[0023] In certain embodiments, R.sub.4 represents H for all
occurrences.
[0024] In certain embodiments, L represents alkyl-Y-alkyl,
alkyl-Y-acyl, or alkyl.
[0025] In certain embodiments, the compound is free of hydrolyzable
linkages. Hydrolyzable linkages, as the term is used herein, are
saturated (sp.sup.3-hybridized) carbons bound to two heteroatoms,
of which at least one is selected from S, N, or O.
[0026] In certain embodiments, M represents a substituted or
unsubstituted methylene group, such as --CH.sub.2--, --CHF--,
--CHOH--, --CH(Me)--, --C(.dbd.O)--, etc.
[0027] In certain embodiments, Cy represents a carbocycle or a
nitrogen-bearing heterocycle. Cy is preferably uncharged.
[0028] In certain embodiments, Cy represents a phenyl, pyridyl,
cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In certain embodiments,
Cy is phenyl.
[0029] In certain embodiments, K is absent.
[0030] In certain embodiments, K represents alkyl-Y-alkyl,
alkyl-Y-acyl, or alkyl.
[0031] In certain embodiments, Hc represents a bicyclic structure,
preferably including heteroatoms in both rings. In certain
embodiments, the ring(s) of Hc consist of C and N atoms. In certain
embodiments, Hc represents a bicyclic heteroaryl structure.
[0032] In certain embodiments, K is directly attached to a
heteroatom of Hc, or X represents NR.
[0033] In certain embodiments, Hc includes at least one aryl
substituent.
[0034] In certain embodiments, Hc-X taken together represent one of
the following structures: 2
[0035] wherein W represents O or S, and one of R.sub.1, R.sub.2,
and R.sub.3 represents a bond to K, and the others represent,
independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl,
heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl,
alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to
which it is attached, represent amidine, amide, carbamate, urea, or
guanidine.
[0036] In certain embodiments wherein Hc-X is represented by xix or
xx, R.sub.3 represents a bond to K, R.sub.2 is selected from
hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl,
heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl,
and alkanoyl; and R.sub.1 is selected from hydrogen, halogen, aryl,
and heteroaryl. In certain embodiments, R.sub.2 is selected from
hydrogen, (CH.sub.2).sub.nPh, where Ph is phenyl or substituted
phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl,
C.sub.1--C.sub.6 alkanoyl, C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6
alkenyl, and C.sub.2--C.sub.6 alkynyl, where the alkyl, alkenyl and
alkynyl groups may be substituted by NR.sub.5R.sub.6, phenyl,
thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and
where R.sub.5 and R.sub.6 are independently hydrogen,
C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6 alkenyl, C.sub.2--C.sub.6
alkynyl, (CH.sub.2).sub.nPh where Ph is phenyl and n is 0, 1, 2, or
3; cycloalkyl, heteroaryl, and R.sub.5 and R.sub.6 taken together
with the nitrogen to which they are attached can complete a ring
having 3 to 7 carbon atoms and optionally containing 1, 2, or 3
heteroatoms selected from the group consisting of nitrogen,
substituted nitrogen, oxygen and sulfur. In certain embodiments,
R.sub.1 is a substituted aryl moiety selected from of monohaloaryl,
dihaloaryl, monomethylaryl, and dimethylaryl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0037] In certain embodiments wherein Hc-X is represented by xvi or
xvii, at least one of R.sub.1, R.sub.2, or R.sub.3 represents a
bond to K, R.sub.3, if not a bond to K, is selected from hydrogen
or alkyl, R.sub.2, if not a bond to K, is selected from alkyl,
cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R.sub.1, if not a
bond to K, is selected from hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl,
alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0038] In certain embodiments wherein Hc-X is represented by xviii,
R.sub.2 represents a bond to K, and R.sub.1 and R.sub.3 are
selected, independently, from hydrogen, alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl,
alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl
heterocyclyl. In certain embodiments, R.sub.1 is alkyl or branched
alkyl and R.sub.3 is aryl, heteroaryl, or cycloalkyl. In certain
embodiments, R.sub.3 is selected from monohaloaryl, dihaloaryl,
monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or
dihalocycloalkyl. In certain embodiments, at least one of R.sub.1,
R.sub.2, and R.sub.3, other than the bond to K, represents an aryl
or heteroaryl substituent, preferably a substituted or
unsubstituted phenyl.
[0039] In certain embodiments wherein Tb is represented by vii or
viii, the compound is free of hydrolyzable linkages. In certain
embodiments, L and K do not comprise nitrogen. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0040] In certain embodiments, Tb is represented by xi, xii, xiv,
or xv. In certain embodiments, K and L do not include an amide
bond, or are preferably free of nitrogen atoms. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, the compound does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In certain embodiments, Cy represents a
phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring
system, preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0041] In certain embodiments wherein Tb is represented by the
moiety xiii, that moiety is not present in another portion of the
compound, e.g., Hc is not xiii, etc. In certain embodiments, K does
not include an amide bond, or is preferably free of nitrogen atoms.
In certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, He represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, the compound does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In certain embodiments, Cy represents a
phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring
system, preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0042] In certain embodiments wherein Tb is represented by x, K
does not include an amide bond, is free of carbonyls, is free of
amine substituents, or is free of nitrogen atoms. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, the compound does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In certain embodiments, Cy represents a
phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring
system, preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0043] In certain embodiments wherein Tb is represented by ii, iii,
iv, or v, the compound does not include a hydrolyzable linkage. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In certain embodiments,
K is directly attached to a heteroatom of Hc. In certain
embodiments, K is absent.
[0044] In certain embodiments wherein Tb is represented by ix, Cy
is preferably uncharged, and/or L-Cy-K is preferably free of
hydrolyzable linkages. In certain embodiments, the compound is free
of hydrolyzable linkages. In certain embodiments, Cy is preferably
selected from aryl, carbocyclic, nitrogen-containing heterocyclic,
and nitrogen-containing heteroaryl groups, and preferably does not
include S or O atoms in the ring structure. In preferred
embodiments, Cy contains 0 or 1 heteroatoms. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0045] In certain embodiments wherein Tb is represented by i, Cy is
preferably uncharged, and/or L-Cy-K is preferably free of
hydrolyzable linkages. In certain embodiments, Cy is preferably
selected from aryl, carbocyclic, nitrogen-containing heterocyclic,
and nitrogen-containing heteroaryl groups, and preferably does not
include S or O atoms in the ring structure. In preferred
embodiments, the ring system of Cy contains 0 or 1 heteroatoms. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0046] In certain embodiments wherein Tb is represented by i, Z and
L are absent. In certain embodiments, Cy represents an aryl or
heteroaryl group, such as a phenyl or pyridyl group. In certain
embodiments, Cy is preferably uncharged, and/or the compound is
preferably free of hydrolyzable linkages. In certain embodiments,
Cy is preferably selected from aryl, carbocyclic,
nitrogen-containing heterocyclic, and nitrogen-containing
heteroaryl groups, and preferably does not include S or O atoms in
the ring structure. In preferred embodiments, the ring system of Cy
contains 0 or 1 heteroatoms, or is preferably phenyl. In certain
embodiments, Hc represents heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb, where L and/or K is absent) may be attached to one of the
two rings, and the other substituent to the other of the two rings.
In embodiments wherein X is absent, K is preferably directly
attached to a heteroatom of Hc. In certain embodiments, K is
absent.
[0047] In certain embodiments of Formula I, Tb is selected from i
and ix, and K is absent or represents --Y--, such as --NH--. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, Cy is aryl or heteroaryl, preferably
aryl. In certain embodiments, Hc is further substituted with an
aryl group, e.g., at a position of R.sub.1, R.sub.2, and R.sub.3
not substituted with K. In certain embodiments, each of R.sub.1,
R.sub.2, and R.sub.3 represents a hydrocarbon substituent. In
certain embodiments, L represents alkyl, alkyl-Y-alkyl or
alkyl-Y-acyl, wherein Y is preferably NR, such as NH or NMe.
[0048] In certain embodiments of Formula I, Tb is x and K is
absent. In certain embodiments, Hc is selected from xvi, xvii,
xviii, xix, and xx. In certain embodiments, Hc is further
substituted with an aryl group, e.g., at a position of R.sub.1,
R.sub.2, and R.sub.3 not substituted with K. In certain
embodiments, each of R.sub.1, R.sub.2, and R.sub.3 represents a
hydrocarbon substituent. In certain embodiments, L represents
alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably NR,
such as NH or NMe.
[0049] In certain embodiments, a subject compound has the structure
of Formula (II):
Hc-X--K-Z-Tb (II)
[0050] wherein Hc, X, K, Z, and Tb are as defined above.
[0051] In certain embodiments of Formula II, Tb is selected from x,
xi, xii, xiii, xiv, and xv. In embodiments wherein Tb is selected
from x, xi, xii, xiii, xiv, and xv, Z may be absent or represent O
or NR, preferably being absent.
[0052] In certain embodiments, R.sub.4 represents H for all
occurrences.
[0053] In certain embodiments, the compound is free of hydrolyzable
linkages. Hydrolyzable linkages, as the term is used herein, are
saturated (sp.sup.3-hybridized) carbons bound to two heteroatoms,
of which at least one is selected from S, N, or O.
[0054] In certain embodiments, M represents a substituted or
unsubstituted methylene group, such as --CH.sub.2--, --CHF--,
--CHOH--, --CH(Me)--, --C(.dbd.O)--, etc.
[0055] In certain embodiments, K is absent.
[0056] In certain embodiments, K represents alkyl-Y-alkyl,
alkyl-Y-acyl, or alkyl.
[0057] In certain embodiments, Hc represents a bicyclic structure,
preferably including heteroatoms in both rings. In certain
embodiments, the ring(s) of Hc consist of C and N atoms.
[0058] In certain embodiments, K is directly attached to a
heteroatom of Hc, or X represents NR.
[0059] In certain embodiments, Hc includes at least one aryl
substituent.
[0060] In certain embodiments, Hc-X taken together represent one of
the following structures: 3
[0061] wherein W represents O or S, and one of R.sub.1, R.sub.2,
and R.sub.3 represents a bond to K, and the others represent,
independently, hydrogen, halogen, amidine, amide, carbamate, urea,
guanidine, alkyl, aralkyl, aryl, cycloalkyl, heteroaryl,
heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl, alkyl alkynyl,
or alkanoyl, or taken together with the nitrogen to which it is
attached, represent amidine, amide, carbamate, urea, or
guanidine.
[0062] In certain embodiments wherein Hc-X is represented by xix or
xx, R.sub.3 represents a bond to K, R.sub.2 is selected from
hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl,
heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl,
and alkanoyl; and R.sub.1 is selected from hydrogen, halogen, aryl,
and heteroaryl. In certain embodiments, R.sub.2 is selected from
hydrogen, (CH.sub.2).sub.nPh, where Ph is phenyl or substituted
phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl,
C.sub.1--C.sub.6 alkanoyl, C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6
alkenyl, and C.sub.2--C.sub.6 alkynyl, where the alkyl, alkenyl and
alkynyl groups may be substituted by NR.sub.5R.sub.6, phenyl,
thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and
where R.sub.5 and R.sub.6 are independently hydrogen,
C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6 alkenyl, C.sub.2--C.sub.6
alkynyl, (CH.sub.2).sub.nPh where Ph is phenyl and n is 0, 1, 2, or
3; cycloalkyl, heteroaryl, and R.sub.5 and R.sub.6 taken together
with the nitrogen to which they are attached can complete a ring
having 3 to 7 carbon atoms and optionally containing 1, 2, or 3
heteroatoms selected from the group consisting of nitrogen,
substituted nitrogen, oxygen and sulfur. In certain embodiments,
R.sub.1 is a substituted aryl moiety selected from of monohaloaryl,
dihaloaryl, monomethylaryl, and dimethylaryl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0063] In certain embodiments wherein Hc-X is represented by xviii,
R.sub.2 represents a bond to K, and R.sub.1 and R.sub.3 are
selected, independently, from hydrogen, alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl,
alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl
heterocyclyl. In certain embodiments, R.sub.1 is alkyl or branched
alkyl and R.sub.3 is aryl, heteroaryl, or cycloalkyl. In certain
embodiments, R.sub.3 is selected from monohaloaryl, dihaloaryl,
monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or
dihalocycloalkyl. In certain embodiments, at least one of R.sub.1,
R.sub.2, and R.sub.3, other than the bond to K, represents an aryl
or heteroaryl substituent, preferably a substituted or
unsubstituted phenyl.
[0064] In certain embodiments wherein Hc-X is represented by xvi or
xvii, at least one of R.sub.1, R.sub.2, or R.sub.3 represents a
bond to K, R.sub.3, if not a bond to K, is selected from hydrogen
or alkyl, R.sub.2, if not a bond to K, is selected from alkyl,
cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R.sub.1, if not a
bond to K, is selected from hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl,
alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0065] In certain embodiments wherein Tb is represented by vii or
viii, the compound is free of hydrolyzable linkages. In certain
embodiments, K does not comprise nitrogen. In certain embodiments,
Hc represents a heterocyclic bicycle. In certain embodiments, Hc
represents a bicyclic heteroaryl structure. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, R.sub.4 represents H for all occurrences. In
embodiments wherein X is absent, K is preferably directly attached
to a heteroatom of Hc. In certain embodiments, K is absent.
[0066] In certain embodiments, Tb is represented by xi, xii, xiv,
or xv. In certain embodiments, K does not include an amide bond, or
are preferably free of nitrogen atoms. In certain embodiments, Hc
represents a heterocyclic bicycle. In certain embodiments, Hc
represents a bicyclic heteroaryl structure. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, the compound does not include a hydrolyzable linkage.
In certain embodiments, R.sub.4 represents H for all occurrences.
In embodiments wherein X is absent, K is preferably directly
attached to a heteroatom of Hc. In certain embodiments, K is
absent.
[0067] In certain embodiments wherein Tb is represented by the
moiety xiii, that moiety is not present in another portion of the
compound, e.g., Hc is not xiii, etc. In certain embodiments, K does
not include an amide bond, or is preferably free of nitrogen atoms.
In certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, the compound does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In embodiments wherein X is absent, K is
preferably directly attached to a heteroatom of Hc. In certain
embodiments, K is absent.
[0068] In certain embodiments wherein Tb is represented by x, K
does not include an amide bond, is free of carbonyls, is free of
amine substituents, or is free of nitrogen atoms. In certain
embodiments, the compound does not include a hydrolyzable linkage.
In certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In embodiments wherein X is absent, K is preferably
directly attached to a heteroatom of Hc. In certain embodiments, K
is absent.
[0069] In certain embodiments wherein Tb is represented by ii, iii,
iv, or v, the compound does not include a hydrolyzable linkage. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, K is directly attached to a
heteroatom of Hc. In certain embodiments, K is absent.
[0070] In certain embodiments wherein Tb is represented by ix, the
compound is preferably free of hydrolyzable linkages. In certain
embodiments, the compound is free of hydrolyzable linkages. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In embodiments wherein X is absent, K is preferably
directly attached to a heteroatom of Hc. In certain embodiments, K
is absent.
[0071] In certain embodiments wherein Tb is represented by i, Hc
represents a heterocyclic bicycle. In certain embodiments, Hc
represents a bicyclic heteroaryl structure. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, R.sub.4 represents H for all occurrences. In
embodiments wherein X is absent, K is preferably directly attached
to a heteroatom of Hc. In certain embodiments, K is absent.
[0072] In certain embodiments of Formula II, Tb is selected from i
and ix, and K is branched or unbranched alkyl. In certain
embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In
certain embodiments, Hc is further substituted with an aryl group,
e.g., at a position of R.sub.1, R.sub.2, and R.sub.3 not
substituted with K. In certain embodiments, each of R.sub.1,
R.sub.2, and R.sub.3 represents a hydrocarbon substituent.
[0073] In certain embodiments of Formula II, Tb is xii, and K is
absent or represents --Y--, such as --NH--. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, Hc is further substituted with an aryl group, e.g., at
a position of R.sub.1, R.sub.2, and R.sub.3 not substituted with K.
In certain embodiments, each of R.sub.1, R.sub.2, and R.sub.3
represents a hydrocarbon substituent.
[0074] In certain embodiments of Formula II, Tb is x, and K
represents alkyl or --Y--. In certain embodiments, Hc is selected
from xvi, xvii, xviii, xix, and xx. In certain embodiments, Hc is
further substituted with an aryl group, e.g., at a position of
R.sub.1, R.sub.2, and R.sub.3 not substituted with K. In certain
embodiments, each of R.sub.1, R.sub.2, and R.sub.3 represents a
hydrocarbon substituent. In certain embodiments of Formula I or II,
Tb represents 4
[0075] In still other embodiments of the present invention,
pharmaceutical compositions are provided comprising any one of the
compounds of the present invention, or a pharmaceutically
acceptable derivative thereof, and one or more pharmaceutically
acceptable excipients.
[0076] In yet other embodiments, compounds of the invention, or
compositions containing such compounds are administered to cells or
to animals, preferably to a mammal in need therof, as a method for
treating bone disorders. In particular cases, it will be
advantageous to carry out such inventive methods using a
pharmaceutical composition comprising a bone targeted compound
which is capable of inhibiting bone resorption. In other cases, it
will be advantageous to carry out that method using a
pharmaceutical composition comprising a bone targeted compound that
specifically acts as a Src kinase inhibitor. In other cases, it
will be advantageous to carry out that method using a bone targeted
compound of the present invention having a payload attached thereto
that is capable of treating bone disorders by other means.
[0077] In still other embodiments, it will be advantageous to carry
out inventive methods using a pharmaceutical composition comprising
a bone targeting moiety that, alone, is capable of effecting
treatment of bone disorders by inhibiting bone resorption or by
other means.
Definitions
[0078] As mentioned above, this invention provides a novel class of
bone targeted compounds useful for the treatment of bone disorders,
preferably by inhibition of bone resorption. Compounds of this
invention include those of Formula I and Formula II, set forth
herein, and are illustrated in part by the various classes,
subgenera and subsets of compounds described above, and by the
various subgenera and species disclosed elsewhere in the
specification, claims and figures. It will be appreciated that
inventive compounds may be provided in the form of an individual
enantiomer, diastereomer or geometric isomer, or may be in the form
of a mixture of stereoisomers.
[0079] Also included are pharmaceutically acceptable derivatives of
the foregoing compounds, where the phrase "pharmaceutically
acceptable derivative" denotes any pharmaceutically acceptable
salt, ester, or salt of such ester, of an inventive compound, or
any other adduct or derivative which, upon administration to a
patient, is capable of providing (directly or indirectly) a
compound as otherwise described herein, or a metabolite or residue
thereof, preferably one which is capable of inhibiting bone
resorption. Pharmaceutically acceptable derivatives thus include
among others pro-drugs. A pro-drug is a derivative of a compound,
usually with significantly reduced pharmacological activity, which
contains an additional moiety which is susceptible to removal in
vivo yielding the parent molecule as the pharmacologically active
species. An example of a pro-drug is an ester which is cleaved in
vivo to yield a compound of interest. Pro-drugs of a variety of
compounds, and materials and methods for derivatizing the parent
compounds to create the pro-drugs, are known and may be adapted to
the present invention. One technique for providing a prodrug of a
compound of the present invention is described generally in Niemi
et al., J. Med. Chem. 1999, 42, 5053-5058.
[0080] The terms "inhibition of bone resorption" or "inhibition of
osteoclast activity" or "inhibition of Src kinase activity"
preferably refer to specific inhibition. Any of a variety of in
vivo or in vitro assays may be employed to assess the ability of
inventive compounds and compositions to treat or prevent bone
disorders and/or other conditions, and in particular to inhibit
bone resorption and/or to inhibit Src tyrosine phosphorylation
(see, for example, the Exemplification section, which describes a
useful rabbit osteoclast assay for studying effects on bone
resorption, and a useful Src kinase inhibition assay). In
particularly preferred embodiments of the invention, the observed
effects on bone metabolism are selective in that the inventive
compounds or compositions do not exert significant negative effects
on biological processes other than bone metabolism, or specifically
bone resporption or Src kinase activity. For example, particularly
preferred inventive compositions show specific inhibition of Src
kinase activity as compared with the activity of non-Src kinanses,
or kinases located at sites away from bone. In some cases, such
specific inhibition may result from specific localization of the
inventive composition to bone sites, so that compositions delivered
in vivo do not have the opportunity to inhibit processes that occur
away from bone; in other cases, specific inhibition may be
attributed to specific action of the inventive payload on the
osteoclast activity or on Src kinase activity, as compared with
other cells or kinases.
[0081] The term "payload" includes therapeutic agents (e.g., a
small molecule, a drug, a radiotherapeutic atom, etc.), detectable
labels (e.g., fluorescent, radioactive, radiopaque, etc.), or any
other moiety desired to be delivered to a site of action (e.g., a
bone or other site suffering an abnormal condition).
[0082] A "small molecule" as the term is used herein refers to an
organic molecule of less than about 2500 amu, preferably less than
about 1000 amu.
[0083] "Subject" shall mean a human or animal (e.g., rat, mouse,
cow, pig, horse, sheep, monkey, cat, dog, goat, etc.).
[0084] A "target" shall mean an in vivo site to which targeted
agents bind. A target may refer to a molecular structure to which a
targeting moiety binds, such as a hapten, epitope, receptor, dsDNA
fragment, carbohydrate, or enzyme. Alternatively or additionally, a
target may be a type of tissue, e.g., bone. A preferred target is
bone. In certain preferred embodiments, target cells include
osteoclasts.
[0085] The term "targeting moiety" refers to any molecular
structure which assists the inventive composition in localizing to
a particular target area, entering a target cell(s), and/or binding
to a target receptor. Preferred targeting moieties according to the
present invention include bone targeting moieties, as described
herein.
[0086] A "therapeutic agent" shall mean an agent capable of having
a biological effect on a host. Preferred therapeutic agents are
capable of preventing and/or treating one or more symptoms of a
bone disorder, such as a metabolic bone disorder. Other preferred
therapeutic agents are capable of preventing or treating other bone
disorders or related conditions. Examples of therapeutic agents
considered to be within the scope of the present invention include
boron-containing compounds (e.g. carborane), chemotherapeutic
nucleotides, drugs (e.g., antibiotics, antivirals, antifungals),
enediynes (e.g., calicheamicins, esperamicins, dynemicin,
neocarzinostatin chromophore, and kedarcidin chromophore), heavy
metal complexes (e.g., cisplatin), hormone antagonists (e.g.,
tamoxifen), non-specific (non-antibody) proteins (e.g., sugar
oligomers), oligonucleotides (e.g., antisense oligonucleotides that
bind to a target nucleic acid sequence (e.g., mRNA sequence)),
peptides, photodynamic agents (e.g., rhodamine 123), radionuclides
(e.g., I-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166,
Sm-153, Cu-67 and Cu-64), toxins (e.g., ricin), and
transcription-based pharmaceuticals. In one preferred embodiment of
the present invention in which compositions are provided for
treating or preventing the establishment or growth of a tumor, the
therapeutic agent is a radionuclide, toxin, hormone antagonist,
heavy metal complex, oligonucleotide, chemotherapeutic nucleotide,
peptide, non-specific (non-antibody) protein, a boron compound or
an enediyne. In a preferred embodiment in which compositions are
provided for treating osteoporosis, the therapeutic agent is a Src
kinase inhibitor, capable of inhibiting the overactivity of
osteoclasts.
[0087] With respect to the compounds of the present invention, a
named R group will generally have the structure which is recognized
in the art as corresponding to R groups having that name. For the
purposes of illustration, representative R groups as enumerated in
the specification and claims of the present application are defined
herein. These definitions are intended to supplement and
illustrate, not preclude, the definitions known to those of skill
in the art.
[0088] The term "independently selected" is used herein to indicate
that the R groups can be identical or different.
[0089] The term "alkyl" refers to the radical of saturated
aliphatic groups, including straight-chain alkyl groups,
branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl
substituted cycloalkyl groups, and cycloalkyl substituted alkyl
groups. In preferred embodiments, a straight chain or branched
chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,
C.sub.1--C.sub.30 for straight chain, C.sub.3--C.sub.30 for
branched chain), and more preferably 20 or fewer. Likewise,
preferred cycloalkyls have from 3-10 carbon atoms in their ring
structure, and more preferably have 5, 6 or 7 carbons in the ring
structure.
[0090] Moreover, the term "alkyl" (or "lower alkyl") as used
throughout the specification, examples, and claims is intended to
include both "unsubstituted alkyls" and "substituted alkyls", the
latter of which refers to alkyl moieties having substituents
replacing a hydrogen on one or more carbons of the hydrocarbon
backbone. Such substituents can include, for example, a halogen, a
hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a
formyl, or an acyl), a thiocarbonyl (such as a thioester, a
thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a
phosphonate, a phosphinate, an amino, an amido, an amidine, an
imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a
sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a
heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
It will be understood by those skilled in the art that the moieties
substituted on the hydrocarbon chain can themselves be substituted,
if appropriate. For instance, the substituents of a substituted
alkyl may include substituted and unsubstituted forms of amino,
azido, imino, amido, phosphoryl (including phosphonate and
phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl
and sulfonate), and silyl groups, as well as ethers, alkylthios,
carbonyls (including ketones, aldehydes, carboxylates, and esters),
--CF.sub.3, --CN and the like. Exemplary substituted alkyls are
described below. Cycloalkyls can be further substituted with
alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls,
carbonyl-substituted alkyls, --CF.sub.3, --CN, and the like.
[0091] The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group (e.g., an aromatic or heteroaromatic
group). Exemplary aralkyl groups include, but are not limited to,
benzyl and more generally (CH.sub.2).sub.nPh, where Ph is phenyl or
substituted phenyl, and n is 1, 2, or 3.
[0092] The terms "alkenyl" and "alkynyl" refer to unsaturated
aliphatic groups analogous in length and possible substitution to
the alkyls described above, but that contain at least one double or
triple bond, respectively.
[0093] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to ten carbons, more preferably from one to six
carbon atoms in its backbone structure. Likewise, "lower alkenyl"
and "lower alkynyl" have similar chain lengths. Preferred alkyl
groups are lower alkyls. In preferred embodiments, a substituent
designated herein as alkyl is a lower alkyl.
[0094] The term "aryl" as used herein includes 5-, 6- and
7-membered single-ring aromatic groups that may include from zero
to four heteroatoms, for example, benzene, pyrrole, furan,
thiophene, imidazole, oxazole, thiazole, triazole, pyrazole,
pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those
aryl groups having heteroatoms in the ring structure may also be
referred to as "aryl heterocycles" or "heteroaromatics." The
aromatic ring can be substituted at one or more ring positions with
such substituents as described above, for example, halogen, azide,
alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,
amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido,
ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic
moieties, --CF.sub.3, --CN, or the like. The term "aryl" also
includes polycyclic ring systems having two or more cyclic rings in
which two or more carbons are common to two adjoining rings (the
rings are "fused rings") wherein at least one of the rings is
aromatic, e.g., the other cyclic rings can be cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
[0095] The terms ortho, meta and para apply to 1,2-, 1,3- and
1,4-disubstituted benzenes, respectively. For example, the names
1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
[0096] The terms "heterocyclyl" or "heterocyclic group" refer to 3-
to 10-membered ring structures, more preferably 3- to 7-membered
rings, whose ring structures include one to four heteroatoms.
Heterocycles can also be polycycles. Heterocyclyl groups include,
for example, thiophene, thianthrene, furan, pyran, isobenzofuran,
chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole,
isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline,
phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
oxolane, thiolane, oxazole, piperidine, piperazine, morpholine,
lactones, lactams such as azetidinones and pyrrolidinones, sultams,
sultones, and the like. The heterocyclic ring can be substituted at
one or more positions with such substituents as described above, as
for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,
phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,
ketone, aldehyde, ester, a heterocyclyl, an aromatic or
heteroaromatic moiety, --CF.sub.3, --CN, or the like.
[0097] The terms "polycyclyl" or "polycyclic group" refer to two or
more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls
and/or heterocyclyls) in which two or more carbons are common to
two adjoining rings, e.g., the rings are "fused rings". Rings that
are joined through non-adjacent atoms are termed "bridged" rings.
Each of the rings of the polycycle can be substituted with such
substituents as described above, as for example, halogen, alkyl,
aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,
sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,
ester, a heterocyclyl, an aromatic or heteroaromatic moiety,
--CF.sub.3, --CN, or the like.
[0098] The term "carbocycle", as used herein, refers to an aromatic
or non-aromatic ring in which each atom of the ring is carbon.
[0099] As used herein, the term "nitro" means --NO.sub.2; the term
"halogen" designates --F, --Cl, --Br or --I; the term "sulfhydryl"
means --SH; the term "hydroxyl" means --OH; and the term "sulfonyl"
means --SO.sub.2--.
[0100] The terms "amine" and "amino" are art-recognized and refer
to both unsubstituted and substituted amines, e.g., a moiety that
can be represented by the general formula: 5
[0101] wherein R.sub.9, R.sub.10 and R'.sub.10 each independently
represent a hydrogen, an alkyl, an alkenyl,
--(CH.sub.2).sub.m--R.sub.8, or R.sub.9 and R.sub.10 taken together
with the N atom to which they are attached complete a heterocycle
having from 4 to 8 atoms in the ring structure; R.sub.8 represents
an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a
polycycle; and m is zero or an integer in the range of 1 to 8. In
preferred embodiments, only one of R.sub.9 or R.sub.10 can be a
carbonyl, e.g., R.sub.9, R.sub.10 and the nitrogen together do not
form an imide. In even more preferred embodiments, R.sub.9 and
R.sub.10 (and optionally R'.sub.10) each independently represent a
hydrogen, an alkyl, an alkenyl, or --(CH.sub.2).sub.m--R.sub.8.
Thus, the term "alkylamine" as used herein means an amine group, as
defined above, having a substituted or unsubstituted alkyl attached
thereto, i.e., at least one of R.sub.9 and R.sub.10 is an alkyl
group.
[0102] The term "acylamino" is art-recognized and refers to a
moiety that can be represented by the general formula: 6
[0103] wherein R.sub.9 is as defined above, and R'.sub.11
represents a hydrogen, an alkyl, an alkenyl or
--(CH.sub.2).sub.m--R.sub.8, where m and R.sub.8 are as defined
above.
[0104] The term "amido" is art recognized as an amino-substituted
carbonyl and includes a moiety that can be represented by the
general formula: 7
[0105] wherein R.sub.9, R.sub.10 are as defined above. Preferred
embodiments of the amide will not include imides which may be
unstable.
[0106] The term "amidine" is art-recognized as a group that can be
represented by the general formula: 8
[0107] wherein R.sub.9, R.sub.10 are as defined above.
[0108] The term "guanidine" is art-recognized as a group that can
be represented by the general formula: 9
[0109] wherein R.sub.9, R.sub.10 are as defined above.
[0110] The term "alkylthio" refers to an alkyl group, as defined
above, having a sulfur radical attached thereto. In preferred
embodiments, the "alkylthio" moiety is represented by one of
--S-alkyl, --S-alkenyl, --S-alkynyl, and
--S--(CH.sub.2).sub.m--R.sub.8, wherein m and R.sub.8 are defined
above. Representative alkylthio groups include methylthio, ethyl
thio, and the like.
[0111] The term "carbonyl" is art recognized and includes such
moieties as can be represented by the general formula: 10
[0112] wherein X is a bond or represents an oxygen or a sulfur, and
R.sub.11 represents a hydrogen, an alkyl, an alkenyl,
--(CH.sub.2).sub.m--R.sub.8 or a pharmaceutically acceptable salt,
R'.sub.11 represents a hydrogen, an alkyl, an alkenyl or
--(CH.sub.2).sub.m--R.sub.8, where m and R.sub.8 are as defined
above. Where X is an oxygen and R.sub.11 or R'.sub.11 is not
hydrogen, the formula represents an "ester". Where X is an oxygen,
and R.sub.11 is as defined above, the moiety is referred to herein
as a carboxyl group, and particularly when R.sub.11 is a hydrogen,
the formula represents a "carboxylic acid". Where X is an oxygen,
and R'.sub.11 is hydrogen, the formula represents a "formate". In
general, where the oxygen atom of the above formula is replaced by
sulfur, the formula represents a "thiolcarbonyl" group. Where X is
a sulfur and R.sub.11 or R'.sub.11 is not hydrogen, the formula
represents a "thiolester." Where X is a sulfur and R.sub.11 is
hydrogen, the formula represents a "thiolcarboxylic acid." Where X
is a sulfur and R.sub.11' is hydrogen, the formula represents a
"thiolformate." On the other hand, where X is a bond, and R.sub.11
is not hydrogen, the above formula represents a "ketone" group.
Where X is a bond, and R.sub.11 is hydrogen, the above formula
represents an "aldehyde" group.
[0113] The terms "alkoxyl" or "alkoxy" as used herein refers to an
alkyl group, as defined above, having an oxygen radical attached
thereto. Representative alkoxyl groups include methoxy, ethoxy,
propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons
covalently linked by an oxygen. Accordingly, the substituent of an
alkyl that renders that alkyl an ether is or resembles an alkoxyl,
such as can be represented by one of --O-alkyl, --O-alkenyl,
--O-alkynyl, --O--(CH.sub.2).sub.m--R.sub.8, where m and R.sub.8
are described above.
[0114] The term "sulfonate" is art recognized and includes a moiety
that can be represented by the general formula: 11
[0115] in which R.sub.41 is an electron pair, hydrogen, alkyl,
cycloalkyl, or aryl.
[0116] The terms triflyl, tosyl, mesyl, and nonaflyl are
art-recognized and refer to trifluoromethanesulfonyl,
p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl
groups, respectively. The terms triflate, tosylate, mesylate, and
nonaflate are art-recognized and refer to trifluoromethanesulfonate
ester, p-toluenesulfonate ester, methanesulfonate ester, and
nonafluorobutanesulfonate ester functional groups and molecules
that contain said groups, respectively.
[0117] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent
methyl, ethyl, phenyl, trifluoromethanesulfonyl,
nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl,
respectively. A more comprehensive list of the abbreviations
utilized by organic chemists of ordinary skill in the art appears
in the first issue of each volume of the Journal of Organic
Chemistry; this list is typically presented in a table entitled
Standard List of Abbreviations. The abbreviations contained in this
list, and all abbreviations utilized by organic chemists of
ordinary skill in the art are hereby incorporated by reference.
[0118] The term "sulfate" is art recognized and includes a moiety
that can be represented by the general formula: 12
[0119] in which R.sub.41 is as defined above.
[0120] The term "sulfonamido" is art recognized and includes a
moiety that can be represented by the general formula: 13
[0121] in which R.sub.9 and R'.sub.11 are as defined above.
[0122] The term "sulfamoyl" is art-recognized and includes a moiety
that can be represented by the general formula: 14
[0123] in which R.sub.9 and R.sub.10 are as defined above.
[0124] The term "sulfonyl", as used herein, refers to a moiety that
can be represented by the general formula: 15
[0125] in which R.sub.44 is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,
or heteroaryl.
[0126] The term "sulfoxido" as used herein, refers to a moiety that
can be represented by the general formula: 16
[0127] in which R.sub.44 is selected from the group consisting of
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
aralkyl, or aryl.
[0128] A "phosphoryl" can in general be represented by the formula:
17
[0129] wherein Q.sub.1 represented S or O, and R.sub.46 represents
hydrogen, a lower alkyl or an aryl. When used to substitute, e.g.,
an alkyl, the phosphoryl group of the phosphorylalkyl can be
represented by the general formula: 18
[0130] wherein Q.sub.1 represented S or O, and each R.sub.46
independently represents hydrogen, a lower alkyl or an aryl,
Q.sub.2 represents O, S or N. When Q.sub.1 is an S, the phosphoryl
moiety is a "phosphorothioate".
[0131] As used herein, the definition of each expression, e.g.
alkyl, m, n, etc., when it occurs more than once in any structure,
is intended to be independent of its definition elsewhere in the
same structure.
[0132] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc.
[0133] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
herein above. The permissible substituents can be one or more and
the same or different for appropriate organic compounds. For
purposes of this invention, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. This invention is not intended to be limited in
any manner by the permissible substituents of organic
compounds.
[0134] The phrase "protecting group" as used herein means temporary
substituents which protect a potentially reactive functional group
from undesired chemical transformations. Examples of such
protecting groups include esters of carboxylic acids, silyl ethers
of alcohols, and acetals and ketals of aldehydes and ketones,
respectively. The field of protecting group chemistry has been
reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991, incorporated
herein by reference).
[0135] Certain compounds of the present invention may exist in
particular geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substituent such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in this invention.
[0136] Isomeric mixtures containing any of a variety of isomer
ratios may be utilized in accordance with the present invention.
For example, where only two isomers are combined, mixtures
containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3,
98:2, 99:1, or 100:0 isomer ratios are all contemplated by the
present invention. Those of ordinary skill in the art will readily
appreciate that analogous ratios are contemplated for more complex
isomer mixtures.
[0137] If, for instance, a particular enantiomer of a compound of
the present invention is desired, it may be prepared by asymmetric
synthesis, or by derivation with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts are formed with an appropriate
optically-active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0138] Contemplated equivalents of the compounds described above
include compounds which otherwise correspond thereto, and which
have the same general properties thereof (e.g., bone targeting
agents), wherein one or more simple variations of substituents are
made which do not adversely affect the efficacy of the compound in
targeting bone. In general, the compounds of the present invention
may be prepared by the methods illustrated in the general reaction
schemes as, for example, described below, or by modifications
thereof, using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants which are in themselves known, but
are not mentioned here.
[0139] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE
INVENTION
[0140] As discussed above, there remains a need to develop
selective and potent agents for treatment of bone disorders,
preferably metabolic bone disorders. Thus, in general, the present
invention provides compounds comprising a bone targeting agent and
a payload for use in the treatment of bone disorders and other
related disorders. In certain embodiments, the present invention
provides compounds, pharmaceutical compositions and methods of
selective treatment of metabolic bone disorders. In certain
embodiments, these compounds and compositions are used to treat
disorders resulting from overactive osteoclast function. In certain
other preferred embodiments, these compounds and compositions are
used to treat osteoporosis.
[0141] Clearly, because of the numerous factors involved in bone
metabolism, there are several approaches for the development of
novel therapeutics. As described above, one approach would be to
inhibit the activity of osteoclasts by inhibition of a proton pump,
or by inhibition of Src tyrosine phosphorylation. Other approaches
might involve the promotion of osteoblast activity. Irrespective of
the approach taken, however, there remains a need for the
development of selective and potent therapeutics capable of
targeting bone tissue directly.
[0142] In view of this need for improved agents, the present
invention provides novel compounds comprising a bone targeting
moiety and a payload. Thus, in certain embodiments, the present
invention contemplates the use of bone targeting agents, as
described in more detail herein, having a specific payload attached
thereto. The specific payload attached thereto may be useful in the
inhibition of osteoclast activity via a proton pump, or via
inhibition of Src tyrosine kinase, or via any other mechanism that
affects the functioning of osteoclast or osteoblast cells. In
certain other embodiments, the bone targeting agents themselves act
as selective and potent inhibitors of osteoclast function.
[0143] Thus, the present invention, provides, in certain
embodiments, compositions comprising a compound having the
structure of Formula (I):
Hc-X--K-Cy-L-Z-Tb (I)
[0144] wherein
[0145] L and K, independently, are absent or represent
-M.sub.n-Y-M.sub.p-;
[0146] X, Y, and Z, independently, are absent or represent NR, O,
or S;
[0147] M represents, independently for each occurrence, a
substituted or unsubstituted methylene group, such as --CH.sub.2--,
--CHF--, --CHOH--, --CH(Me)--, --C(.dbd.O)--, etc., or two M taken
together represent substituted or unsubstituted ethene or
ethyne;
[0148] R represents, independently for each occurrence, H or
substituted or unsubstituted aryl, heterocyclyl, heteroaryl,
aralkyl, alkenyl or alkyl.
[0149] Cy represents a substituted or unsubstituted aryl,
heterocyclyl, heteroaryl, or cycloalkyl, including polycyclic
groups;
[0150] p and n, independently, represent integers from 0-10,
preferably from 0-5, even more preferably, from 0-3.
[0151] Hc represents a heterocycle, preferably a
nitrogen-containing heterocycle; and
[0152] Tb represents a bone-targeting moiety preferably selected
from: 19
[0153] wherein R.sub.4, independently for each occurrence,
represents H, lower alkyl, or a pharmaceutically active small
molecule or a prodrug form thereof, preferably H or
C.sub.1--C.sub.3 lower alkyl.
[0154] In embodiments wherein Tb is selected from i, v, vi, vii,
viii, and ix, Z is preferably absent. In embodiments wherein Tb is
selected from ii, iii, and iv, Z may be absent or represent O or
NR. In embodiments wherein Tb is selected from x, xi, xii, xiii,
xiv, and xv, Z may be absent or represent O or NR, preferably being
absent.
[0155] In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, an occurrence of R.sub.4
represents --CH.sub.2OC(.dbd.O)-(drug) or
--CH.sub.2OC(.dbd.O)-(prodrug).
[0156] In certain embodiments, L represents alkyl-Y-alkyl,
alkyl-Y-acyl, or alkyl.
[0157] In certain embodiments, L-Cy-K--X-Hc is free of hydrolyzable
linkages. Hydrolyzable linkages, as the term is used herein, are
saturated (sp.sup.3-hybridized) carbons bound to two heteroatoms,
of which at least one is selected from S, N, or O.
[0158] In certain embodiments, M represents, independently for each
occurrence, a substituted or unsubstituted methylene group, such as
--CH.sub.2--, --CHF--, --CHOH--, --CH(Me)-, --C(.dbd.O)--, etc.
[0159] In certain embodiments, Cy represents a carbocycle or a
nitrogen-bearing heterocycle. Cy is preferably uncharged.
[0160] In certain embodiments, Cy is substituted with a second
bone-targeting group (Tb), optionally through a linking group (such
as -L-Z-).
[0161] In certain embodiments, Cy represents a phenyl, pyridyl,
cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In certain embodiments,
Cy is phenyl.
[0162] In certain embodiments, K is absent.
[0163] In certain embodiments, K represents alkyl-Y-alkyl,
alkyl-Y-acyl, or alkyl.
[0164] In certain embodiments, Hc represents a bicyclic structure,
preferably including heteroatoms in both rings. In certain
embodiments, the ring(s) of Hc consist of C and N atoms. In certain
embodiments, Hc represents a bicyclic heteroaryl structure.
[0165] In certain embodiments, K is directly attached to a
heteroatom of Hc, or X represents NR.
[0166] In certain embodiments, Hc includes at least one aryl
substituent.
[0167] In certain embodiments, Hc-X taken together represent one of
the following structures: 20
[0168] wherein W represents O or S, and one of R.sub.1, R.sub.2,
and R.sub.3 represents a bond to K, and the others represent,
independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl,
heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl,
alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to
which it is attached, represent amidine, amide, carbamate, urea, or
guanidine.
[0169] In certain embodiments wherein Hc-X is represented by xix or
xx, R.sub.3 represents a bond to K, R.sub.2 is selected from
hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl,
heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl,
and alkanoyl; and R.sub.1 is selected from hydrogen, halogen, aryl,
and heteroaryl. In certain embodiments, R.sub.2 is selected from
hydrogen, (CH.sub.2).sub.nPh, where Ph is phenyl or substituted
phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl,
C.sub.1--C.sub.6 alkanoyl, C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6
alkenyl, and C.sub.2--C.sub.6 alkynyl, where the alkyl, alkenyl and
alkynyl groups may be substituted by NR.sub.5R.sub.6, phenyl,
thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and
where R.sub.5 and R.sub.6 are independently hydrogen,
C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6 alkenyl, C.sub.2--C.sub.6
alkynyl, (CH.sub.2).sub.nPh where Ph is phenyl and n is 0, 1, 2, or
3; cycloalkyl, heteroaryl, and R.sub.5 and R.sub.6 taken together
with the nitrogen to which they are attached can complete a ring
having 3 to 7 carbon atoms and optionally containing 1, 2, or 3
heteroatoms selected from the group consisting of nitrogen,
substituted nitrogen, oxygen and sulfur. In certain embodiments,
R.sub.1 is a substituted aryl moiety selected from of monohaloaryl,
dihaloaryl, monomethylaryl, and dimethylaryl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0170] In certain embodiments wherein Hc-X is represented by xviii,
R.sub.2 represents a bond to K, and R.sub.1 and R.sub.3 are
selected, independently, from hydrogen, alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl,
alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl
heterocyclyl. In certain embodiments, R.sub.1 is alkyl or branched
alkyl and R.sub.3 is aryl, heteroaryl, or cycloalkyl. In certain
embodiments, R.sub.3 is selected from monohaloaryl, dihaloaryl,
monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or
dihalocycloalkyl. In certain embodiments, at least one of R.sub.1,
R.sub.2, and R.sub.3, other than the bond to K, represents an aryl
or heteroaryl substituent, preferably a substituted or
unsubstituted phenyl.
[0171] In certain embodiments wherein Hc-X is represented by xvi or
xvii, at least one of R.sub.1, R.sub.2, or R.sub.3 represents a
bond to K, R.sub.3, if not a bond to K, is selected from hydrogen
or alkyl, R.sub.2, if not a bond to K, is selected from alkyl,
cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R.sub.1, if not a
bond to K, is selected from hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl,
alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0172] In certain embodiments wherein Tb is represented by vii or
viii, L-Cy-K--X-Hc is free of hydrolyzable linkages. In certain
embodiments, L and K do not comprise nitrogen. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0173] In certain embodiments, Tb is represented by xi, xii, xiv,
or xv. In certain embodiments, K and L do not include an amide
bond, or are preferably free of nitrogen atoms. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, L-Cy-K--X-Hc does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In certain embodiments, Cy represents a
phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring
system, preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0174] In certain embodiments wherein Tb is represented by the
moiety xiii, that moiety is not present in another portion of the
compound, e.g., Hc is not xiii, etc. In certain embodiments, K does
not include an amide bond, or is preferably free of nitrogen atoms.
In certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, L-Cy-K--X-Hc does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In certain embodiments, Cy represents a
phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring
system, preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0175] In certain embodiments wherein Tb is represented by x, K
does not include an amide bond, is free of carbonyls, is free of
amine substituents, or is free of nitrogen atoms. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, L-Cy-K--X-Hc does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In certain embodiments, Cy represents a
phenyl, pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring
system, preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0176] In certain embodiments wherein Tb is represented by ii, iii,
iv, or V, L-Cy-K--X-Hc does not include a hydrolyzable linkage. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In certain embodiments,
K is directly attached to a heteroatom of Hc. In certain
embodiments, K is absent.
[0177] In certain embodiments wherein Tb is represented by ix, Cy
is preferably uncharged, and/or L-Cy-K is preferably free of
hydrolyzable linkages. In certain embodiments, L-Cy-K--X-Hc is free
of hydrolyzable linkages. In certain embodiments, Cy is preferably
selected from aryl, carbocyclic, nitrogen-containing heterocyclic,
and nitrogen-containing heteroaryl groups, and preferably does not
include S or O atoms in the ring structure. In preferred
embodiments, Cy contains 0 or 1 heteroatoms. In certain
embodiments, Hc represents a heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0178] In certain embodiments wherein Tb is represented by i, Cy is
preferably uncharged, and/or L-Cy-K is preferably free of
hydrolyzable linkages. In certain embodiments, Cy is preferably
selected from aryl, carbocyclic, nitrogen-containing heterocyclic,
and nitrogen-containing heteroaryl groups, and preferably does not
include S or O atoms in the ring structure. In preferred
embodiments, the ring system of Cy contains 0 or 1 heteroatoms. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb) may be attached to one of the two rings, and the other
substituent to the other of the two rings. In embodiments wherein X
is absent, K is preferably directly attached to a heteroatom of Hc.
In certain embodiments, K is absent.
[0179] In certain embodiments wherein Tb is represented by i, Z and
L are absent. In certain embodiments, Cy represents an aryl or
heteroaryl group, such as a phenyl or pyridyl group. In certain
embodiments, Cy is preferably uncharged, and/or L-Cy-K--X-Hc is
preferably free of hydrolyzable linkages. In certain embodiments,
Cy is preferably selected from aryl, carbocyclic,
nitrogen-containing heterocyclic, and nitrogen-containing
heteroaryl groups, and preferably does not include S or O atoms in
the ring structure. In preferred embodiments, the ring system of Cy
contains 0 or 1 heteroatoms, or is preferably phenyl. In certain
embodiments, Hc represents heterocyclic bicycle. In certain
embodiments, Hc represents a bicyclic heteroaryl structure. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, Cy represents a phenyl,
pyridyl, cyclopentyl, cyclohexyl, or a fused bicyclic ring system,
preferably having between 8 and 11 atoms, such as a fused
cyclohexyl/cyclopentyl ([4.3.0]-bicyclononane) ring system. When Cy
represents a fused ring system, one substituent of L and K (or Hc
or Tb, where L and/or K is absent) may be attached to one of the
two rings, and the other substituent to the other of the two rings.
In embodiments wherein X is absent, K is preferably directly
attached to a heteroatom of Hc. In certain embodiments, K is
absent.
[0180] In certain embodiments of Formula I, Tb is selected from i
and ix, and K is absent or represents --Y--, such as --NH--. In
certain embodiments, Hc is selected from xvi, xvii, xviii, xix, and
xx. In certain embodiments, Cy is aryl or heteroaryl, preferably
aryl. In certain embodiments, Hc is further substituted with an
aryl group, e.g., at a position of R.sub.1, R.sub.2, and R.sub.3
not substituted with K. In certain embodiments, each of R.sub.1,
R.sub.2, and R.sub.3 represents a hydrocarbon substituent. In
certain embodiments, L represents alkyl, alkyl-Y-alkyl or
alkyl-Y-acyl, wherein Y is preferably NR, such as NH or NMe.
[0181] In certain embodiments of Formula I, Tb is x and K is
absent. In certain embodiments, Hc is selected from xvi, xvii,
xviii, xix, and xx. In certain embodiments, Hc is further
substituted with an aryl group, e.g., at a position of R.sub.1,
R.sub.2, and R.sub.3 not substituted with K. In certain
embodiments, each of R.sub.1, R.sub.2, and R.sub.3 represents a
hydrocarbon substituent. In certain embodiments, L represents
alkyl, alkyl-Y-alkyl or alkyl-Y-acyl, wherein Y is preferably NR,
such as NH or NMe.
[0182] In certain embodiments, a subject compound has the structure
of Formula (II):
Hc-X--K-Z-Tb (II)
[0183] wherein Hc, X, K, Z, and Tb are as defined above.
[0184] In certain embodiments of Formula II, Tb is selected from x,
xi, xii, xiii, xiv, and xv. In embodiments wherein Tb is selected
from x, xi, xii, xiii, xiv, and xv, Z may be absent or represent O
or NR, preferably being absent.
[0185] In embodiments wherein Tb is selected from i, v, vi, vii,
viii, and ix, Z is preferably absent. In embodiments wherein Tb is
selected from ii, iii, and iv, Z may be absent or represent O or
NR.
[0186] In certain embodiments, R.sub.4 represents H for all
occurrences.
[0187] In certain embodiments, K--X-Hc is free of hydrolyzable
linkages. Hydrolyzable linkages, as the term is used herein, are
saturated (sp.sup.3-hybridized) carbons bound to two heteroatoms,
of which at least one is selected from S, N, or O.
[0188] In certain embodiments, M represents a substituted or
unsubstituted methylene group, such as --CH.sub.2--, --CHF--,
--CHOH--, --CH(Me)--, --C(.dbd.O)--, etc.
[0189] In certain embodiments, K is absent.
[0190] In certain embodiments, K represents alkyl-Y-alkyl,
alkyl-Y-acyl, or alkyl.
[0191] In certain embodiments, Hc represents a bicyclic structure,
preferably including heteroatoms in both rings. In certain
embodiments, the ring(s) of Hc consist of C and N atoms.
[0192] In certain embodiments, K is directly attached to a
heteroatom of Hc, or X represents NR.
[0193] In certain embodiments, Hc includes at least one aryl
substituent.
[0194] In certain embodiments, Hc-X taken together represent one of
the following structures: 21
[0195] wherein W represents O or S, and one of R.sub.1, R.sub.2,
and R.sub.3 represents a bond to K, and the others represent,
independently, hydrogen, halogen, alkyl, aralkyl, aryl, cycloalkyl,
heteroaryl, heterocyclic, cycloalkyl, polycyclic, alkyl alkenyl,
alkyl alkynyl, or alkanoyl, or taken together with the nitrogen to
which it is attached, represent amidine, amide, carbamate, urea, or
guanidine.
[0196] In certain embodiments wherein Hc-X is represented by xix or
xx, R.sub.3 represents a bond to K, R.sub.2 is selected from
hydrogen, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, heteroaryl,
heterocyclyl, cycloalkyl, polycyclyl, alkyl alkenyl, alkyl alkynyl,
and alkanoyl; and R.sub.1 is selected from hydrogen, halogen, aryl,
and heteroaryl. In certain embodiments, R.sub.2 is selected from
hydrogen, (CH.sub.2).sub.nPh, where Ph is phenyl or substituted
phenyl and n is 0, 1, 2, or 3; heteroaryl, cycloalkyl,
C.sub.1--C.sub.6 alkanoyl, C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6
alkenyl, and C.sub.2--C.sub.6 alkynyl, where the alkyl, alkenyl and
alkynyl groups may be substituted by NR.sub.5R.sub.6, phenyl,
thioalkyl, alkyloxy, hydroxy, carboxy, halogen, cycloalkyl, and
where R.sub.5 and R.sub.6 are independently hydrogen,
C.sub.1--C.sub.6 alkyl, C.sub.2--C.sub.6 alkenyl, C.sub.2--C.sub.6
alkynyl, (CH.sub.2).sub.nPh where Ph is phenyl and n is 0, 1, 2, or
3; cycloalkyl, heteroaryl, and R.sub.5 and R.sub.6 taken together
with the nitrogen to which they are attached can complete a ring
having 3 to 7 carbon atoms and optionally containing 1, 2, or 3
heteroatoms selected from the group consisting of nitrogen,
substituted nitrogen, oxygen and sulfur. In certain embodiments,
R.sub.1 is a substituted aryl moiety selected from of monohaloaryl,
dihaloaryl, monomethylaryl, and dimethylaryl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0197] In certain embodiments wherein Hc-X is represented by xviii,
R.sub.2 represents a bond to K, and R.sub.1 and R.sub.3 are
selected, independently, from hydrogen, alkyl, cycloalkyl, aryl,
heterocyclyl, heteroaryl, aralkyl, heteroalkyl, heteroaralkyl,
alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, and alkyl
heterocyclyl. In certain embodiments, R.sub.1 is alkyl or branched
alkyl and R.sub.3 is aryl, heteroaryl, or cycloalkyl. In certain
embodiments, R.sub.3 is selected from monohaloaryl, dihaloaryl,
monohaloheteroaryl, dihaloheteroaryl, monohalocycloalkyl, or
dihalocycloalkyl. In certain embodiments, at least one of R.sub.1,
R.sub.2, and R.sub.3, other than the bond to K, represents an aryl
or heteroaryl substituent, preferably a substituted or
unsubstituted phenyl.
[0198] In certain embodiments wherein Hc-X is represented by xvi or
xvii, at least one of R.sub.1, R.sub.2, or R.sub.3 represents a
bond to K, R.sub.3, if not a bond to K, is selected from hydrogen
or alkyl, R.sub.2, if not a bond to K, is selected from alkyl,
cycloalkyl, alkyl alkenyl, alkyl alkynyl, and R.sub.1, if not a
bond to K, is selected from hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl, aralkyl, heteroalkyl, alkyl alkenyl,
alkyl alkynyl, alkyl cycloalkyl, or alkyl heterocyclyl. In certain
embodiments, at least one of R.sub.1, R.sub.2, and R.sub.3, other
than the bond to K, represents an aryl or heteroaryl substituent,
preferably a substituted or unsubstituted phenyl.
[0199] In certain embodiments wherein Tb is represented by vii or
viii, K--X-Hc is free of hydrolyzable linkages. In certain
embodiments, K does not comprise nitrogen. In certain embodiments,
Hc represents a heterocyclic bicycle. In certain embodiments, Hc
represents a bicyclic heteroaryl structure. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, R.sub.4 represents H for all occurrences. In
embodiments wherein X is absent, K is preferably directly attached
to a heteroatom of Hc. In certain embodiments, K is absent.
[0200] In certain embodiments, Tb is represented by xi, xii, xiv,
or xv. In certain embodiments, K does not include an amide bond, or
are preferably free of nitrogen atoms. In certain embodiments, Hc
represents a heterocyclic bicycle. In certain embodiments, Hc
represents a bicyclic heteroaryl structure. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, K--X-Hc does not include a hydrolyzable linkage. In
certain embodiments, R.sub.4 represents H for all occurrences. In
embodiments wherein X is absent, K is preferably directly attached
to a heteroatom of Hc. In certain embodiments, K is absent.
[0201] In certain embodiments wherein Tb is represented by the
moiety xiii, that moiety is not present in another portion of the
compound, e.g., Hc is not xiii, etc. In certain embodiments, K does
not include an amide bond, or is preferably free of nitrogen atoms.
In certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, K--X-Hc does not include a
hydrolyzable linkage. In certain embodiments, R.sub.4 represents H
for all occurrences. In embodiments wherein X is absent, K is
preferably directly attached to a heteroatom of Hc. In certain
embodiments, K is absent.
[0202] In certain embodiments wherein Tb is represented by x, K
does not include an amide bond, is free of carbonyls, is free of
amine substituents, or is free of nitrogen atoms. In certain
embodiments, K--X-Hc does not include a hydrolyzable linkage. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In embodiments wherein X is absent, K is preferably
directly attached to a heteroatom of Hc. In certain embodiments, K
is absent.
[0203] In certain embodiments wherein Tb is represented by ii, iii,
iv, or v, K--X-Hc does not include a hydrolyzable linkage. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In certain embodiments, K is directly attached to a
heteroatom of Hc. In certain embodiments, K is absent.
[0204] In certain embodiments wherein Tb is represented by ix,
K--X-Hc is preferably free of hydrolyzable linkages. In certain
embodiments, the compound is free of hydrolyzable linkages. In
certain embodiments, Hc represents a heterocyclic bicycle. In
certain embodiments, Hc represents a bicyclic heteroaryl structure.
In certain embodiments, Hc is selected from xvi, xvii, xviii, xix,
and xx. In certain embodiments, R.sub.4 represents H for all
occurrences. In embodiments wherein X is absent, K is preferably
directly attached to a heteroatom of Hc. In certain embodiments, K
is absent.
[0205] In certain embodiments wherein Tb is represented by i, Hc
represents a heterocyclic bicycle. In certain embodiments, Hc
represents a bicyclic heteroaryl structure. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, R.sub.4 represents H for all occurrences. In
embodiments wherein X is absent, K is preferably directly attached
to a heteroatom of Hc. In certain embodiments, K is absent.
[0206] In certain embodiments of Formula II, Tb is selected from i
and ix, and K is branched or unbranched alkyl. In certain
embodiments, Hc is selected from xvi, xvii, xviii, xix, and xx. In
certain embodiments, Hc is further substituted with an aryl group,
e.g., at a position of R.sub.1, R.sub.2, and R.sub.3 not
substituted with K. In certain embodiments, each of R.sub.1,
R.sub.2, and R.sub.3 represents a hydrocarbon substituent.
[0207] In certain embodiments of Formula II, Tb is xii, and K is
absent or represents --Y--, such as --NH--. In certain embodiments,
Hc is selected from xvi, xvii, xviii, xix, and xx. In certain
embodiments, Hc is further substituted with an aryl group, e.g., at
a position of R.sub.1, R.sub.2, and R.sub.3 not substituted with K.
In certain embodiments, each of R.sub.1, R.sub.2, and R.sub.3
represents a hydrocarbon substituent.
[0208] In certain embodiments of Formula II, Tb is x, and K
represents alkyl or --Y--. In certain embodiments, Hc is selected
from xvi, xvii, xviii, xix, and xx. In certain embodiments, Hc is
further substituted with an aryl group, e.g., at a position of
R.sub.1, R.sub.2, and R.sub.3 not substituted with K. In certain
embodiments, each of R.sub.1, R.sub.2, and R.sub.3 represents a
hydrocarbon substituent.
[0209] In certain embodiments, a subject compound has the structure
of formula III:
[0210] Tb-L-V, wherein Tb, R, and L are as defined above, and
[0211] V represents OR, NR.sub.2, or SR.
[0212] In embodiments wherein Tb is selected from i, ii, iii, iv,
v, vi, vii, viii, and ix, L is preferably not absent, and even more
preferably represents alkyl. In certain embodiments, Tb represents
i, ii, iii, or iv, preferably i. In certain embodiments, Tb
represents v or vi. In certain embodiments, Tb represents vii or
viii. In certain embodiments, Tb represents ix. In certain
embodiments, V represents NR.sub.2. In certain embodiments, all
occurrences of R in V are H.
[0213] In certain embodiments, Tb is selected from x, xi, xii,
xiii, xiv, xv, xxi, xxii, xxiii, xxiv, and xxv. In certain
embodiments, Tb is selected from xi, xii, xiv, or xv. In certain
embodiments, Tb is x. In certain embodiments, Tb is xiii. In
certain embodiments, V represents NR.sub.2. In certain embodiments,
Tb is xxi, xxii, xxiii, xxiv, or xxv. In certain embodiments, Tb is
xx. In certain embodiments, all occurrences of R in V are H. In
certain embodiments, L represents lower alkyl or is absent.
[0214] In certain embodiments, a subject compound has the structure
of Formula IV: Tb-Cy-L-V, wherein Tb, Cy, L, and V are as defined
above, and Tb is selected from i, ii, iii, iv, v, vi, vii, viii,
and ix. In certain embodiments, Tb represents i, ii, iii, or iv,
preferably i. In certain embodiments, Tb represents v or vi. In
certain embodiments, Tb represents vii or viii. In certain
embodiments, Tb represents ix. In certain embodiments, L is absent.
In certain embodiments, Cy represents a phenyl ring. In certain
embodiments, V represents NR.sub.2. In certain embodiments, all
occurrences of R in V are H. In certain embodiments, L represents
lower alkyl or is absent.
[0215] In certain embodiments, a subject compound has the structure
of Formula V:
[0216] Tb-L-U, wherein Tb, R, and L are as defined above, and
[0217] U represents a sulfonate ester (e.g., triflate, tosylate,
mesylate, etc.), halogen (e.g., Cl, Br, I, preferably Br, I),
formyl (CHO), or a suitable leaving group (e.g., a moiety whose
conjugate acid, UH, has a pKa lower than 5, preferably lower than
0).
[0218] In embodiments wherein Tb is selected from i, ii, iii, iv,
v, vi, vii, viii, and ix, L is preferably not absent, and even more
preferably represents alkyl. In certain embodiments, Tb represents
i, ii, iii, or iv, preferably i. In certain embodiments, Tb
represents v or vi. In certain embodiments, Tb represents vii or
viii. In certain embodiments, Tb represents ix.
[0219] In certain embodiments, Tb is selected from x, xi, xii,
xiii, xiv, xv, xxi, xxii, xxiii, xxiv, and xxv. In certain
embodiments, Tb is selected from xi, xii, xiv, or xv. In certain
embodiments, Tb is x. In certain embodiments, Tb is xiii. In
certain embodiments, V represents NR.sub.2. In certain embodiments,
Tb is xxi, xxii, xxiii, xxiv, or xxv. In certain embodiments, Tb is
xx.
[0220] In certain embodiments, a subject compound has the structure
of Formula VI:
[0221] Tb-Cy-L-U, wherein Tb, Cy, L, and U are as defined above,
and Tb is selected from i, ii, iii, iv, v, vi, vii, viii, and ix.
In certain embodiments, Tb represents i, ii, iii, or iv, preferably
i. In certain embodiments, Tb represents v or vi. In certain
embodiments, Tb represents vii or viii. In certain embodiments, Tb
represents ix. In certain embodiments, L is absent. In certain
embodiments, Cy represents a phenyl ring.
[0222] In certain embodiments of Formulas I-VI, Tb represents:
22
[0223] In certain embodiments of Formulas I-VI, Tb may have a
structure selected from: 23
[0224] wherein M is defined as above,
[0225] x represents 1,2, 3, 4, 5, or 6;
[0226] each occurence of Y is independently a covalent bond, --O--,
--S--, or --N(R.sub.J).sub.2, wherein R.sub.J, for each occurence,
is independently hydrogen, aliphatic, heteroaliphatic, aryl,
heteroaryl, alkylaryl, or alkylheteroaryl;
[0227] R.sub.6 represents from 0-3 substituents selected from
halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl,
thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino,
cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate,
sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate,
--(CH.sub.2).sub.palkyl, --(CH.sub.2).sub.palkenyl,
--(CH.sub.2).sub.palkynyl, --(CH.sub.2).sub.paryl,
--(CH.sub.2).sub.paralkyl, --(CH.sub.2).sub.pOH,
--(CH.sub.2).sub.pO-lower alkyl, -(CH.sub.2).sub.pO-lower alkenyl,
--O(CH.sub.2).sub.nR, --(CH.sub.2).sub.pSH,
--(CH.sub.2).sub.pS-lower alkyl, --(CH.sub.2).sub.pS-lower alkenyl,
--S(CH.sub.2).sub.nR, --(CH.sub.2).sub.pN(R).sub.2,
--(CH.sub.2).sub.pNR-lower alkyl, --(CH.sub.2).sub.pNR-lower
alkenyl, --NR.sub.8(CH.sub.2).sub.nR, or protected forms of the
above, and wherein p is 1-10; and
[0228] each occurrence of R.sub.4 is independently hydrogen or a
lower alkyl.
[0229] In certain embodiments, M, where it occurs in Tb is selected
from CH.sub.2, CHJ and CJ.sub.2, wherein J represents a halogen,
such as F, Cl, Br, or I, preferably F or Cl, even more preferably
F.
[0230] In certain embodiments, R.sub.6 is selected from lower
alkyl, hydrophilic groups, and lower alkyl substituted with
hydrophilic groups. Representative hydrophilic groups include
hydroxyl, sulfhydryl, amino, amido, carboxyl, sulfonate,
phosphonate, and salts thereof.
[0231] In certain embodiments of Formulas I-VI, Tb has the
structure xxxxii: 24
[0232] wherein A represents a group selected from
GPO.sub.3(R.sub.4).sub.2- , GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and
[0233] B represents a group selected from NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, and GSO.sub.3R.sub.4;
and G is absent or represents a linkage of one or two atoms, such
as CF.sub.2, CH.sub.2, O, S, NR, CH.sub.2S, CH.sub.2NR, CH.sub.2O,
etc. 25
[0234] In certain embodiments, the phenyl ring may bear one or more
additional R.sub.6 substituents. In certain embodiments, G is
absent, while in other embodiments, G is present. In certain
embodiments, at least one occurrence of G is absent. In certain
embodiments, Tb has a structure such as:
[0235] In certain embodiments of Formulas I-VI, Tb has the
structure xxxxiii: 26
[0236] wherein B is defined as above.
[0237] In certain embodiments, the pyridyl ring may bear one or
more additional R.sub.6 substituents.
[0238] In certain embodiments of Formulas I-VI, Tb has the
structure xxxxiv or xxxxv: 27
[0239] wherein C represents H, R.sub.6, NH.sub.2, OH,
GPO.sub.3(R.sub.4).sub.2, GCO.sub.2R.sub.4, or GSO.sub.3R.sub.4,
and in xxxxiv, any one occurrence of A or B is present, and the
other occurrences may represent a bond to Z, H, or R.sub.6 as
desired.
[0240] In certain embodiments, the pyridyl ring may bear one or
more additional R.sub.6 substituents.
[0241] In certain embodiments of Formulas I-VI, Tb represents a
heteroaryl, preferably a nitrogen-containing heteroaryl, bearing
one B substituent, preferably an A substituent, or two B
substituents, and optionally including one or more R.sub.6
substituents. In preferred embodiments, the heteroaryl group is
selected from thiazoline, oxazoline, pyrrole, pyrazole, imidazole,
pyridine, pyrazine, pyridazine, and pyrimidine, preferably
pyridine, pyrazole, pyrazine, and pyrimidine.
[0242] Solid Phase Synthesis and Combinatorial Libraries ofBone
Targeting Agents
[0243] The inventive compounds may be prepared by any available
method. Preferably, they are synthesized, for example using
solution phase or solid phase techniques. Often, solid-phase
syntheses will be modified versions of the compounds described
herein that allow their attachment to a solid support. Thus, the
present invention also contemplates particularly preferred because
it enables the use of more rapid split and pool techniques to
generate larger libraries (e.g., greater than 10,000 members) more
easily. It will be appreciated that solid phase parallel synthesis
techniques also can be utilized, such as those described in U.S.
Pat. Nos. 5,712,171 and 5,736,412, incorporated herein by
reference.
[0244] A solid support, for the purposes of this invention, is
defined as an insoluble material to which compounds are attached
during a synthesis sequence. The use of a solid support is
advantageous for the synthesis of libraries because the isolation
of support-bound reaction products can be accomplished simply by
washing away reagents from the support-bound material and therefore
the reaction can be driven to completion by the use of excess
reagents. Additionally, the use of a solid support also enables the
use of specific encoding techniques to "track" the identity of the
inventive compounds in the library. A solid support can be any
material which is an insoluble matrix and can have a rigid or
semi-rigid surface. Exemplary solid supports include, but are not
limited to, pellets, disks, capillaries, hollow fibers, needles,
pins, solid fibers, cellulose beads, pore-glass beads, silica gels,
polystyrene beads optionally cross-linked with divinylbenzene,
grafted co-poly beads, poly-acrylamide beads, latex beads,
dimethylacrylamnide beads optionally crosslinked with
N-N'-bis-acryloylethylenediamine, and glass particles coated with a
hydrophobic polymer. One of ordinary skill in the art will realize
that the choice of particular solid support will be limited by the
compatability of the support with the reaction chemistry being
utilized. In one particularly preferred embodiment, a Tentagel
amino resin, a composite of 1) a polystyrene bead crosslinked with
divinylbenzene and 2) PEG (polyethylene glycol), is employed for
use in the present invention. Tentagel is a particularly useful
solid support because it provides a versatile support for use in
on-bead or off-bead assays, and it also undergoes excellent
swelling in solvents ranging from toluene to water.
[0245] The compounds of the present invention may be attached
directly to the solid support or may be attached to the solid
support through a linking reagent. Direct attachment to the solid
support may be useful if it is desired not to detach the library
member from the solid support. For example, for direct on-bead
analysis of biological/pharmacological activitiy or analysis of the
compound structure, a stronger interaction between the library
member and the solid support may be desirable. Alternatively, the
use of a linking reagent may be useful if more facile cleavage of
the inventive library members from the solid support is
desired.
[0246] Furthermore, any linking reagent used in the present
invention may comprise a single linking molecule, or alternatively
may comprise a linking molecule and one or more spacer molecules. A
spacer molecule is particularly useful when the particular reaction
conditions require that the linking molecule be separated from the
library member, or if additional distance between the solid
support/linking unit and the library member is desired. In one
particularly preferred embodiment, photocleavable linkers are
employed to attach the solid phase resin to the component.
Photocleavable linkers are particularly advantageous for the
presently claimed invention because of the ability to use these
linkers in in vivo screening strategies. Once the inventive
compound is released from the solid support via photocleavage, the
compound is able to enter the cell. Exemplary photocleavable
linkers include, but are not limited to ortho-Nitrobenzyl
photolinkers and dithiane protected benzoin photolinkers. One of
ordinary skill in the art will readily appreciate that the method
of the present invention is not limited to the use of
photocleavable linkers; rather other linkers may be employed,
preferably those that are capable of delivering the desired
compounds in vivo.
[0247] In one embodiment of the present invention, the synthesis of
libraries of bone targeting agents is performed using established
combinatorial methods for solution phase, solid phase, or a
combination of solution phase and solid phase synthesis techniques.
The synthesis of combinatorial libraries is well known in the art
and has been reviewed ( see, e.g., "Combinatorial Chemistry",
Chemical and Engineering News, Feb. 24, 1997, p. 43; Thompson, L.
A., Ellman, J. A., Chem. Rev. 1996, 96, 555, incorporated herein by
reference.) One of ordinary skill in the art will realize that the
choice of method will depend upon the specific number of compounds
to be synthesized, the specific reaction chemistry, and the
availability of specific instrumentation, such as robotic
instrumentation for the preparation and analysis of the inventive
libraries. In particularly preferred embodiments, the reactions to
be performed on the inventive scaffolds to generate the libraries
are selected for their ability to proceed in high yield, and in a
stereoselective fashion, if applicable.
[0248] In one embodiment of the present invention, libraries are
generated using a solution phase technique. Traditional advantages
of solution phase techniques for the synthesis of combinatorial
libraries include the availability of a much wider range of organic
reactions, and the relative ease with which products can be
characterized.
[0249] In a preferred embodiment, for the generation of a solution
phase combinatorial library, a parallel synthesis technique is
utilized, in which all of the products are assembled separately in
their own reaction vessels. In a particularly preferred parallel
synthesis procedure, a microtitre plate containing n rows and m
columns of tiny wells which are capable of holding a few
milliliters of the solvent in which the reaction will occur, is
utilized. It is possible to then use n variants of reactant A, and
m variants of reactant B, to obtain n x m variants, in n x m wells.
One of ordinary skill in the art will realize that this particular
procedure is most useful when smaller libraries are desired, and
the specific wells can provide a ready means to identify the
library members in a particular well.
[0250] In another embodiment of the present invention, a solid
phase synthesis technique is utilized, in which the desired
scaffold structures are attached to the solid phase directly or
though a linking unit, as discussed above. Advantages of solid
phase techniques include the ability to more easily conduct
multi-step reactions and the ability to drive reactions to
completion because excess reagents can be utilized and the
unreacted reagent washed away. Perhaps one of the most significant
advantages of solid phase synthesis is the ability to use a
technique called "split and pool", in addition to the parallel
synthesis technique, develped by Furka. (Furka et al., Abstr. 14th
Int. Congr. Biochem., Prague, Czechoslovakia, 1988, 5, 47; Furka et
al., Int. J. Pept. Protein Res. 1991, 37, 487; Sebestyen et al.,
Bioorg. Med. Chem. Lett., 1993, 3, 413) In this technique, a
mixture of related compounds can be made in the same reaction
vessel, thus substantially reducing the number of containers
required for the synthesis of very large libraries, such as those
containing as many as or more than one million library members. As
an example, the solid support scaffolds can be divided into n
vessels, where n represents the number species of reagent A to be
reacted with the scaffold structures. After reaction, the contents
from n vessels are combined and then split into m vessels, where m
represents the number of species of reagent B to be reacted with
the scaffold structures. This procedure is repeated until the
desired number of reagents is reacted with the scaffold structures
to yield the inventive library.
[0251] The use of solid phase techniques in the present invention
may also include the use of a specific encoding technique. Specific
encoding techniques have been reviewed by Czarnik. (Czarnik, A. W.,
Current Opinion in Chemical Biology, 1997, 1, 60) As used in the
present invention, an encoding technique involves the use of a
particular "identifiying agent" attached to the solid support,
which enables the determination of the structure of a specific
library member without reference to its spatial coordinates. One of
ordinary skill in the art will also realize that if smaller solid
phase libraries are generated in specific reaction wells, such as
96 well plates, or on plastic pins, the reaction history of these
library members may also be identified by their spatial coordinates
in the particular plate, and thus are spatially encoded. It is most
preferred, however for large combinatorial libraries, to use an
alternative encoding technique to record the specific reaction
history.
[0252] Examples of alternative encoding techniques that can be
utilized in the present invention include, but are not limited to,
spatial encoding techniques, graphical encoding techniques,
including the "tea bag" method, chemical encoding methods, and
spectrophotometric encoding methods. Spatial encoding refers to
recording a reation's history based on its location. Graphical
encoding techniques involve the coding of each synthesis platform
to permit the generation of a relational database. Examples of
preferred spectrophotometic encoding methods include the use of
mass spectroscopy, fluorescence emission, and nuclear magnetic
resonance spectroscopy. In a preferred embodiment, chemical
encoding methods are utilized, which uses the structure of the
reaction product to code for its identity. Decoding using this
method can be performed on the solid phase or off of the solid
phase. One of ordinary skill in the art will realize that the
particular encoding method to be used in the present invention must
be selected based upon the number of library members desired, and
the reaction chemistry employed.
[0253] Subsequent characterization of the library members, or
individual compounds, can be performed using standard analytical
techniques, such as mass spectrometry, Nuclear Magnetic Resonance
Spectroscopy, and gas chromatrography.
[0254] Once specific libraries of compounds have been prepared,
specific assay techniques, such as those described herein, may be
utilized to test the ability of compounds to function as Src kinase
inhibitors. In certain preferred embodiments, high throughput assay
techniques are utilized.
[0255] Uses of Compounds of the Invention
[0256] As discussed above, the compounds of the present invention
are useful in the selective treatment or prevention of bone
disorders. These compounds or pharmaceutical compositions may
effect treatment via inhibition of osteoclast activity, promotion
of osteoblast activity, or promotion or inhibition of other
cellular events necessary for healthy bone metabolism. In certain
preferred embodiments, these compounds are useful for the treatment
or prevention of diseases and conditions associated with bone
metabolic disorders such as osteoclast overactivity. In still other
preferred embodiments, the compounds of the present invention are
targeted Src kinase inhibitors and thus inhibit bone resorption by
osteoclasts.
[0257] The present invention therefore provides a method for the
treatment, prophylaxis, and/or prevention of bone and other related
disorders which method comprises the administration of an effective
non-toxic amount of an inventive compound, or a pharmaceutically
composition thereof. As mentioned above, although the inventive
compounds effect treatment via several mechanisms, (i.e. inhibition
of osteoclast activity, promotion of osteoblast activity, or
regulation of other cellular events necessary for healthy bone
metabolism), in certain preferred embodiments, these compounds are
selective inhibitors of osteoclast activity.
[0258] In a further aspect, the present invention provides an
inhibitor of mammalian osteoclasts, for example any one of the
compounds of the present invention or a pharmaceutical composition
thereof. In still another aspect, the present invention provides
compounds or pharmaceutical compositions that are selective Src
kinase inhibitors. In particular, the method of present invention
comprises providing any one of the compounds of the present
invention or a pharmaceutically composition thereof, for use in the
treatment of and/or prophylaxis of osteoporosis and related
osteopenic diseases.
[0259] It will also be appreciated that, although many of the
compounds and compositions described herein comprise a bone
targeting moiety and a payload, the present invention also
contemplates the use of bone targeting agents alone for the
treatment of bone disorders, preferably by the selective inhibition
of osteoclast activity.
[0260] It will further be appreciated that, in addition to the
treatment or prevention of osteoporosis, particularly osteoporosis
associated with the peri and post menopausal conditions, the
present invention also contemplates the treatment and prophylaxis
or prevention of Paget's disease, hypercalcemia associated with
bone neoplasms and other types of osteoporotic diseases and related
disorders, including but not limited to involutional osteoporosis,
Type I or postmenopausal osteoporosis, Type II or senile
osteoporosis, juvenile osteoporosis, idiopathic osteoporosis,
endocrine abnormality, hyperthyroidism, hypogonadism, ovarian
agensis or Turner's syndrome, hyperadrenocorticism or Cushing's
syndrome, hyperparathyroidism, bone marrow abnormalities, multiple
myeloma and related disorders, systemic mastocytosis, disseminated
carcinoma, Gaucher's disease, connective tissue abnormalities,
osteogenesis imperfecta, homocystinuria, Ehlers-Danlos syndrome,
Marfan's syndrome, Menke's syndrome, immobilization or
weightlessness, Sudeck's atrophy, chronic obstructive pulmonary
disease, chronic heparin administration, and chronic ingestion of
anticonvulsant drugs
[0261] In addition to providing compounds for the selective
inhibition of Src tyrosine kinase (and thus the inhibition of
osteoclast activity), the present invention contemplates the use of
alternate payloads to achieve desired therapeutic effects. The
targeted constructs of the present invention may include any of a
wide variety of chemical entities to be delivered to the target
site or into target cells. Generally, the payloads may be
categorized as therapeutic agents (such as Src kinase inhibitors)
or imaging agents. Imaging agents comprise those payloads which are
detectable, e.g., by emitting light, radioactive emissions, or
chemical signals, by absorbing radiation (e.g., x-rays), or by
otherwise changing a characteristic of treated cells relative to
untreated cells. Therapeutic agents include payloads which are
biologically active, preferably by countering an abnormal condition
of the bone targeted site (e.g., tumor or infection).
[0262] A therapeutic agent useful in a targeted compound may be any
of a number of chemical entities, e.g., an enzyme, drug,
radionuclide, enzyme inhibitor, etc. For example, moieties useful
as therapeutic agents include inhibitors of osteoclast activity
such as Src kinase inhibitors, cathespin inhibitors, or proton pump
inhibitors, amino acids and their derivatives; analgesics such as
acetaminophen, aspirin, and ibuprofen; antifungal agents including:
allyamines, imidazoles, polyenes, and triazoles; antigens and
antibodies thereto; antihistamines such as chlorpheniramine and
brompheniramine; antihypertensive agents such as clonidine,
methyldopa, prazosin, verapamil, nifedipine, captopril, and
enalapril; antiinflammatory agents including non-steroidal agents,
such as aminoarylcarboxylic acid derivatives, arylacetic acid
derivatives, arylbutyric acid derivatives, arylcarboxylic acids,
arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic
acid derivatives thiazinecarboxamides and others, as well as
steroidal agents, such as glucocorticoids; antimicrobials such as
aminoglycosides, amphenicols, cinoxacin, ciprofloxacin,
2,4-diaminopyrimidines, .beta.-lactams (e.g., carbapenems,
cephalosporins, cephamycins, monobactams, oxacephems and
penicillins), lincosamides, macrolides, nitrofurans, norfloxacin,
peptides, polypeptides, and proteins (e.g., defensins, bacitracin,
polymyxin, cecropins, magainin II, indolicidin, ranalexin,
protegrins, gallinacins, tritrpticin, lactoferricin, drosomycin,
holotricin, thanatin, dermaseptin, iturins, syringomycins,
nikkomycins, polyoxins, FR-900403, echinocandins, pneumocandins,
aculeacins, mulundocandins, WF 11899, aureobasidins, schizotrin A,
cepacidines, zeamatin, cyclopeptides and D4e1), quinolones and
analogs, sulfonamides, sulfones, tetracyclines; apoproteins,
antivirals including: purines/pyrimidinones (e.g. acyclovir,
dideoxy -cytidine, -adenosine, or -inosine, interferons,
amantadine, ribavirin); beta-blockers such as propranolol,
metoprolol, atenolol, labetolol, timolol, penbutolol, and pindolol;
cancer drugs including chemotherapeutic agents; cardiovascular
agents including cardiac glycosides, antianginals and vasodilators;
coenzymes; enzymes; enzyme inhibitors; expectorants; glycoproteins;
H-2 antagonists such as nizatidine, cimetidine, famotidine, and
ranitidine; haptens and antibodies thereto; hormones, lipids,
liposomes; protein analogs in which at least one non-peptide
linkage replaces a peptide linkage; phospholipids; prostaglandins;
radionuclides (e.g. .sup.131I, .sup.186Re, .sup.188Re, .sup.90Y,
.sup.212Bi, .sup.211At, .sup.89Sr, .sup.166Ho, .sup.153Sm,
.sup.67Cu and .sup.64Cu); receptors and other membrane proteins;
retro-inverso oligopeptides; stimulants; toxins such as aflatoxin,
digoxin, rubratoxin, and xanthotoxin; tranquilizers such as
diazepam, chordiazepoxide, oxazepam, alprazolam, and triazolam; and
vitamins and mineral and nutritional additives. For other
therapeutic agents, see, e.g., the Merck Index. The present
invention contemplates agents that are useful for treating or
preventing the progression of a bone or other related disorder,
preferably by inhibiting osteoclast activity.
[0263] In an exemplary embodiment, the compounds and compositions
of the present invention are also inhibitors of cathepsin K, and
thus can be used to treat bone disorders. In particular, it has
been discovered that osteoclasts contain large quantities of
cathepsin K and it has been suggested that cathepsin K thus plays
an important role in bone resorption (Smith et al., Exp. Opin.
Ther. Patents 1999, 9, 683-694 and references cited therein). For
example, it has been reported that the enzyme is active over a pH
range (3.5-4.0) consistent with the pH of the local bone
environment during resorption, that a cathepsin K antisense
nucleotide was effective in the inhibition of osteoclast bone
resorption, and that there is a link between mutations in the human
cathepsin K gene and the rare skeletal dysplasia, pycnodysostosis,
a disease characterized by abnormal bone resorption (see, Smith et
al.). Thus compounds of the present that are cathepsin K inhibitors
would be useful as agents for the inhibition of bone resorption and
thus could be used to treat osteoporosis or other disorders
resulting from abnormal bone resorption.
[0264] Bone-targeted compounds can alternatively or additionally be
labeled with any of a variety of imaging agents which are known in
the art and which will depend to some extent on the means used to
detect or monitor the compound in vivo or in vitro. Preferred
imaging agents for performing positron emission tomography (PET)
and single photon emission computer tomography (SPECT) include
F-18, Tc-99m, and I-123. Preferred imaging agents for magnetic
resonance imaging (MRI) include an appropriate atom with unpaired
spin electrons or a free radical.
[0265] When the payload is intended to perform in an imaging
capacity, the payload comprises a moiety such as a radionuclide or
paramagnetic contrast agent, fluorescent or chemiluminescent label,
or other type of detectable marker. The imaging agents described
above may contain any label in accordance with the invention.
Highly specific and sensitive labels are provided by radionuclides,
which can then be detected using positron emission tomography (PET)
or Single Photon Emission Computed Tomography (SPECT) imaging. More
preferably, the imaging agent of the invention contains a
radionuclide selected from the group consisting of .sup.131I,
.sup.125I, .sup.123I, .sup.99mTc, .sup.18F, .sup.68Ga, .sup.67Ga,
.sup.72As, .sup.89Zr, .sup.64Cu, .sup.62Cu, .sup.111In, .sup.203Pb,
.sup.198Hg, .sup.11C, .sup.97Ru, and .sup.201Tl or a paramagnetic
contrast agent, such as gadolinium, cobalt, nickel, manganese, and
iron. As will be appreciated, these atoms may be directly
incorporated into the bone targeting moiety or the payload.
[0266] Therapeutic/Prophylactic Administration and Pharmceutical
Compositions
[0267] As discussed above, the compounds of the present invention
are useful in the treatment of bone disorders, preferably
imbalances in bone metabolism, such as overactivity of bone
resorption. In certain preferred embodiments, the compounds of the
present invention are useful as inhibitors of Src tyrosine
phosphorylation.
[0268] When the compounds of the present invention are used for
therapeutic and/or prophylactic administration, they can exist in
free form, or, where appropriate, in salt form. Pharmceutically
acceptable salts of many types of compounds and their preparation
are well-known to those of skill in the art. The pharmaceutically
acceptable salts of compounds of this invention include the
conventional non-toxic salts or the quaternary ammonium salts of
such compounds which are formed, for example, from inorganic or
organic acids of bases.
[0269] The compounds of the invention may form hydrates or
solvates. It is known to those of skill in the art that charged
compounds form hydrated species when lyophilized with water, or
form solvated species when concentrated in solution with an
appropriate organic solvent.
[0270] This invention relates to pharmaceutical compositions
comprising a therapeutically (or prophylactically) effective amount
of the compound, and a pharmaceutically acceptable carrier or
excipient. Carriers include, e.g., saline, buffered saline,
dextrose, water, glycerol, ethanol, and combinations thereof, and
are discussed in greater detail below. The composition, if desired,
can also contain minor amounts of wetting or emulsifying agents, or
pH buffering agents. The composition can be a liquid solution,
suspension, emulsion, tablet, pill, capsule, sustained release
formulation, or powder. The compsition can be formulated as a
suppository, with traditional binders and carriers such as
triglycerides. Oral formulation can include standard carriers such
as pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
Formulation may involve mixing, granulating and compressing or
dissolving the ingredients as appropriate to the desired
preparation.
[0271] The pharmaceutical carrier may be, for example, either a
solid or liquid.
[0272] Illustrative solid carriers include lactose, terra alba,
sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,
stearic acid and the like. A solid carrier can include one or more
substances which may also act as flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidannts, compression
aids, binders or tablet-disintegrating agents; it can also be an
encapsulating material. In powders the carrier is a finely divided
solid which is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is mixed with a
carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain up to 99% of the active
ingredient. Suitable solid carriers include, for example, calcium
phosphate, magnesium stearate, talc, sugars, lactose, dextrin,
starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl
cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange
resins.
[0273] Illustrative liquid carriers include syrup, peanut oil,
olive oil, water, et. Liquid carriers are used in preparing
solutions, suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved or suspended
in a pharmceutically acceptable oils or fats. The liquid carrier
can contain other suitable pharmaceutical additives such as
solubilizers, emulsifiers, buffers, preservatives, sweeteners,
flavoring aents, suspending agents, thickening agents, colors,
viscosity regulators, stabilizers or osmo-regulators. Suitable
examples of liquid carriers for oral and parenteral administration
include water (partially containing additives as above, e.g.
cellulose derivatives, preferably sodium carboxymethyl cellulose
solution), alcohols (including monohydric alcohols and polyhydric
alcohols, e.g. glycols) and their derivatives, and oils (e.g.
fractionated coconut oil and arachis oil). For parenteral
administration, the carrier can also be an oily ester such as ethyl
oleate and isopropyl myristate. Sterile liquid carders are useful
in sterile liquid form compositions for parenteral administration.
The liquid carrier for pressurized compositions can be halogenated
hydrocarbon or other pharmaceutically propellant. Liquid
pharmaceutical compositions which are sterile solutions or
suspensions can be utilized by, for example, intramuscular,
intraperitoneal or subcutaneous injection. Sterile solutions can
also be administered intravenously. The compound can also be
administered orally either in liquid or solid composition form.
[0274] The carrier or excipient may include time delay material
well known to the art, such as glyceryl monostearate or glyceryl
distearate along or with a wax, ethylcellulose,
hydroxypropylmethylcellulose, methylmethacrylate and the like. When
formulated for oral administration, 0.01% Tween 80 in PHOSAL PG-50
(phospholipid concentrate with 1,2-propylene glycol, A. Nattermann
& Cie. GmbH) has been recognized as providing an acceptable
oral formulation for other compounds, and may be adapted to
formulations for various compounds of this invention.
[0275] A wide variety of pharmaceutical forms can be employed. If a
solid carrier is used, the preparation can be tableted, placed in a
hard gelatin capsule in powder or pellet form or in the form of a
troche or lozenge. The amount of solid carrier will vary widely but
preferably will be from about 25 mg to about 1 g. If a liquid
carrier is used, the preparation will be in the form of a syrup,
emulsion, soft gelatin capsule, sterile injectible solution or
suspension in an ampule or vial or nonaqueous liquid
suspension.
[0276] To obtain a stable water soluble dosage form, a
pharmaceutically acceptable salt of the compound may be dissolved
in an aqueous solution or an organic or inorganic acid, such as a
0.3 M solution of succinic acid or citric acid. Alternatively,
acidic derivatives can be dissolved in suitable basic solutions. If
a soluble salt form is not available, the compound is dissolved in
a suitable cosolvent or combinations thereof. Examples of such
suitable cosolvents include, but are not limited to, alcohol,
propylene glycol, polyethylene glycol 300, polysorbate 80,
glycerin, polyoxyethylated fatty acids, fatty alcohols or glycerin
hydroxy fatty acids esters and the like in concentrations ranging
from 0-60% of the total volume.
[0277] Various delivery systems are know and can be used to
administer the compound, or the various formulations thereof,
including tablets, capsules, injectable solutions, encapsulation in
liposomes, microparticles, microcapsules, etc. Methods of
introduction include but are not limited to dermal, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, pulmonary, epidural, ocular and (as is usually
preferred) oral routes. The compound may be administered by any
convenient or otherwise appropriate route, for example by infusion
or bolus injection, by absorption through epithelial or
mucocutaneous linings (e.g. oral mucosa, rectal and intestinal
mucosa, etc.) and may be administered together with other
biologically active agents. Administration can be systemic or
local. For treatment or prophylaxis of nasal, bronchial or
pulmonary conditions, preferred routes are oral, nasal or via a
bronchial aerosol or nebulizer.
[0278] In certain embodiments, it may desirable to administer the
compound locally to an area in need of treatment; this may be
achieved by, for example, and not by way of limitation, local
infusion during surgery, topical application, by injection, by
means of a catheter, by means of a suppository, or by means of a
skin patch or implant, said implant being of a porous, non-porous,
or gelatinous material, including membranes, such as sialastic
membranes, or fibers.
[0279] In a specific embodiment, the composition is formulated in
accordance with routine procedures as a pharmaceutical composition
adapted for intravenous administration to human beings. Typically,
compositions for intravenous administration are solutions in
sterile isotonic aqueous buffer. Where necessary, the composition
may also include a solubilizing agent and a local anesthetic to
ease pain at the side of the injection. Generally, the ingredients
are supplied either separately or mixed together in unit dosage
form, for example, as a lyophilized powder or water free
concentrate in a hermetically sealed container such as an ampoule
or sachette indicating the quantitity of active agent. Where the
composition is to be administered by infusion, it can be dispensed
with an infusion bottle containing sterile pharmaceutical grade
water or saline. Where the composition is administered by
injection, an ampoule of sterile water for injection or saline can
be provided so that the ingredients may be mixed prior to
administration.
[0280] Administration to an individual of an effective amount of
the compound can also be accomplished topically by administering
the compound(s) directly to the affected area of the skin of the
individual. For this purpose, the compound is administered or
applied in a composition including a pharmacologically acceptable
carrier, such as a gel, an ointment, a lotion, or a cream, which
includes, without limitation, such carriers as water, glycerol,
alcohol, propylene glycol, fatty acids, triglycerides, fatty acid
esters, or mineral oils.
[0281] Other topical carriers include liquid petroleum, isopropyl
palmitate, polyethylene glycol, ethanol (95%), polyoxyethylene
monolaurate (5%) in water, or sodium lauryl sulfate (5%) in water.
Other materials such as anti-oxidants, humectants, viscosity
stabilizers, and similar agents may be added as necessary.
Percutaneous penetration enhancers such as Azone may also be
included.
[0282] In addition, in certain instances, it is expected that the
compound may be disposed witin devices placed upon, in, or under
the skin. Such devices include patches, implants, and injections
which release the compound into the skin, by either passive or
active release mechanisms.
[0283] Materials and methods for producing the various
formaulations are well known in the art and may be adapted for
practicing the subject invention. See e.g. U.S. Pat. Nos. 5,182,293
and 4,837,311 (tablets, capsules and other formulations as well as
intravenous formulations) and European Patent Application
Publication Nos. 0 649 659 (published Apr. 6, 1995; illustrative
formulation for IV administration) and 0 648 494 (published Apr.
19, 1995; illustrative formulation for oral administration).
[0284] The effective dose of the compound will typically be in the
range of about 0.01 to about 50 mg/kgs, preferably about 0.1 to
about 10 mg/kg of mammalian body weight, administered in single or
multiple doses. Generally, the compound may be administered to
patients in need of such treatment in a daily dose range of about 1
to about 2000 mg per patient.
[0285] The amount of compound which will be effective in the
treatment or prevention of a particular disorder or condition will
depend in part on the nature and severisty of the disorder or
condition, which can be determined by standard clinical techniques.
In addition, in vitro or in vivo assays may optionally be employed
to help identify optimal dose ranges. Effective doses may be
extrapolated from dose-response curves derived from in vitro or
animal model test systems. The precise dosage level should be
determined by the attending physician or other health care provider
and will depend upon well known factors, including route of
administration, and the age, body weight, sex and general health of
the individual; the nature, severity and clinical stage of the
disease; the use (or not) of concomitant therapies.
[0286] Treatment Kits
[0287] In other embodiments, the present invention relates to a kit
for conveniently and effectively carrying out the methods in
accordance with the present invention. In general, the
pharmaceutical pack or kit comprises one or more containers filled
with one or more of the ingredients of the pharmaceutical
compositions of the invention. Such kits are especially suited for
the delivery of solid oral forms such as tablets or capsules. Such
a kit preferably includes a number of unit dosages, and may also
include a card having the dosages oriented in the order of their
intended use. If desired, a memory aid can be provided, for example
in the form of numbers, letters, or other markings or with a
calendar insert, designating the days in the treatment schedule in
which the dosages can be administered. Alternatively, placebo
dosages, or calcium dietary supplements, either in a form similar
to or distinct from the bone targeted dosages, can be included to
provide a kit in which a dosage is taken every day. Optionally
associated with such container(s) can be a notice in the form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceutical products, which notice reflects approval
by the agency of manufacture, use or sale for human
administration.
Equivalents
[0288] The representative examples which follow are intended to
help illustrate the invention, and are not intended to, nor should
they be construed to, limit the scope of the invention. Indeed,
various modifications of the invention and many further embodiments
thereof, in addition to those shown and described herein, will
become apparent to those skilled in the art from the full contents
of this document, including the examples which follow and the
references to the scientific and patent literature cited herein. It
should further be appreciated that the contents of those cited
references are incorporated herein by reference to help illustrate
the state of the art.
[0289] The following examples contain important additional
information, exemplification and guidance which can be adapted to
the practice of this invention in its various embodiments and the
equivalents thereof.
[0290] Exemplification
[0291] The described phosphorus-containing moieties can be
synthesized according to the schemes outlined below:
[0292] A) Embodiments Wherein Tb is i
EXAMPLE 1
[0293] [(3 -Amino-propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid
diethvl ester 28
[0294] [(3-Benzyloxy-propyl)-ethoxy-phosphinoylmethyl]-phosphonic
acid diethyl ester
[0295] To an oven-dried flask was added 10.25 g (44.7 mmol) of
(3-Bromo-propoxymethyl)-benzene and 7.67 mL (44.7mmol) of triethyl
phosphite. The flask was fitted with a short-path distillation
head, for removal of bromoethane, and the mixture heated at
150.degree. C. for 4 h. The reaction was cooled to ambient
temperature, and then diluted with 120 mL of absolute ethanol and
1.8 N KOH (120 mL, 216 mol). The distillation head was replaced
with a reflux condenser and the solution heated at reflux for 5 h.
The reaction was cooled then concentrated in vacuo. The basic
aqueous layer was extracted with EtOAc (2.times.) and then
acidified to pH 3 with conc. HCl. The aqueous layer was extracted
with EtOAc (3.times.) and the combined extracts were dried over
MgSO.sub.4 and concentrated. The resulting crude product (8.24 g)
was used as is in the next reaction. .sup.31P NMR (300 MHz,
DMSO-d.sub.6) .delta. 34.113.
[0296] To a solution of the crude phosphonate (8.24 g, 32.5 mmol)
in 100 mL CH.sub.2Cl.sub.2, under an atmosphere of N.sub.2, was
added 10.8 mL (113.8 mmol) of oxalyl chloride. DMF (several drops)
was slowly added to initiate the reaction. After gas evolution had
ceased, the reaction was stirred for 30 min at ambient temperature.
Upon concentration in vacuo, the residue was titurated several
times with hexane, then dissolved in 167 mL of anhydrous THF. In a
separate flask, a cooled (-78.degree. C., under N.sub.2) solution
of diethyl methylphosphonate (10.25 mL, 69.9 mmol) in 337 mL of
anhydrous THF was added 2.5 M n-butyl lithium (27.95 mL, 69.9 mmol)
dropwise. The reaction mixture was stirred for 30 min at
-78.degree. C., at which time the in situ generated acid chloride
was added dropwise. The solution was stirred for an additional 2.5
h at -78.degree. C., quenched with 5 mL glacial acetic acid, and
then warmed to ambient temperature. Water was added to the reaction
mixture and the THF was removed in vacuo. The aqueous layer was
extracted with EtOAc (3.times.) and the combined organics washed
with saturated NaHCO.sub.3, brine, then dried over MgSO.sub.4 and
concentrated. The crude product was purified by silica gel
chromatography (eluted with 50:1 CH.sub.2Cl.sub.2/MeOH) affording
6.15 g of a yellow oil. .sup.31P NMR (300 MHz, DMSO-d.sub.6)
.delta. 51.479, 26.291.
[0297] [(3-Amino-propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid
diethyl ester
[0298] To a solution of
[(3-Benzyloxy-propyl)-ethoxy-phosphinoylmethyl]-ph- osphonic acid
diethyl ester (5.7 g, 14.5 mmol) in 100 mL of EtOH was added 1.2 g
of palladium on carbon. The mixture was flushed with H.sub.2 and
stirred at ambient temperature (H.sub.2 balloon) for 1 h. The
reaction mixture was filtered through Celite and the solvent
evaporated to provide 3.5 g of a pale yellow oil. .sup.31P NMR (300
MHz, DMSO-d.sub.6) d 52.219, 26.317.
[0299] To a cooled (0.degree. C., under N.sub.2) solution of the
crude alcohol (3.5 g, 14.5 mmol) in 53 mL of CH.sub.2Cl.sub.2 was
added 2.4 mL (17.4 mmol) of triethylamine followed by 1.25 mL (16
mmol) of methanesulfonyl chloride. The reaction mixture was warmed
to ambient temperature and stirred for 1 h. The reaction mixture
was then quenched with water and the layers separated. The organic
layer was washed with water and brine, dried over Na.sub.2SO.sub.4,
and concentrated. The crude orange-yellow oil (5.5 g) was used as
is in the next reaction. .sup.31P NMR (300 MHz, DMSO-d.sub.6)
.delta. 51.135, 26.614.
[0300] To a solution of the crude mesylate (5.5 g, 14.4 mmol) in 17
mL DMF was added 4.7 g (72.4 mmol) of sodium azide. The resulting
slurry was heated at 55.degree. C. and stirred overnight. The
reaction mixture was diluted with EtOAc and washed with water
(2.times.). The combined organics were then dried over
Na.sub.2SO.sub.4 and concentrated. The crude azide (2.61 g) was
used as is in the next reaction. .sup.31P NMR (300 MHz,
DMSO-d.sub.6) d 51.230, 26.183.
[0301] To a solution of the crude azide (2.61 g, 8 mmol) in 100 mL
of EtOH was added 0.8 g of palladium on carbon. The mixture was
flushed with H.sub.2 and stirred at ambient temperature (H.sub.2
balloon) for 16 h. The reaction mixture was filtered through Celite
and the solvent evaporated to provide 2.3 g of a yellow oil:
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.03 (m, 6H), 2.84-2.52
(m, 4H), 1.91-1.80 (m, 2H), 1.65-1.61 (m,2H), 1.23 (m,9H). .sup.31P
NMR (300 MHz, DMSO-d.sub.6) .delta. 51.757, 26.344.
EXAMPLE 2
[0302]
({3-[3-(4-Amino-3-p-tolyl-pyrazolo[3,4-d]pyrimidin-1-yl)-benzoylami-
no]-propyl}-hydroxy-phosphinoylmethyl)-phosphonic acid 29
[0303] The title compound was made as for example 16 (below) using
[(3-amino-propyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl
ester.
EXAMPLE 3
[0304] Synthesis of Phenyl-i Compounds
[0305] For the synthesis of these examples, one of two coupling
procedures can be used, either the coupling of sulfone 1/2 with the
aniline or the coupling of amine 3/4 with the aryl bromide. 30
[0306] Synthesis of Aniline 6
[0307] (a) A mixture of diethyl (ethoxyphosphinyl)methylphosphonate
(2.35 g, 9.62 mmol), Et.sub.3N (3.8 mL, 27.5 mmol),
1-iodo-4-nitrobenzene (2.28 g, 9.17 mmol) and Pd(PPh.sub.3).sub.4
(265 mg, 0.229 mmol) in CH.sub.3CN (14 mL) under N.sub.2 was
stirred at 80.degree. C. for 2.5 h. After cooling to rt, the
reaction mixture was poured into 50 mL of 1 N aq HCl and extracted
with CH.sub.2Cl.sub.2. The extract was washed with H.sub.2O (50 mL)
and brine (50 mL). The aqueous washes were reextracted once with
CH.sub.2Cl.sub.2, and the combined extracts were dried over
Na.sub.2SO.sub.4 and concentrated. The crude material was purified
by flash chromatography on silica gel. Elution with 30:1
CHCl.sub.3-MeOH followed by 20:1 CHCl.sub.3-MeOH and finally 15:1
CHCl.sub.3-MeOH afforded 3.28 g (98%) of the desired
(arylphosphinylmethyl)phosphonate.
[0308] (b) A mixture of the nitroarene (940 mg, 2.57 mmol) and
SnCl.sub.2.multidot.2H.sub.2O (2.9 g, 12.9 mmol) in EtOH (.about.10
mL) was stirred at 70.degree. C. for 44 min and then concentrated
at rt. The residue was taken up in CH.sub.2Cl.sub.2 and washed with
half saturated aq NaHCO.sub.3 (40 mL), H.sub.2O (40 mL) and brine
(40 mL). The aqueous washes were reextracted once with
CH.sub.2Cl.sub.2, and the combined extracts were dried over
K.sub.2CO.sub.3 and concentrated. The crude material was purified
by flash chromatography on silica gel. Elution with 20:1
CHCl.sub.3-MeOH followed by 15:1 CHCl.sub.3-MeOH afforded 657 mg
(76%) of aniline 6. 31
[0309] (a) A mixture of aniline 6 (1.89 g, 5.65 mmol) and sulfone 1
(866 mg, 2.25 mmol) in 2-methoxyethyl ether (3 mL) was stirred at
150.degree. C. for 6 h. The reaction mixture was allowed to cool to
rt. It was then diluted with a small amount of CHCl.sub.3 and
purified by flash chromatography on silica gel. Elution with 30:1
CHCl.sub.3-MeOH, 20:1 1 CHCl.sub.3-MeOH, and 15:1 1 CHCl.sub.3-MeOH
afforded material that was still very impure. The chromatography
was repeated using the same eluants to provide material that was
still fairly impure. This material was then purified by reversed
phase HPLC using water-acetonitrile (+0.1% TFA). The fractions
containing product were collected and concentrated to a small
volume (.about.20 mL). The residue was then partitioned between
CH.sub.2Cl.sub.2 and saturated aqueous NaHCO.sub.3. The layers were
separated, and the aqueous layer was reextracted twice with
CH.sub.2Cl.sub.2. The combined extracts were dried over
K.sub.2CO.sub.3 and concentrated to 429 mg (30%) of pure coupled
product.
[0310] (b) To a solution of the coupled product (420 mg, 0.657
mmol) in 10 mL of CH.sub.3CN at -10.degree. C. was added TMSI (1.40
mL, 9.85 mmol). The reaction mixture was stirred at -10.degree. C.
for 15 min. and at rt for 75 min. The reaction mixture was then
diluted with saturated aqueous NaHCO.sub.3 (.about.13 mL), a few
drops of aqueous NaHSO.sub.3 and H.sub.2O (.about.2 mL). The
mixture was further diluted with a small amount of DMF and then
purified by reversed phase HPLC using water-acetonitrile (+0.1%
TFA). The fractions containing product were then lyophilized to
afford pure i-A. 32
[0311] Synthesis of Aryl Bromide 8
[0312] A mixture of diethyl (ethoxyphosphinyl)methylphosphonate
(1.85 g, 7.58 mmol), 1-bromo-4-iodobenzene (1.95 g, 6.89 mmol), NMM
(1.51 mL, 13.8 mmol) and Pd(PPh.sub.3).sub.4 (199 mg, 0.172 mmol)
in CH.sub.3CN was stirred at 100.degree. C. overnight. After
cooling to rt, the reaction mixture was concentrated. The residue
was then partitioned between 1 N aq HCl and CH.sub.2Cl.sub.2. The
layers were separated, and the organic layer was washed with
H.sub.2O and brine. The aqueous washes were reextracted once with
CH.sub.2Cl.sub.2, and the combined extracts were dried over
Na.sub.2SO.sub.4 and concentrated. The crude material was purified
by flash chromatography on silica gel. Elution with 30:1
CHCl.sub.3-MeOH followed by 20:1 CHCl.sub.3-MeOH and finally 15:1
CHCl.sub.3-MeOH afforded 1.52 g (55%) of aryl bromide 8
contaminated with a trace amount of Ph.sub.3PO. 33
[0313] (a) Into a glass pressure tube containing sulfone 2 (235 mg,
0.684 mmol) at -78.degree. C. was condensed NH.sub.3 (.about.2 mL).
The tube was capped and allowed to warm to rt. The reaction mixture
was allowed to stir at rt overnight, and then the NH.sub.3 was
allowed to evaporate. The residue was purified by flash
chromatography on silica gel. Elution with 40:1 CHCl.sub.3-MeOH
afforded 193 mg (quant) of amine 4.
[0314] (b) A mixture of amine 4 (176 mg, 0.628 mmol), aryl bromide
8 (301 mg, 0.753 mmol), powdered Cs.sub.2CO.sub.3 (368 mg, 1.13
mmol), BINAP (59 mg, 0.0942 mmol) and Pd(OAc).sub.2 (14 mg,
0.0.0628) in toluene (3.5 mL) was stirred at 100.degree. C.
overnight. After cooling, the reaction mixture was partitioned
between CH.sub.2Cl.sub.2 and 1 N aq HCl. The layers were separated,
and the organic layer was washed with H.sub.2O and brine. The
aqueous washes were reextracted once with CH.sub.2Cl.sub.2, and the
combined extracts were dried over Na.sub.2SO.sub.4 and
concentrated. The crude material was purified by flash
chromatography on silica gel. Elution with 30:1 CHCl.sub.3-MeOH
followed by 20:1 CHCl.sub.3-MeOH and finally 15:1 CHCl.sub.3-MeOH
afforded 231 mg (62%) of the desired coupled product.
[0315] (c) The coupled product was then converted to i-B in the
same fashion as previously described (i-A, (b)). 34
[0316] Synthesis of Aniline 7
[0317] (a) The intermediate (arylphosphinyl)methylphosphonate was
prepared from N-(t-butylcarbonyl)-3-iodoaniline in a manner
analogous to that described for the synthesis of aryl bromide
8.
[0318] (b) The intermediate carbamate was converted to aniline 7 in
a manner analogous to that described for 5 (f). 35
[0319] (a) Aniline 7 was condensed with sulfone 1 in a manner
analogous to the condensation of aniline 6 with sulfone 1 (i-A,
(a)).
[0320] (b) The coupled product was then converted to i-C in the
same fashion as previously described (i-A, (b)).
[0321] B) Embodiments Wherein Tb is vi
[0322] A bone-targeting group vi was synthesized according to the
following scheme: 36
[0323] Diethyl (4-(N-trifluoroacetyl amino benzyl) phosphonate
2
[0324] To diethyl (4-aminobenzyl)phosphonate (10 g) in anhydrous
dichloromethane (100 mL) was added pyridine (4.0 mL) followed by
trifluoroacetic anhydride (7.0 mL) and stirred at rt overnight
(.about.18 hrs). Reaction mixture was washed carefully with a
saturated solution of aqueous sodium bicarbonate (10 mL), brine (10
mL) and the dichloromethane was dried (Na.sub.2SO.sub.4) to afford
product 2 (93%). MS: 338 (M-1) 37
[0325] Diethyl (4-(N-trifuoroacetylamino)-.alpha.-bromobenzyl)
phosphonate 3
[0326] To the above compound 2 (9.75 g, 41.13 mmols) in anhydrous
carbon tetrachloride (100 mL) was added NBS (1.6 g , 41.13 mmols)
and heated to reflux under intense visible light with stirring
under which time a white precipitate formed. The reaction was
cooled to rt and then filtered. The filtrate was half concentrated
then left in the freezer overnight to crystallize. The crystalline
product 3 was seperated by filtration (7.2 g, 60%). MS: 416, 418
(M-1 Br.sup.79Br.sup.80). 38
[0327]
1-(Bis-diethylphosphonomethylene-4-(N-trifluoroacetylamino)benzene
4
[0328] To compound 3 (7.2 g, 17.22 mmols) in anhydrous THF (50 mL)
was added triethylphosphite (0.82 mL, 17mmol) and stirred under
reflux for 4 h. Reaction mixture was cooled to rt and concentrated.
Residue was taken up in boiling ethyl ether and cooled to rt. Solid
was filtered off to afford 6.0 g product (73%). Pale pink solid.
MS: 476 (M+H), 475 (M-H). 39
[0329] 1-(Bis-diethylphosphonomethylene)-4-aminobenzene 1
[0330] The above N-trifluoroacetate salt 4 (1.2 g, 2.52 mmols) in
NaOH solution (0.1 N, 10 mL) was heated to 60.degree. C. for 5 h.
The reaction mixture was cooled to rt, and extracted with methylene
chloride. Combined organic layers were dried over sodium sulfate
and concentrated to afford the product 1 (0.85 g, 97%). MS: 412
(M+23).
EXAMPLE 4
[0331]
({14-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-p-
yrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-phosphono-methyl)-phosphonic
acid 40
[0332] a) (4-Bromo-benzyl)-phosphonic acid diethyl ester 41
[0333] A mixture of triethylphosphite (25 mL, 14.6 mmol) and
4-bromobenzylbromide (2.50 g, 10.0 mmol) was heated to 130.degree.
C. and allowed to stir for 5 h. The solution was cooled to rt and
chromatographed over silica gel (EtOAc:hexanes, stepwise gradient
1:1 to 100% EtOAc) to give 3.21 g (>100%) of a yellowish oil.
Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 307
(M+H).
[0334] b)
[(4-Bromo-phenyl)-(diethoxy-phosphoryl)-methyl]-phosphonic acid
diethyl ester 42
[0335] To a cooled (-50.degree. C.) solution of
(4-bromo-benzyl)-phosphoni- c acid diethyl ester (3.21 g, 10.4
mmol) in THF (25 mL) was added a 1M solution of lithium
hexamethyldisilylazide in THF (25 mL) over 3 min.
Diethylchlorophosphate (2.9 mL, 20 mmol) was added and the mixture
was allowed to stir at 50.degree. C. After 0.5 h, satd NH.sub.4Cl
was added and the mixture diluted with EtOAc and H.sub.2O. The
aqueous layer was extracted with fresh EtOAc and the combined
organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was chromatographed
over silica gel (CHCl.sub.3:MeOH, stepwise gradient 99:1 to 96:4)
to give 1.35 g (29%) of a colorless oil. Electrospray Mass Spectrum
(50/50 acetonitrile/water) m/z 441 (M-H).
[0336] c)
[{4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-(diethoxy-phosphoryl)-methyl]-p-
hosphonic acid diethyl ester 43
[0337] (4-Bromopyridin-2-yl)-phosphonic acid diethyl ester (64 mg,
0.22 mmol),
2-amino-6-(2,6-dichlorophenyl)pyrido-8-methyl-8H-pyrido[2,3-d]pyri-
midin-7-one (60 mg, 0.19 mmol), palladium acetate (3.6 mg, 0.0.016
mmol), [(4-Bromo-phenyl)-(diethoxy-phosphoryl)-methyl]-phosphonic
acid diethyl ester (100 mg, 0.23 mmol), (S)-BINAP (18 mg, 0.029
mmol) and cesium carbonate (91 mg, 0.28 mmol) were placed in
toluene (1 mL), flushed with argon, sealed and heated to
100.degree. C.. After 45 h, the reaction was allowed to cool to rt
and diluted with H.sub.2O. The mixture was extracted twice with
EtOAc and the combined organic extracts washed with brine and dried
over Na.sub.2SO.sub.4. The solution was concentrated and
chromatographed over silica gel (CHCl.sub.3:MeOH, stepwise gradient
99:1 to 95:5) to give 44 mg (41%) of a yellow solid. Electrospray
Mass Spectrum (50/50 acetonitrile/water) mn/z 681 (M-H).
[0338] d)
({4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl}-phosphono-methyl)-phosphonic
acid 44
[0339] To a cooled solution (0.degree. C.)
[{4-[6-(2,6-Dichloro-phenyl)-8--
methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-phenyl-
}-(diethoxy-phosphoryl)-methyl]-phosphonic acid diethyl ester (44
mg, 0.77 mmol) in MeCN (1.2 mL) was added iodotrimethylsilane (0.3
mL). After 5 h, the reaction was quenched with sodium hydroxide (1
N) and satd sodium thiosulfate. The mixture was filtered and the
filtrate chromatographed using reversed-phase HPLC to give 5 mg
(11%) of a yellow solid after lyophilization. Electrospray Mass
Spectrum (50/50 acetonitrile/water) m/z 571 (M+H).
[0340] C) Embodiments Wherein Tb is ix
EXAMPLE 5
[0341] Synthesis of analogs of
5-(3-methoxyphenyl)-7-[4-(2-hydroxyethylphe-
nyl)-4-aminopyrrolo[2,3-d]-pyrimidine 8 and
5-(3-hydroxyphenyl)-7-[4-(2-hy-
droxyethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine 12
[0342] The 8-series and 12-series of compounds were synthesized
according to Scheme 3 & Scheme 4. Compounds 9, 10, 11 were
synthesized following Scheme 3. Compounds 13 and 14 were sythesized
following Scheme 4. Essentially the synthesis consists of
phosphorylation of the primary alcohol 12 in Scheme 3 (described in
Method A) and demethylation of the methyl ether (described in
Method B) followed by phosphorylation in Scheme 4. 45 46
[0343] Method A
[0344] To the alcohol (1 mmol ) in trimethylphosphate (1 mL) under
anhydrous condition was added the bis-phosphonomethylene dichloride
(4 mmol) at 0.degree. C. and stirred at this temp. for 16 h. The
reaction mixture was then quenched with ammonium hydroxide and
washed with ether. The aqueous layer was purified by preparative
HPLC. 47
[0345]
5-(3-methoxyphenyl)-7-{4-[2-O-(triethylbisphosphonomethylene)ethyl]-
phenyl)}-4-amino pyrrolo[2,3-d]-pyrimidine 9
[0346] This was prepared from 8A. Purified by HPLC as a white
solid. MS: 517 (M-H), 518 (M+H). 48
[0347]
5-(3-methoxyphenyl)-7-{4-[2-O-(triethylbisphosphonomethylene)ethyl]-
phenyl}-4-(N,N-dimethylamino pyrrolo[2,3-d]pyrimidine 10
[0348] This was prepared from 8B. Purified by HPLC as a white
solid. MS: 545 (M-H), 547 (M+H). 49
[0349]
5-(3-methoxyphenyl)-7-{4-N-{N'-methyl-[(N'-2'-(O-(triethylbis
phosphonomethylene)
ethyl}aminoethylphenyl)-4-(amino-pyrrolo[2,3-d]-pyrim- idine 11
[0350] This was prepared from 8C. Purified by HPLC as a white
solid. MS: 574 (M-H), 576 (M+H).
[0351] Method B
[0352] To 1 mmol of methyl ether (8A, 8B & 8C) in methylene
chloride (5 mL) was added boron tribromide in methylene chloride (1
M solution, 10 mmol) at 20.degree. C. and after stirring at this
temperature for 3 h, reaction was quenched with methanol (5 mL) and
concentrated. Compounds were purified by HPLC. 50
[0353]
5-(3-Hydroxyphenyl)-7-{4-[2-O-ethylphenyl)-4-aminopyrrolo[2,3-d]pyr-
imidine 12A
[0354] Prepared from 8A following Method B. Off-white solid. MS:
345 (M-1), 347 (M+H). 51
[0355]
5-(3-Hydroxyphenyl)-7-{4-(2-N-(N'-methyl-N'-2'-hydroxyethyl)-aminoe-
thylphenyl)-4-amino-pyrrolo[2,3-d]pyrimidine 12B
[0356] Prepared from 8B using Method B. Off-white solid. MS: 402
(M-H), 404 (M+H). 52
[0357] 5-(3-Hydroxyphenyl)-7-{4-(2-N-(4'-hydroxypiperidinyl)
aminoethylphenyl)-4-amino-pyrrolo[2,3-d]pyrimidine 12C
[0358] Prepared from 8C using Method B. Off-white solid. MS: 428
(M-H), 430 (M+H) 53
[0359]
5-(3-Hydroxyphenyl)-7-{4-[2-O-(triethylbisphosphonomethylene)ethylp-
henyl)-4-aminopyrrolo[2,3-d]-pyrimidine 13
[0360] Prepared from 12A using Method A. White solid. MS: 503
(M-H), 505 (M+H). 54
[0361]
5-(3-Hydroxyphenyl)-7-{4-N-{N'-methyl-[(N'-2'-(O-(triethylbisphosph-
onomethylene) ethyl)
aminoethylphenyl)-4-amino-pyrrolo[2,3-d]-pyrimidine 14
[0362] Prepared from 12B using Method A. White solid. MS: 560
(M-H), 562 (M+H).
[0363] Scheme 5 describes the synthesis of compound 15 starting
from 5-iodopyrrolo-pyrimidine (J. Med. Chem., 1990). 55
[0364] 4-Chloro-5-iodo-7-isopropyl-pyrrolo[2,3-d]pyrimidine 16
[0365] To a solution of
4-chloro-5-iodo-7-H-pyrrolo[2,3-d]-pyrimidine (484 mg, 1.729 mmol)
in DMF (5 mL) at 0.degree. C. was added sodium hydride (138.4 mg,
60% emulsion, 3.46 mmol). After 30 min at rt., 2-iodopropane (518
.mu.L, 5.19 mmol) was added and the mixture was allowed to stir at
rt for 3 h. DMF was poured into water and the aqueous later was
extracted with ethyl acetate (3.times.30 mL). The organic layer was
washed with water (5 mL), dried (sodium sulfate) and concentrated
to give a pale yellow solid (520 mg, quantitative). MS: 301 (M-H).
56
[0366] 4-Chloro-5-(3-hydroxymethyl
phenyl)-7-isopropyl-pyrrolo[2,3-d]-pyri- midine 17
[0367] A. To a solution of
4-chloro-5-iodo-7-isopropyl-pyrrolo[2,3-d]-pyri- midine (522 mg,
1.729 mmol) and 3-formylphenylboronic acid (285 mg, 1.902 mmol) in
DMF 13.5 mL) was added tetrakis triphenylphosphine palladium(0)
(95.58 mg, 0.0865 mmol, 5%) strictly in an argon atmosphere
followed by a solution of sodiumbicarbonate (2 M, 1.73 mL) and this
mix was heated to 80.degree. C. for 18 h. The reaction was
monitored by HPLC. It was diluted with water and extracted with
ethyl acetate (50 mL, .times.3). Ethyl acetate layer was washed
(water), dried (sodium sulfate) and concentrated and the resulting
gum was purified by column chromatography on silica gel using
hexane/ethyl acetate to give 306 mg (63%) of pale yellow gum.
MS:298 (M-H), 300 (M+H).
[0368] B. To a solution of the above aldehyde (300 mg, 1.008 mmol)
in methanol (20 mL) was added sodium borohydride (45 mg, 1.296
mmol) and the reaction was monitored by HPLC. After 1 h methanol
was removed in vacuo. To the residue was added water (10 mL) and
the aqueous layer was extracted in ethyl acetate. Ethyl acetate was
dried (sodium sulfate) and concentrated to give a white solid 17
which was used as such in the next step. MS: 300 (M-H), 302 (M+H).
57
[0369] 4-Amino-5- (3-hydroxymethyl
phenyl)-7-isopropyl-pyrrolo[2,3-d]pyrim- idine 18
[0370] To the above chloro compound (281 mg, 0.931 mmol) in dioxane
(10 mL) was added ammonium hydroxide (10 mL) and sealed and heated
at 120.degree. C. for 2 days. The solvent was concentrated to give
a white solid (200 mg) which was clean enough to take it to the
next step. MS : 281 (M-H), 282 (M+H). 58
[0371] 4-Amino-5-[(3-O-bisphosphonomethylene
methyl)]phenyl-7-isopropyl-py- rrolo[2,3-d]-pyrimidine 15
[0372] Prepared from 18 using Method A as a white solid. MS: 439
(M-H), 441 (M+H).
EXAMPLE 6
[0373]
({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-ethox-
y}-hydroxy-phosphorylmethyl)-phosphonic acid 59
[0374] 6-Chloro-2-fluoro-9H-purine
[0375] A 0.3 M aqueous solution of NaNO.sub.2 (200 mL, 60 mmol) was
added dropwise to a cooled (-15.degree. C.), vigorously stirred
suspension of 2-amino-6-chloro-9H-purine (6.0 g, 35.4 mmol) in 120
mL HBF.sub.4 (48 w % in H.sub.2O, 0.92 mol) over 75 min. The pale
yellow reaction was stirred at r. t. for 20 min and then recooled
to -15.degree. C. and neutralized to PH=6.0 with aqueous NaOH (50 w
% in H.sub.2O). The water was removed in vacuo and the resulting
orange solid chromatographed on silica gel (90:10 CH.sub.2Cl.sub.2:
MeOH, Rf 0.50). The final product was obtained as white solid (3.0
g, 49.1%).
[0376] 6-Chloro-2-fluoro-9-isopropyl-9H-purine
[0377] 6-Chloro-2-fluoro-9H-purine (517.7 mg, 3 mmol), 2-propanol
(198.3 mg, 3.3 mmol), PPh.sub.3 (866 mg, 3.3 mmol) was mixed under
N.sub.2 in a 50 mL round-bottom flask at 0.degree. C. DEAD (575 mg,
3.3 mmol) was added via syringe dropwise to the mixture. The
temperature was raised to r. t. and the mixture was stirred
overnight. Sovent was removed in vacuo and the resulting residue
was chromatographed on silica gel (CH.sub.2Cl.sub.2/EtOAc, 4:1, Rf
0.62). The product was obtained as a white solid (411 mg, 64%).
[0378]
(3-Chlorophenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl)amine
[0379] 6-Chloro-2-fluoro-9-isopropyl-9H-purine (214 mg, 1 mmol) was
mixed with 3-chloroaniline (127.6 mg, 1 mmol) in 12 mL n-BuOH. DIEA
(357.6 mg, 2.8 mmol) was added and the solution was heated at
90.degree. C. overnight. Solvent was removed in vacuo and the
residue was chromatographed on silica gel (CH.sub.2Cl.sub.2/EtOAc
2:2, Rf 0.44) to get the product as a white solid (148 mg,
48%).
[0380]
2-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)ethanol
[0381] (3-Chlorophenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl)amine
(92 mg, 0.3 mmol) and ethanolamine (92 mg, 1.5 mmol) was mixed in 5
mL nBuOH/DMSO (4/1 v/v) and heated at 120.degree. C. overnight.
Solvent was removed in vacuo. The residue was chromatographed on
silica gel (EtOAc, Rf 0.45) to get the product as a greenish solid
(24 mg, 90%).
[0382]
({2-[6-(3-Chloro-phenylamino)9-isopropyl-9H-purin-2-ylamino]-ethoxy-
}-hydroxy-phosphorylmethyl)-phosphonic acid
[0383]
2-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)ethanol
(180 mg, 0.52 mmol) was dissolved in 3 mL trimethyl phosphate at
0.degree. C. Methylenebis(phosphonic dichloride) (514 mg, 2.1 mmol)
was added in one portion and the reaction was stirred at 0.degree.
C. for 16 hrs. The solution was neutralized with 5 N ammonia to PH
6.0. The resulting mixture was purified by RP HPLC. Lyophilization
left a white solid (147 mg, 56%).
EXAMPLE 7
[0384]
({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-3-met-
hyl-butoxy}-hydroxy-phosphorylmethyl-phosphonic acid 60
[0385] (a)
2-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)-3-met-
hyl-butan-1-ol
[0386] The title compound was synthesized in a manner similar to
that described in example 6 (d). ES-MS: m/z 388 (M-H).
[0387] (b)
({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-3-
-methyl-butoxy}-hydroxy-phosphorylmethyl)-phosphonic acid
[0388] The title compound was synthesized in a manner similar to
that described in example 6 (e). ES-MS: m/z 546 (M-H).
EXAMPLE 8
[0389]
({3-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-propo-
xy}-hydroxy-phosphorylmethyl)-phosphonic acid 61
[0390] (a)
3-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)-prona-
nol
[0391] The title compound was synthesized in a manner similar to
that described in example 6 (d). ES-MS: m/z 360 (M-H).
[0392] (b)
({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-p-
ropoxy}-hydroxy-phosphorylmethyl)-phosphonic acid
[0393] The title compound was synthesized in a manner similar to
that described in example 6 (e). ES-MS: m/z 518 (M-H).
EXAMPLE 9
[0394]
({4-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-butox-
y}-hydroxy-phosphorylmethyl)-phosphonic acid 62
[0395] (a)
4-(6-(3-chlorophenylamino-9-isopropyl-9H-purin-2-ylamino)-butan-
ol
[0396] The title compound was synthesized in a manner similar to
that described in example 6 (d). ES-MS: m/z 374 (M-H).
[0397] (b)
({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-b-
utoxy}-hydroxy-phosphorylmethyl)-phosphonic acid
[0398] The title compound was synthesized in a manner similar to
that described in example 6 (e). ES-MS: m/z 532 (M-H).
EXAMPLE 10
[0399]
({2-[6-(3-Chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-3-met-
hyl-butoxy}-hydroxy-phosphorylmethyl)-phosphonic acid 63
[0400] (a)
(3-Chloro-phenyl)-(2-fluoro-9-isopropyl-9H-purin-6-yl)-methyl-a-
mine
[0401] The title compound was synthesized in a manner similar to
that described in example 6 (c). ES-MS: m/z 319 (M-H).
[0402] (b)
2-{6-[(3-chloro-phenyl)-methyl-amino]-9-isopropyl-9H-purin-2-yl-
amino}-3-methyl-butan-1-ol
[0403] The title compound was synthesized in a manner similar to
that described in example 6 (d). ES-MS: m/z 402 (M-H).
[0404] (c)
[(2-{6-[(3-Chloro-phenyl)-methyl-amino]-9-isopropyl-9H-purin-2--
ylamino}-3-methyl-butoxy)-hydroxy-phosphorylmethyl-phosphonic
acid
[0405] The title compound was synthesized in a manner similar to
that described in example 6 (e). ES-MS: m/z 560 (M-H).
EXAMPLE 11
[0406]
({2-[6-(3-Chloro-phenylamino)-9-methyl-9H-purin-2-ylamino]-3-methyl-
-butoxy}-hydroxy-phosphorylmethyl)-phosphonic acid 64
[0407] (a) 6-Chloro-2-fluoro-9-methyl-9H-purine
[0408] The title compound was synthesized in a manner similar to
that described in example 6 (b). ES-MS: m/z 186 (M-H).
[0409] (b) (3-Chloro-phenyl)-(2-fluoro-9-methyl-9H-purin-6-yl)
-amine
[0410] The title compound was synthesized in a manner similar to
that described in example 6 (c). ES-MS: m/z 276 (M-H).
[0411] (c)
2-[6-(3-chloro-phenylamino)-9-isopropyl-9H-purin-2-ylamino]-3-m-
ethyl-butan-1-ol
[0412] The title compound was synthesized in a manner similar to
that described in example 6 (d). ES-MS: m/z 360 (M-H).
[0413] (d)
[{2-[6-(3-Chloro-phenylamino)-9-methyl-9H-purin-2-ylamino]-3-me-
thyl-butoxy}-hydroxy-phosphorylmethyl)-phosphonic acid
[0414] The title compound was synthesized in a manner similar to
that described in example 6 (e). ES-MS: m/z 518 (M-H).
EXAMPLE 12
[0415]
{[4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydrofura-
n-2-ylmethoxyl]-hydroxy-phosphorylmethyl}phosphonic acid 65
[0416] (a)
7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine
[0417] To 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.26 g, 4.5
mmol) in 45 mL dry THF was added NaH (217 mg, 9.0 mmol). The
mixture was stirred at r. t. for 1 hr. PhSO.sub.2Cl (875 mg, 5.0
mmol) was added via syringe dropwise. Stirring was continued for
another 2 hrs. Solvent was removed in vacuo. The residue was
diluted with ice-H.sub.2O and then neutralized with saturated
NH.sub.4Cl 13.5 mL. The mixture was extracted with CH.sub.2Cl.sub.2
(2.times.60 mL). The combined organic layer was washed with brine
and dried over MgSO.sub.4. Solvent was removed in vacuo and residue
was chromatographed on silica gel (CH.sub.2Cl.sub.2, Rf 0.44 ). The
product was obtained as a white solid (1.12 g, 59%).
[0418] (b)
7-Benzenesulfonyl-4-chloro-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidin-
e
[0419]
7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.12
g, 2.67 mmol), 4-methylbenzeneboronic acid (373 mg, 2.74 mmol) and
NaHCO.sub.3 (693 mg, 8.25 mmol) was mixed with EtOH (6 mL ),
toluene (43 mL ) and H2O (12 mL ). The mixture was bubbled with Ar
for 1 hour before Pd(PPh.sub.3).sub.2Cl.sub.2 (189 mg, 0.27 mmol)
was added. The reaction mixture was heated at 95.degree. C.
overnight. After cooling to r. t., the reaction mixture was
filtered through a pad of Celite. The filtrate was partitioned
between EtOAc and water, organic layer was separated, dried and
concentrated. Residue was chromatographed on silica gel (3/1
hexane/EtOAc, Rf 0.34) to get product as a white solid (0.74 g,
74%).
[0420] (c) 4-Chloro-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine
[0421]
7-Benzenesulfonyl-4-chloro-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine
(740 mg, 1.93 mmol) in 50 mL THF was added TBAF 1.93 mL (1.0 M
solution in THF). The reaction mixture was heated under reflux for
1.5 hrs. The solvent was removed in vacuo. The residue was
partitioned between EtOAc and water. The organic layer was
separated and the aqueous layer was extracted with EtOAc
(2.times.). Combined organic layer was dried over Na.sub.2SO.sub.4
and concentrated. The residue was chromatographed on silica gel
(2/1 CH.sub.2Cl.sub.2/EtOAc, Rf 0.42) to give product as a white
solid (343 mg, 73%).
[0422] (d) 4-Amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine
[0423] 4-Chloro-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (220 mg, 0.9
mmol) was dissolved in 5 mL dioxane in a pressure tube and then
concentrated ammonia 5 mL was added. The mixture was heated at
120.degree. C. for 4 days. Solvent was removed and the resulting
residue was partitioned between EtOAc/H.sub.2O. Organic layer was
separated and the aqueous layer was extracted with EtOAc
(3.times.). Combined organic layer was dried (Na.sub.2SO.sub.4),
concentrated to provide crude product as a white solid (202 mg,
.about.100%).
[0424] (e) Toluene-4-sulfonic acid
5-dimethoxymethyl-tetrahydro-furan-3-yl ester
[0425] The title compound was synthesized according to the
procedure described in Tetrahedron Lett. 1989, 30, 6259-6262.
[0426] (f)
7-(5-Dimethoxymethyl-tetrahydro-furan-3-yl)-5-p-tolyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamine
[0427] To 4-amino-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg,
1.2 mmol), 18-Crown-6 (316 mg, 1.2 mmol) in 32 mL dry DMF was added
K.sub.2CO.sub.3 (326 mg, 2.4 mmol). The mixture was stirred at r.t.
for 30 min. Then toluene-4-sulfonic acid
5-dimethoxymethyl-tetrahydro-furan-3- -yl ester (100 mg, 1.2 mmol)
in 15 mL DMF was added and the reaction was heated at 80.degree. C.
overnight. After cooling to r.t., the mixture was partitioned
between EtOAc and water, organic layer was separated and the
aqueous layer was extracted with EtOAc (3.times.). Combined organic
layer was dried (Na.sub.2SO.sub.4), concentrated and the residue
was chromatographed on silica gel (10% MeOH in EtOAc, Rf 0.38). The
product is obtained as a liquid (357 mg, 80%).
[0428] (g)
[4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl]-tetrahydrof-
uran-2-yl]-methanol
[0429]
7-(5-Dimethoxymethyl-tetrahydro-furan-3-yl)-5-p-tolyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamine (357 mg, 1 mmol) was dissolved in 10 mL
dioxane and 1% TFA/H.sub.2O 10 mL was added and the mixture was
heated at 80.degree. C. overnight. The solution was added 1 N NaOH
until PH=6.0. NaBH.sub.4 (38 mg, 1 mmol) was added and the solution
was stirred at r. t. for 10 min. Solvent was removed in vacuo and
the resulting residue was partitioned between EtOAc and H.sub.2O.
Organic layer was separated and the aqueous layer was extracted
with EtOAc (3.times.). Combined organic layer was dried
(Na.sub.2SO.sub.4), concentrated and the residue was
chromatographed on silica gel (10% MeOH in EtOAc, Rf 0.38). The
product was obtained as a white solid (201 mg, 62%).
[0430] (h)
{[4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]-pyrimidin-7-yl)-tetrahydr-
ofuran-2-ylmethoxyl]-hydroxy-phosphorylmethyl phosphonic acid
[0431]
[4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl]-tetrahydrofuran-
-2-yl]-methanol was dissolved in 4 mL trimethyl phosphate and was
cooled to -5-0.degree. C. Methylenebis (phosphonic dichloride) (212
mg, 0.8 mmol) was added in one portion and the resulting mixture
was stirred at that temperature for 2 hrs. The reaction mixture was
transferred via syringe to 20 mL cold 10% NaHCO.sub.3. The mixture
was neutralized with 1 N HCl, and then purified by RP HPLC. The
final product was obtained as a white solid (31 mg, 32%). ES-MS:
m/z 481 (M-H).
EXAMPLE 13
[0432]
{[4-(4-Amino-3p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl)--
butoxy]-hydroxy-phosphorylmethyl}-phosphonic acid 66
[0433] (a) Acetic acid
4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]p-
rimidin-1-yl)-butyl ester
[0434] The title compound was made according to the procedure
detailed in J. Med. Chem. 1990, 33, 1980-1983.
[0435] (b)
4-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1-y-
l)-butan-1-ol
[0436] Acetic acid
4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrim-
idin-1-yl)-butyl ester (0.85 g, 2.5 mmol), and
LiOH.multidot.H.sub.2O (0.25 g, 5.96 mmol) were dissolved in THF (3
mL)/H.sub.2O (10 mL) and heated to 70.degree. C. for 2 h. After
cooling, the mixture was dumped into water and extracted with
EtOAc. The combined extracts were washed with water, dried over
magnesium sulfate, and concentrated to a yellow solid which was
used without purification in the next reaction (0.20 g, 27%).
[0437] (c) Toluene-4-sulfonic acid
4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyra-
zolo[3,4-d]pyrimidin-1-yl)-butyl ester
[0438] A mixture of
4-(4-amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyri-
midin-1-yl)-butan-l-ol (0.19 g, 0.66 mmol), TsCl (0.28 g, 1.50
mmol), DMAP (0.19 g, 1.56 mmol) and CH.sub.2Cl.sub.2 (10 mL) were
stirred for 24 h at rt. The mixture was dumped into water and
extracted with CH.sub.2Cl.sub.2. The combined extracts were washed
with water, dried over magnesium sulfate, and concentrated to a
yellow solid which was purified over silica gel (1%
MeOH/CH.sub.2Cl.sub.2) to yield a white foam (0.25 g, 85%). MS
[M+H].sup.+452.
[0439] (d)
{[4-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1-
-yl)-butoxy]-hydroxy-phosphorylmethyl}-phosphonic acid
[0440] The title compound was made following the procedure detailed
in JOC 1987, 52, 1794. MS [M-H].sup.-454.
[0441] D) Embodiments Wherein Tb is x
[0442] Bis-3,4-(diethylphophonyl)-.beta.-phenylethyl amine 5 67
[0443] N-t-butoxycarbonyl-3-hydroxytyramine
[0444] To a solution of 3-hydroxytyramine hydrochloride (5.0 g,
26.36 mmol) in dixane/water (50/30 mL) at 0.degree. C. was added
sodium bicarbonate (6.64g, 79.08 mmol) and stirred for 10 min. To
this was added Boc anhydride (7.48 g, 34.275 mmol) and stirred at
rt for 18 h. After removing dioxane in vacuo, the slurry was taken
up in water (.about.60 mL) and extracted in ethyl acetate (25
mL.times.3). The organics were washed with 1N HCl (10 mL.times.2)
followed by brine (10 mL); dried (sodium sulfate) and concentrated
which when cooled in the refregerator crystallized the next day
(3.87 g, 57%). MS: 252 (M-H).
[0445] N-t-butoxycarbonyl-bis-3,4-O-triflyl-.beta.-phenylethyl
amine
[0446] To a solution of N-Boc-3-hydroxytyramine (3.87 g, 15.28
mmol) in anhydrous dichloromethane (70 mL) was added triethyl amine
(61.12 mmol) followed by N-phenyl triflamide (16.37 g, 45.84 mmol)
and stirred at rt for 24 h. Reaction mixture was diluted with
dichloromethane (100 mL) and washed successively with 1N HCl
(3.times.10 mL) and brine (10 mL) and dried (sodium sulfate). After
concentration of dichloromethane extract the brown oil was
chromatographed on silicagel using hexane/ethyl acetate (10-100%)
to give product as a viscous oil (6.32 g, 80%). MS: 516 (M-H).
[0447]
N-t-butoxycarbonyl-bis-3,4-(diethylphophonyl)-.beta.-phenylethyl
amine
[0448] To the
N-t-butoxycarbonyl-bis-3,4-O-triflyl-.beta.-phenylethyl amine (6.32
g, 12.21 mmol) in acetonitrile in an atmosphere of argon was
carefully added diethyl phosphite (3.46 mL, 26.87 mmol),
N-methylmorpholine (3.09 mL, 30.54 mmol),
tetrakistriphenylphosphine palladium(0) (1.41 g, 1.221 mmol) and
after flushing the solution with argon for 10 min. it was stoppered
and heated to 90.degree. C. for 2 days. Acetonitrile was
concentrated, and the residue was diluted with ethyl acetate. The
organic layer was washed with citric acid (10%, 10 mL.times.2),
brine (10 mL) and dried (sodium sulfate). The yellow gum after
concentration of ethyl acetate was purified by flash column
chromatography on silica gel using ethyl acetate in hexane
(33%-100%) followed by ethyl acetate/methanol (9/1) to give a pale
yellow gum (992 mg, 16.5%). MS: 492 (M-H).
[0449] Bis-3,4-(diethylphophonyl)-.beta.-phenylethyl amine
[0450] To the
N-t-butoxycarbonyl-bis-3,4-(diethylphophonyl)-.beta.-phenyle- thyl
amine (0.992 g, 2.01 mmol) in dichloromethane (10 mL) was added TFA
(25% in dichloromethane, 2.5 mL). After 1.5 h the solvents were
removed in vacuo and the residue was diluted with saturated sodium
bicarbonate and dichloromethane (5 mL and 50 mL). The aqueous layer
was re extracted with dichloromethane (25 mL.times.2). Combined
organics were concentrated to give a pale brown gum (0.758 g, 96%)
which was pure enough for the next step. MS:392 (M-H), 416
(M+23).
EXAMPLE 14
[0451] [4-Aminomethyl-2-(diethoxy-phosphoryl)-phenyl]-phosphonic
acid diethyl ester 68
[0452] (b) (3,4-Dihydroxy-benzyl)-carbamic acid tert-butyl
ester
[0453] 4-Aminomethyl-benzene-1,2-diol hydrobromide (5.6 g, 25.2
mmol) was dissolved in CH.sub.3CN/H.sub.2O 1:1 (100 mL).
NaHCO.sub.3 (4.3 g, 50.4 mmol) was added followed by Boc.sub.2O
(5.5 g, 25.2 mmol). The mixture was stirred for 18 h, concentrated,
and extracted with EtOAc. The combined extracts were washed with
water, dried over magnesium sulfate, and concentrated to a tan
solid which was used without purification in the next reaction.
[0454] (c) Trifluoro-methanesulfonic acid
5-(tert-butoxycarbonylamino-meth-
yl)-2-trifluoromethanesulfonyloxy-phenyl ester
[0455] (3,4-Dihydroxy-benzyl)-carbamic acid tert-butyl ester (5.5
g, 23.0 mmol), N-phenyltrifluoromethanesulfonimide (26.9 g, 75
mmol), and Et.sub.3N (14.9 mL, 107 mmol) were dissolved in
CH.sub.2Cl.sub.2 (80 mL) and stirred for 24 h. The mixture was
dumped into water and the layers seperated. The aqueous layer was
extracted with methylene chloride. The combined extracts were
washed with water, dried over magnesium sulfate, concentrated, and
purified by silica gel chromatography (hexane/EtOAc 3:1) to yield
the product as a brown oil (9.0 g, 78%).
[0456] (d)
[4-(tert-Butoxycarbonylamino-methyl)-2-(diethoxy-phosphoryl)-ph-
enyl]-phosphonic acid diethyl ester
[0457] Trifluoro-methanesulfonic acid
5-(tert-butoxycarbonylamino-methyl)--
2-trifluoromethanesulfonyloxy-phenyl ester (5 g, 10.o mmol),
diethyl phosphite (2.8 mL, 20.3 mmol), N-methylmorpholine (2.7 mL,
25.1 mmol) and tetrakis(triphenylphosphine)-palladium(0) (1.2 g)
were dissolved in anhydrous acetonitrile (100 mL) and heated in a
sealed tube at 90.degree. C. for 48 h. After cooling, the mixture
was diluted with EtOAc (200 mL) and washed with water, 1 N HCl and
brine. The organic layer was dried over magnesium sulfate,
concentrated, and purified by silica gel chromatography (5%
MeOH/CHCl.sub.3) to yield the product as a colorless oil (2.0 g,
42%). .sup.1H NMR (300 Mhz, CDCl.sub.3) .delta. 1.35 (m, 12 H),
3.79 (bs, 2 H), 3.96 (m, 8H), 7.45 (m, 1H), 7.91 (m, 2H).
[0458] (e)
[4-Aminomethyl-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid
diethyl ester
[0459]
[4-(tert-Butoxycarbonylamino-methyl)-2-(diethoxy-phosphoryl)-phenyl-
]-phosphonic acid diethyl ester (2.0 g, 4.2 mmol) was dissolved in
TFA/CH.sub.2Cl.sub.2 (25%, 20 mL) and stirred for 3 h. The mixture
was evaporated under a stream of N.sub.2, dissolved in EtOAc and
washed with sat'd NaHCO.sub.3. The organic layer was dried over
magnesium sulfate, and concentrated to a brown oil (0.9 g, 2.3
mmol) which was used without purification in the next reaction.
EXAMPLE 15
[0460] 3-(3,4-Bis-phosphono-phenyl)-propionic acid
4-(4-amino-5-p-tolyl-py-
rrolo[2,3-d]pyrimidin-7-yl)-tetrahydro-furan-2-ylmethyl ester
69
[0461] (a) 3-[3,4-Bis-(diethoxy-phosphoryl)-phenyl]-propionic acid
4-(4-amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydro-furan-2-ylm-
ethyl ester
[0462]
[4-(4-Amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl]-tetrahydrofuran-
-2-yl]-methanol (32.4 mg, 0.1 mmol),
3-[3,4-bis-(diethoxy-phosphoryl)-phen- yl]-propionic acid (47 mg,
0.11 mmol), DCC (22.7 mg, 0.11 mmol) and DMAP (5 mg, 0.041 mmol)
was mixed in 2 mL dry DMF under N.sub.2. The reaction mixture was
stirred at r.t. overnight. The product was purified by RP HPLC to
get a liquid (17 mg, 25%).
[0463] (b) 3-(3,4-Bis-phosphono-phenyl)-propionic acid
4-(4-amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydro-furan-2-ylm-
ethyl ester
[0464] 3-[3,4-Bis-(diethoxy-phosphoryl)-phenyl]-propionic acid
4-(4-amino-5-p-tolyl-pyrrolo[2,3-d]pyrimidin-7-yl)-tetrahydro-furan-2-ylm-
ethyl ester (18 mg, 0.025 mmol) was dissolved in 2 mL dry
acetonitrile under N.sub.2. The solution was cooled to -12.degree.
C. TMSI (100 mg, 0.5 mmol) was added via syringe and the reaction
was stirred at that temperature for 16 hrs. To the solution was
added 10% NaHCO.sub.3 until pH=7.0. Then a few drops of sat.
Na.sub.2S.sub.2O.sub.3 was added just enough to make the yellow
color disappear. The resulting mixture was purified by RP HPLC. The
final product is a white powder (6.5 mg, 42%). ES-MS: m/z 616
(M-H).
EXAMPLE 16
[0465]
(4-{[3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1--
yl)-benzoylamino]-methyl}-2-phosphono-phenyl)-phosphonic acid
70
[0466] (a)
3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1-y-
l)-benzoic acid
[0467] The title compound was made as for example 19(b).
[0468] (b) [4-{[3-(4-Amino-3-p-tolyl-pyrazolo[3
4-d]pyrimidin-1-yl)-benzoy-
lamino]-methyl}-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid
diethyl ester
[0469]
3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl)-b-
enzoic acid (0.015 g, 0.043 mmol),
[4-aminomethyl-2-(diethoxy-phosphoryl)-- phenyl]-phosphonic acid
diethyl ester (0.021 g, 0.054 mmol), HOBt (0.007 g, 0.052 mmol),
and EDC.multidot.HCl (0.01 g, 0.052 mmol) were dissolved in DMF (1
mL) and stirred at rt for 1 h. Purification by RP HPLC
(CH.sub.3CN/H.sub.2O) and lyophylization yielded a white powder
(0.023 g, 75%). MS [M+H].sup.+708.
[0470] (c)
(4-{[3-(4-Amino-3-p-tolyl-3a,7a-dihydro-pyrazolo[3,4-d]pyrimidi-
n-1-yl)-benzoylamino]-methyl}-2-phosphono-phenyl)-phosphonic
acid
[0471]
[4-{[3-(4-Amino-3-p-tolyl-pyrazolo[3,4-d]pyrimidin-1-yl)-benzoylami-
no]-methyl}-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid diethyl
ester (0.023 g, 0.033 mmol) dissolved in CH.sub.3CN (1 mL) was
treated with TMSI (0.093 mL, 0.65 mmol). The mixture was stirred
for 4 h, made basic with 1N NaOH, and decolorized with solid
NaSHO.sub.3. The resulting solution was diluted with DMF (5 mL) and
purified by RP HPLC (CH.sub.3CN/H.sub.2O). Lyophylization yielded a
white powder (0.011 g, 75%). MS [M-H].sup.-593.
[0472] E) Embodiments Wherein Tb is xii
[0473] General Scheme for Embodiments Wherein Tb is a Subsituted
Aryl
[0474] Error! Objects cannot be created from editing field
codes.
EXAMPLE 17
[0475] 71
[0476] Synthesis of Aniline 5
[0477] (a) To a suspension of NaH (220 mg of a 60% dispersion in
mineral oil (5.5 mmol), washed three times with hexanes) in THF (15
mL) at rt under N.sub.2 was added t-butyl 4-hydroxybenzoate (971
mg, 5.0 mmol) in one portion. After H.sub.2 evolution ceased
(.about.10 min.), diethyl chlorophosphate (0.79 mL, 5.5 mmol) was
added. The reaction mixture was stirred at rt overnight and then
poured into 1.0 N aq NaOH (20 mL) and extracted with EtOAc. The
organic extract was washed with H.sub.2O (20 mL) and brine (20 mL),
dried over MgSO.sub.4 and concentrated. The crude oil was purified
by flash chromatography on silica gel. Elution with 2:1
hexanes-EtOAc followed by 1:1 hexanes-EtOAc afforded 1.48 g (90%)
of the phosphate as a colorless oil.
[0478] (b) To a solution of i-Pr.sub.2NEt (1.2 mL, 8.48 mmol) in
THF (22 mL) at 0.degree. C. under N.sub.2 was slowly added 1.6 M
n-BuLi in hexanes (5.3 mL, 8.48 mmol). After 10 min., the LDA
solution was cooled to -78.degree. C., and a solution of the
phosphate (1.40 g, 4.24 mmol) in THF (5 mL) was slowly added via
cannula. A 2 mL rinse of the flask was also added. The reaction
mixture was stirred at -78.degree. C. for 2 h and at 0.degree. C.
for 1 h. The reaction mixture was then diluted with half saturated
aq NH.sub.4Cl (20 mL). The mixture was further acidified by the
addition of a small amount of 6 N aq HCl, and then extracted with
EtOAc. The extract was washed with H.sub.2O (10 mL) and brine (10
mL). The aqueous washes were reextracted once with EtOAc, and the
combined extracts were dried over MgSO.sub.4 and concentrated. The
crude material was purified by flash chromatography on silica gel.
Elution with 5:1 hexanes-EtOAc followed by 3:1 hexanes-EtOAc
afforded 1.32 g (94%) of the desired phosphonate as a light yellow
oil.
[0479] (c) To a solution of the phenol (1.30 g, 3.94 mmol) in
CH.sub.3CN (10 mL) at rt under N.sub.2 was added K.sub.2CO.sub.3
(600 mg, 4.33 mmol) followed by benzyl bromide (0.51 mL, 4.33
mmol). The reaction mixture was stirred at 50.degree. C. After
cooling, the reaction mixture was diluted with EtOAc and washed
with H.sub.2O and brine. The extract was dried over MgSO.sub.4 and
concentrated. The crude material was purified by flash
chromatography on silica gel to afford 1.86 g (quant) of the
desired benzyl ether.
[0480] (d) To a solution of the t-butyl ester (from above) in
CH.sub.2Cl.sub.2 (12 mL) at 0.degree. C. under N.sub.2 was slowly
added TFA (4 mL). The resulting solution was stirred at 0.degree.
C. for 1 h and at rt for 3 h. The reaction mixture was then
concentrated under a stream of N.sub.2 followed by high vacuum to
afford the desired acid as an off-white solid.
[0481] (e) To a solution of the acid (364 mg, 1.00 mmol) in 1:1
toluene-t-BuOH (4 mL) at rt under N.sub.2 was added i-Pr.sub.2NEt
(0.44 mL, 2.5 mmol) followed by (PhO)--.sub.2P(O)N.sub.3 (0.54 mL,
2.5 mmol). The resulting solution was then stirred at reflux for 5
h. The yellow solution was allowed to cool to rt and was then
partitioned between EtOAc and H.sub.2O (20 mL). The layers were
separated, and the organic extract was then washed with H.sub.2O
(20 mL) and brine (20 mL). The EtOAc extract was then dried over
Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash
chromatography on silica gel. Elution with 1:1 EtOAc-hexanes
followed by 2:1 EtOAc-hexanes afforded 146 mg (34%) of the desired
carbamate.
[0482] (f) To a solution of the carbamate (879 mg, 2.02 mmol) in
CH.sub.2Cl.sub.2 (8 mL) at rt under N.sub.2 was added TFA (2 mL).
The solution was stirred at rt for 3 h and then concentrated under
a stream of N.sub.2. The residue was purified by flash
chromatography on silica gel. Elution with 3:1 EtOAc-hexanes
followed by 15:1 CHCl.sub.3-MeOH afforded 612 mg of aniline 5.
[0483] Condensation of Aniline 5 with Sulfone 1 and Subsequent
Deprotection to 9
[0484] (a) A mixture of aniline 5 (605 mg, 1.80 mmol) and sulfone 1
(347 mg, 0.902 mmol) in 2-methoxyethyl ether (5 mL) was stirred at
150.degree. C. for 2 h. The dark solution was allowed to slowly
cool to rt overnight. The precipitate that had formed was then
filtered, washed with Et.sub.2O and dried under high vacuum to
afford 310 mg (54%) of the desired coupling product.
[0485] (b) A solution of the coupling product (from above, 39 mg,
0.610 mmol) in AcOH (.about.3-4 mL) containing a catalytic amount
of 10% Pd/C was stirred under an atmosphere of N.sub.2 (double
stuffed balloon) for 3 h. The reaction mixture was then filtered
through a pad of Celite, and the filtrate concentrated. The residue
was purified by flash chromatography on silica gel. Elution with
1:1 EtOAc-hexanes afforded 24 mg (72%) of phenol 9. 72
[0486] (a) To a solution of phenol 9 (85 mg, 0.155 mmol) and
i-Pr.sub.2NEt (0.03 mL, 0.186 mmol) in CH.sub.2Cl.sub.2 (2 mL) at
0.degree. C. under N.sub.2 was added PhNTf.sub.2 (72 mg, 0.201
mmol). The reaction mixture was stirred at rt for 5 days.
Additional i-Pr.sub.2NEt and PhNTf.sub.2 was added, and the
reaction mixture stirred for an additional day. The reaction
mixture was then diluted with EtOAc and washed with 1.0 M aq HCl
(10 mL), H.sub.2O (10 mL), and brine (10 mL). The EtOAc extract was
dried over Na.sub.2SO.sub.4 and concentrated. The crude material
was purified by flash chromatography on silica gel. Elution with
1:1 EtOAc-hexanes, 3:2 EtOAc-hexanes and finally 2:1 EtOAc-hexanes
afforded 90 mg (86%) of the triflate.
[0487] (b) To a solution of the triflate (43.8 mg, 0.0644 mmol) in
CH.sub.3CN (1.0 mL) at rt under N.sub.2 was added NMM (0.01 mL,
0.0911 mmol), (EtO).sub.2POH (0.011 mL, 0.0841 mmol) and a
catalytic amount of Pd(PPh.sub.3).sub.4. The mixture was then
stirred at 70.degree. C. overnight. The reaction mixture was then
partitioned between EtOAc and 1.0 M aq HCl. The layers were
separated and the organic layer was washed with H.sub.2O and brine.
The organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
The crude material was purified by flash chromatography on silica
gel to afford an inseparable mixture of the desired bisphosphonate
and 9, which was used in the next reaction without further
purification.
[0488] (c) The mixture of products from above was converted to x-A
in the same fashion as previously described (i-A, (b)). 73
[0489] (a) To a solution of phenol 9 (17.9 mg, 0.0326 mmol) in
CH.sub.3CN containing Cs.sub.2CO.sub.3 (16 mg, 0.0489 mmol) at rt
under N.sub.2 was added t-butyl bromoacetate (0.006 mL, 0.0424
mmol). The yellow color of the reaction mixture slowly disappeared
over time, and after 3 h, the reaction mixture was diluted with
EtOAc and washed with H.sub.2O and brine. The EtOAc layer was dried
over Na.sub.2SO.sub.4 and concentrated. The crude residue was used
without further purification.
[0490] (b) The crude residue from above was converted to x-B in the
same fashion as previously described (i-A, (b)). 74
[0491] The crude residue from above (x-B, (a)) was converted to x-C
in the same fashion as previously described (i-A, (b)) except that
the reaction mixture was only allowed to warm to 0.degree. C.
before being quenched. 75
[0492] Phenol 9 was converted to x-D in the same fashion as
previously described (i-A, (b)).
[0493] F) Embodiments Wherein Tb is xiii
EXAMPLE 18
[0494]
4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyri-
do[2,3--d]pyrimidin-2-ylamino]-pyridine-2,6-dicarboxylic acid
76
[0495] a)
4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetahydro-py-
rido[2,3-d]pyrimidin-2-ylamino]-pyridine-2,6-dicarboxylic acid
diethyl ester 77
[0496] 4-Bromo-pyridine-2,6-dicarboxylic acid diethyl ester (39 mg,
0.13 mmol),
2-amino-6-(2,6-dichlorophenyl)pyrido-8-methyl-8H-pyrido[2,3-d]pyri-
midin-7-one (50 mg, 0.16 mmol), 4-bromopyridine-2,6-dicarboxylic
acid diethyl ester (39 mg, 0.13 mmol), palladium acetate (1.5 mg,
0.0067 mmol), (S)-BINAP (6.0 mg, 0.0096 mmol) and cesium carbonate
(60 mg, 0.18 mmol) were placed in toluene (0.5 mL). The flask was
purged with argon, sealed and heated to 100.degree. C. After 20 h,
the reaction was allowed to cool to rt and diluted with EtOAc and
H.sub.2O. The aqueous layer was extracted with fresh EtOAc, the
organic fractions combined, washed with brine and dried over
Na.sub.2SO.sub.4. The solution was concentrated and chromatographed
over silica gel using CHCl.sub.3:MeOH (99:1) to provide 49 mg (69%)
of a yellow solid. Electrospray Mass Spectrum (50/50
acetonitrile/water) m/z 540 (M-H).
[0497] b)
4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-p-
yrido[2,3-d]pyrimidin-2-ylamino]-pyridine-2,6-dicarboxylic acid
78
[0498] To a solution of
4-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8-
a-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridine-2,6-dicarboxylic
acid diethyl ester (49 mg, 0.090 nmmol) in MeOH (0.5 mL) was added
1N sodium hydroxide (0.36 mL) resulting in a suspension. A solution
was obtained after addition of water (0.5 mL) and heating to
80.degree. C. After 3 h, the reaction was allowed to cool to rt,
diluted with MeCN/H.sub.2O/DMF and chromatographed using
reversed-phase HPLC. Concentration and lyophilization of the
purified fractions gave 23 mg (53%) of a yellowish solid.
Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 486
(M+H).
EXAMPLE 19
[0499]
4-(4-Amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-py-
ridine-2,6-dicarboxylic acid 79
[0500] (a) Pyridine-(2,6-dicarboxylic acid diethyl ester)-4-boronic
acid
[0501] A mixture of 4-bromopyridine-2,6-dicarboxylic acid diethyl
ester (0.10 g, 0.33 mmol), bis(pinacoloto)diboron (0.093 g, 0.36
mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride (5 mol %),
potassium acetate (0.097 g, 1.0 mmol) in DMSO (2 mL) was heated to
80.degree. C. for 1 h. Purification by RP HPLC
(CH.sub.3CN/H.sub.2O) and lyophylization yielded a white powder
(0.07 g, 79%). MS [M+H].sup.+268.
[0502] (b)
4-(4-Amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl-
)-pyridine-2,6-dicarboxylic acid diethyl ester
[0503] A mixture of pyridine-(2,6-dicarboxylic acid diethyl
ester)-4-boronic acid (0.093 g, 0.27 mmol),
3-p-Tolyl-3a,7a-dihydro-1H-py- razolo[3,4-d]pyrimidin-4-ylamine
(0.03 g, 0.13 mmol mmol), copper(II) acetate (0.048 g, 0.27 mmol)
and pyridine (0.3 mL) in DMF (5 mL) were stirred open to the air
for 48 h. The mixture was filtered through Celite and the filtrate
purified by RP HPLC (CH.sub.3CN/H.sub.2O). Lyophylization yielded a
white powder (0.02 g, 34%). MS [M+H].sup.+447.
[0504] (c)
4-(4-Amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl-
)-pyridine-2,6-dicarboxylic acid
[0505] To a suspension of
4-(4-amino-5-p-tolyl-4a,7a-dihydro-pyrrolo[2,3-d-
]pyrimidin-7-yl)-pyridine-2,6-dicarboxylic acid diethyl ester (0.02
g, 0.036 mmol) in THF (1 mL) and water (1 mL) was added 2N NaOH (1
mL). The mixture was heated at reflux for 1 h at which point HPLC
indicated completion. The mixture was acidified with TFA, diluted
with DMF (5 mL) and purified by RP HPLC (CH.sub.3CN/H.sub.2O).
Lyophylization yielded a white powder (0.01 g, 71%). MS
[M-H].sup.-389.
[0506] G) Embodiments Wherein Tb is xxii 80
EXAMPLE 20
[0507] Preparation of diethyl 2-(5-bromopyridyl)phosphonate
[0508] A mixture of 2,5-dibromopyridine (500 mg, 2.11 mmol), NMM
(0.46 mL, 4.22 mmol), (EtO).sub.2POH (0.35 mL, 2.53 mmol) and
Pd(PPh.sub.3).sub.4 (122 mg, 0.106 mmol) in CH.sub.3CN was stirred
at 80.degree. C. overnight. After cooling, the reaction mixture was
partitioned between CH.sub.2Cl.sub.2 and water. The organic extract
was then washed with brine, dried over K.sub.2CO.sub.3 and
concentrated. The crude material was purified by flash
chromatography on silica gel to afford 130 mg (21%) of the desired
phosphonate.
[0509]
{5-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyr-
ido[2,3-d]pyrimidin-2-ylamino]-pyridin-2-yl}-phosphonic acid 81
[0510] a)
{5-[6-(2,6-Dichloro-phenyl)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro--
pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-2-yl}-phosphonic acid
diethyl ester (5-Bromo-pyridin-2-yl)-phosphonic acid diethyl ester
82
[0511] b) (4-bromopyridin-2-yl)-phosphonic acid diethyl ester (64
mg, 0.22 mmol),
2-amino-6-(2,6-dichlorophenyl)pyrido-8-methyl-8H-pyrido[2,3-d]pyri-
midin-7-one (70 mg, 0.22 mmol), palladium acetate (5.0 mg, 0.0.023
mmol), (5-bromopyridin-2-yl)-phosphonic acid diethyl ester (64 mg,
0.22 mmol), (S)-BINAP (20 mg, 0.032 mmol) and cesium carbonate (141
mg, 0.43 mmol) were placed in toluene (1 mL), flushed with argon,
sealed and heated to 95.degree. C. After 18 h, the reaction was
allowed to cool to rt and diluted with H.sub.2O. The mixture was
extracted twice with EtOAc and the combined organic extracts washed
with brine and dried over Na.sub.2SO.sub.4. The solution was
concentrated and chromatographed over silica gel (CHCl.sub.3:MeOH,
stepwise gradient 99:1 to 97:3) to give 46 mg (39%) of a yellow
solid. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z
534 (M+H).
[0512] c)
{5-[6-(2,6-Dichloro-phenly)-8-methyl-7-oxo-4a,7,8,8a-tetrahydro--
pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-2-yl}-phosphonic acid
83
[0513] To a cooled solution (0.degree. C.) of
{5-[6-(2,6-Dichloro-phenyl)--
8-methyl-7-oxo-4a,7,8,8a-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyri-
din-2-yl}-phosphonic acid diethyl ester (46 mg, 0.86 mmol) in MeCN
(1.2 mL) was added iodotrimethylsilane (0.3 mL). After 2 h, the
reaction was quenched with sodium hydroxide (1 N) and satd sodium
thiosulfate. The mixture was filtered and the filtrate
chromatographed using reversed-phase HPLC to give 14 mg (34%) of a
colorless solid after lyophilization. Electrospray Mass Spectrum
(50/50 acetonitrile/water) m/z 534 (M+H).
EXAMPLE 21
[0514] Solid-Phase/Combinatorial Approaches
[0515] Compounds were synthesized by solid-phase parallel synthesis
using a Quest 210 synthesizer (Argonaut Technologies) according to
the following scheme for Example 22:
[0516] Solid-Phase Parallel Synthesis Scheme 84
EXAMPLE 22
[0517] (a)
[(4-{2-(2-Dimethylamino-ethylamino)-9-[2-(3-hydroxy-phenyl)-eth-
yl]-9H-purin-6-ylamino}-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic
acid 85
[0518] (b) 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-phenol
[0519] To a solution of 3-hydroxyphenethyl alcohol (6.0 g, 43.4
mmol) in 275 mL of CH.sub.2Cl.sub.2 was added 6.55 g (43.4 mmol) of
TBDMS-Cl (tert-butyldimethylsilyl chloride), cooled to 0.degree.
C., then added 7.0 mL (86.8 mmol) of pyridine. The reaction mixture
was stirred at ambient temperature overnight. Upon concentration,
the crude mixture was purified by silica gel flash chromatography
(eluted with hexane then 5% EtOAc/hexane) to provide 8.9 g of a
clear oil: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.9.17 (s, 1H),
7.04 (m, 1H), 6.60 (m, 3H), 3.73 (t, J=6.9 Hz, 2H), 2.65 (t,J=6.9
Hz, 2H), 0.83 (s, 9H), -0.03 (s, 6H).
[0520] (c) Preparation of Ether Resin (1a)
[0521] To a Teflon.RTM. RV (reaction vessel) containing 0.3 g (0.96
mmol/g, 0.29 mmol) of Wang resin was added a solution of
3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-phenol (0.73 g, 2.9
mmol) and triphenylphosphine (0.38 g, 1.44 mmol) in 1.4 mL of THF.
The RV was cooled to 0.degree. C. (Julabo chiller) and then added,
under an atmosphere of N.sub.2, 2.0 mL (1.44 mmol) of a 0.72 M
solution of DEAD (diethyl azodicarboxylate) in THF. The resin
mixture was warmed, while agitating, to ambient temperature over 2
h and then agitated for an additional 20 h, upon which the RV was
drained and the resin washed successively with THF (5.times.5.0
mL), DMA (5.times.5.0 mL), CH.sub.2Cl.sub.2 (5.times.5.0 mL),
Et.sub.2O (2.times.5.0 mL), CH.sub.2Cl.sub.2 (1.times.5.0 mL),
Et.sub.2O (1.times.5.0 mL), and CH.sub.2Cl.sub.2 (2.times.5.0 mL).
Excess solvent was removed via N.sub.2 flow overnight to provide
the ether resin 1a. The following analytical data was obtained upon
cleavage of 1a (3-5 mg) with 30% TFA/CH.sub.2Cl.sub.2 (.about.5
min): 83% HPLC purity; HPLC RT (retention time, min) matches
commercially available 3-hydroxyphenethyl alcohol (TBS group
removed in TFA cleavage).
[0522] (d) Preparation of Purine Resin (1b)
[0523] To the ether resin 1a (0.29 mmol) was added 6.6 mL (6.57
mmol) of a 1.0 M solution of TBAF (tetrabutylammonium fluoride) in
THF. The resin mixture was agitated for 2 h, upon which the RV was
drained and the resin washed successively with THF (5.times.5.0
mL), DMA (5.times.5.0 mL), CH.sub.2Cl.sub.2 (5.times.5.0 mL),
Et.sub.2O (2.times.5.0 mL), CH.sub.2Cl.sub.2 (1.times.5.0 mL),
Et.sub.2O (1.times.5.0 mL), and CH.sub.2Cl.sub.2 (2.times.5.0 mL).
Excess solvent was removed via N.sub.2 flow overnight to provide
the deprotected resin. A resin aliquot (3-5 mg) was cleaved with
30% TFA/CH.sub.2Cl.sub.2 (.about.5 min) to verify resin bound
compound integrity: 80% HPLC purity; HPLC RT (retention time, min)
matches commercially available 3-hydroxyphenethyl alcohol.
[0524] To the dried resin (0.29 mmol) was added a homogeneous
suspension of 2-fluoro-6-chloropurine (0.50 g, 2.9 mmol) (for the
preparation of 2-fluoro-6-chloropurine see: Gray, N. S.; Kwon, S.;
Schultz, P. G. Tetrahedron Lett. 1997, 38, 1161-1164) and
triphenylphosphine (0.38 g, 1.44 mmol) in 1.75 mL of THF. The RV
was cooled to 0.degree. C. (Julabo chiller) and then added, under
an atmosphere of N.sub.2, 2.0 mL (1.44 mmol) of a 0.72 M solution
of DEAD (diethyl azodicarboxylate) in THF. The resin mixture was
warmed, while agitating, to ambient temperature over 1.5 h and then
agitated for an additional 22 h, upon which the RV was drained and
the resin washed successively with THF (5.times.5.0 mL), DMA
(5.times.5.0 mL), CH.sub.2Cl.sub.2 (5.times.5.0 mL), Et.sub.2O
(2.times.5.0 mL), CH.sub.2Cl.sub.2 (1.times.5.0 mL), Et.sub.2O
(1.times.5.0 mL), and CH.sub.2Cl.sub.2 (2.times.5.0 mL). Excess
solvent was removed via N.sub.2 flow overnight to provide the
purine resin 1b. The following analytical data was obtained upon
cleavage of 1b (3-5 mg) with 30% TFA/CH.sub.2Cl.sub.2 (.about.5
min): 65% HPLC purity, .about.5:1 major/minor peaks (no apparent
3-hydroxyphenethyl alcohol HPLC peak).
[0525] (e) Preparation of Purine Resin (1c)
[0526] To the purine resin 1b (0.29 mmol) was added a solution of
[(4-Amino-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl
ester (0.97 g, 2.88 mmol) and N,N-diisopropylethylamine (0.25 mL,
1.44 mmol) in 3.0 mL of 1:1 n-butanol/DMSO. The sealed RV was
heated at 110.degree. C. for 16 h, upon which the RV was cooled to
ambient temperature, drained, and the resin washed successively
with DMA (5.times.5.0 mL), CH.sub.2Cl.sub.2 (5.times.5.0 mL),
Et.sub.2O (2.times.5.0 mL), CH.sub.2Cl.sub.2 (1.times.5.0 mL),
Et.sub.2O (1.times.5.0 mL), and CH.sub.2Cl.sub.2 (2.times.5.0 mL).
Excess solvent was removed via N.sub.2 flow overnight to provide
the aminated purine resin 1c. The following analytical data was
obtained upon cleavage of 1c (3-5 mg) with 30% TFA/CH.sub.2Cl.sub.2
(.about.5 min): m/z 592 (M+H).
[0527] (f)
[(4-{2-(2-Dimethylamino-ethylamino)-9-[2-(3-hydroxy-phenyl)-eth-
yl]-9H-purin-6-ylamino}-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic
acid
[0528] To the aninated purine resin 1c (0.29 mmol) was added a
solution of N,N-dimethylethylenediamine (0.25 g, 2.88 mmol) and
N,N-diisopropylethylamine (0.25 mL, 1.44 mmol) in 3.0 mL of 1:1
n-butanol/DMSO. The sealed RV was heated at 110.degree. C. for 16
h, upon which the heat was turned off, the RV drained immediately,
and the resin washed (while still hot) successively with DMA
(5.times.5.0 mL), CH.sub.2Cl.sub.2 (5.times.5.0 mL, at ambient
temperature), Et.sub.2O (2.times.5.0 mL), CH.sub.2Cl.sub.2
(1.times.5.0 mL), Et.sub.2O (1.times.5.0 mL), and CH.sub.2Cl.sub.2
(2.times.5.0 mL). Excess solvent was removed via N.sub.2 flow
overnight to provide the bis-aminated purine resin.
[0529] To the bis-aminated purine resin (0.29 mmol) was added 5.6
mL of 30% TFA/CH.sub.2Cl.sub.2 (2% triisopropyl silane). The resin
mixture was agitated for 1 h, upon which the filtrate was collected
and the resin washed with CH.sub.2Cl.sub.2 (3.times.5.0 mL). The
combined filtrates were concentrated (Savant speed-vac), added 3-4
mL CH.sub.2Cl.sub.2, then reconcentrated to provide a dark yellow
oil.
[0530] The oil was dissolved in 6.6 mL of CH.sub.3CN, cooled to
0.degree. C., then added 1.0 mL (7.2 mmol) of TMSI
(iodotrimethylsilane). The resulting yellow solution (some
precipitate) was stored at -20.degree. C. for 2 h (periodic
swirling), then 0.degree. C. for 1 h, upon which 0.4 mL (2.81 mmol)
of TMSI was added and reaction continued at 0.degree. C. for 3 h.
The excess TMSI was quenched at 0.degree. C. with .about.4 mL of
20% aqueous NaHSO.sub.3, the pH adjusted to 11-12 with 10% NaOH,
and the CH.sub.3CN removed by rotary evaporation. The pH was
re-adjusted to 10-11 with TFA, upon which the solution was filtered
(0.2 .mu.m, PTFE filter) and purified by RP-HPLC
(CH.sub.3CN/H.sub.2O). Lyophilization provided a white solid
isolated as its TFA salt (0.035 g): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.9.76 (s, 1H), 9.33 (br s, 1H), 8.07-7.65 (m,
5H), 7.08-6.59 (m, 5H), 4.27 (m, 2H), 3.66 (m, 2H), 3.32 (m, 2H),
3.04 (m, 2H), 2.85 (s, 6H), 2.37 (m, 2H); m/z 576 (M+H).
EXAMPLE 23
[0531]
[(4-{2-(trans-4-Amino-cyclohexylamino)-9-[2-(3-hydroxy-phenyl)-ethy-
l]-9H-purin-6-ylamino}-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic
acid 86
[0532] The title compound was synthesized in a manner similar to
that described for Example 22. The white solid was isolated as a
TFA salt: m/z 602 (M+H)
EXAMPLE 24
[0533] [Hydroxy-(4-{9-[2-(3-hydroxy-phenyl)-ethyl]-2-[2-(3H
-imidazol-4-yl)-ethylamino]-9H-purin-6-ylamino}-phenyl)-phosphinoylmethyl-
]-phosphonic acid 87
[0534] The title compound was synthesized in a manner similar to
that described for Example 22. The white solid was isolated as a
TFA salt: m/z 599 (M+H)
EXAMPLE 25
[0535]
[Hydroxy-(4-{2-(2-hydroxy-ethylamino)-9-[2-(3-hydroxy-phenyl)-ethyl-
]-9H-purin-6-ylamino}-phenyl)-phosphinoylmethyl]-phosphonic acid
88
[0536] The title compound was synthesized in a manner similar to
that described for Example 22. The product was isolated as a white
solid: m/z 549 (M+H)
EXAMPLE 26
[0537]
(5-{2-(trans-4-Amino-cyclohexylamino)-9-[2-(3-hydroxy-phenyl)-ethyl-
]-9H-purin-6-ylamino}-2-phosphono-phenyl)-phosphonic acid 89
[0538] The title compound was synthesized in a manner similar to
that described for Example 22. The white solid was isolated as a
TFA salt: m/z 604 (M+H)
EXAMPLE 27
[0539]
(5-{9-[2-(3-Hydroxy-phenyl)-ethyl-]2-[2-(3H-imidazol-4-yl)-ethylami-
no]-9H-purin-6-ylamino}-2-phosphono-phenyl)-phosphonic acid 90
[0540] The title compound was synthesized in a manner similar to
that described for Example 22. The white solid was isolated as a
TFA salt: m/z 601 (M+H)
EXAMPLE 28
[0541]
(5-{2-(2-Dimethylamino-ethylamino)-9-[2-(3-hydroxy-phenyl)-ethyl]-9-
H-purin-6-ylamino}-2-phosphono-phenyl)-phosphonic acid 91
[0542] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 578 (M+H)
EXAMPLE 29
[0543]
[Hydroxy-(3-{9-[2-(4-hydroxy-phenyl)-ethyl]-6-phenylamino-9H-purin--
2-ylamino}-propyl)-phosphinoylmethyl]-phosphonic acid 92
[0544] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 547 (M+H)
EXAMPLE 30
[0545]
[Hydroxy-(3-{9-[2-(3-hydroxy-phenyl)-ethyl]-6-phenylamino-9H-purin--
2-ylamino}-propyl)-phosphinoylmethyl]-phosphonic acid 93
[0546] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 547 (M+H)
EXAMPLE 31
[0547]
(Hydroxy-{3-[9-(3-hydroxy-benzyl)-6-phenylamino-9H-purin-2-ylamino]-
-propyl}-phosphinoylmethyl)-phosphonic acid 94
[0548] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 533 (M+H)
EXAMPLE 32
[0549]
({3-[6-(3-Chloro-phenylamino)-9-(3-hydroxy-benzyl)-9H-purin-2-ylami-
no]-propyl}-hydroxy-phosphinoylmethyl)-phosphonic acid 95
[0550] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 567 (M+H)
EXAMPLE 33
[0551]
[(3-{6-(3-Chloro-phenylamino)-9-[2-(4-hydroxy-phenyl)-ethyl-9H-puri-
n-2-ylamino}-propyl)-hydroxy-phosphinoylmethyl]-phosphonic acid
96
[0552] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 581 (M+H)
EXAMPLE 34
[0553]
[(3-{6-(3-Chloro-phenylamino)-9-[2-(3-hydroxy-phenyl)-ethyl]-9H-pur-
in-2-ylamino}-propyl)-hydroxy-phosphinoylmethyl]-phosphonic acid
97
[0554] The title compound was synthesized in a manner similar to
that described for Example 22. The product was obtained as a white
solid: m/z 581 (M+H)
EXAMPLE 35
[0555] The above techniques can also be applied to typical,
solution-phase combinatorial synthesis. As described below, a
library of compound were rapidly prepared by coupling
bone-targeting moieties with payload fragments.
[0556] Synthesis of Bone-Targeting Analogs of
4-amino-5-(3-methoxyphenyl)--
7-(4-carboxyphenyl)pyrrolo[2,3-d]-pyrimidine
[0557] These analogs 21A-21D were synthesized according to Scheme 6
starting from the
4-amino-5-(3-methoxyphenyl)-7-(4-carboxyphenyl)pyrrolo[-
2,3-d]-pyrimidine. 98
[0558] Method C
[0559] Carboxylic acid (0.25 mmol) 19/22 was taken up in DMF (5 mL)
and cooled in ice. HATU (0.5 mmol) was then added followed by the
bone-targeting amines A-D and ethyl diisopropyl amine (0.5 mmol).
The reaction mixture was stirred at ambient temp. for 2 days. DMF
was removed in vacuo and the residue was taken up in ethyl acetate.
Ethyl acetate layer was washed with sodium bicarbonate (10%)
followed by 10% citric acid and then water. Organic extract was
dried over sodium sulphate and concentrated and purified by
chromatography using methylene chloride/methanol (5-10%). 99
[0560]
4-amino-5-(3-methoxyphenyl)-7-{4-[N-(4-bisdiethylphosphonomethyl)ph-
enyl]carboxamido)}pyrrolo[2,3-d]pyrimidine 20A
[0561] Prepared from 19 as a pale yellow gum. MS: 720 (M-H), 744
(M+23). 100
[0562] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(3,4-bisdiethylphosphono
phenyl)methyl]carboxamido)}pyrrolo[2,3-d]-pyrimidine 20B
[0563] Prepared from 19 as a pale yellow gum. MS: 720 (M-H).
101
[0564]
4-amino-5-(3-methoxyphenyl)-7-{4-[N-(2-(3,4-bisdiethylphoshonopheny-
l)ethyl)]carboxamido)}pyrrolo[2,3-d]-pyrimidine 20C
[0565] Prepared from 19 as a pale yellow gum. MS: 734 (M-H), 768
(M+23) 102
[0566] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-3-triethyl
bisphosphono-methylenepropyl]phenyl}carboxamido)}pyrrolo[2,3-d]pyrimidine
20D
[0567] Prepared from 19 as a pale yellow gum. MS: 642 (M-H).
[0568] Method D
[0569] To a cooled (-20.degree. C.) solution of the phosphonate
esters 20A-D (0.2 mmol) in acetonitrile (5 mL) was added TMSI (2
mmol) and stirred at 0.degree. C. for 4.5 h after which time it was
quenched with sodium bicarbonate solution followed by a 10%
solution of sodium bisulphite until the color of iodine is
dissipated. The aqueous layer was washed with ethyl acetate and
purified by Preparative HPLC. 103
[0570] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(4-bisphosphono
methyl)phenyl]carboxamido)}pyrrolo[2,3-d]pyrimidine 21A
[0571] Prepared from 20A using Method D as a white solid. MS: 608
(M-H), 610 (M+H). 104
[0572] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(3,4-bisphosphono
phenyl)methyl]carboxamido)}pyrrolo[2,3-d]-pyrimidine 21B
[0573] Prepared from 20B using Method D as a white solid. MS: 608
(M-H), 610 (M+H). 105
[0574] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-(2-(3,4-bisphosphono
phenyl)ethyl)]carboxamido)}pyrrolo[2,3-d]pyrimidine 21C
[0575] Prepared from 20C using Method D as a white solid. MS: 622
(M-H), 646 (M+23). 106
[0576] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-3-bisphosphonomethylene
propyl]phenyl}carboxamido)}pyrrolo[2,3-d]-pyrimidine 21D
[0577] Prepared from 20D using Method D as a white solid. MS: 558
(M-H).
[0578] Synthesis of Bone-Targeting Analogs of
4-amino-5-(3-methoxyphenyl)-- 7-(3-carboxyphenyl)pyrrolo[2,3
-d]pyrimidine
[0579] These analogs 24A-24D were synthesized according to Scheme 7
starting from the
4-amino-5-(3-methoxyphenyl)-7-(3-carboxyphenyl)pyrrolo[-
2,3-d]-pyrimidine. 107
[0580]
4-amino-5-(3-methoxyphenyl)-7-{3-[N-(4-bisdiethylphosphonomethyl)ph-
enyl]carboxamido)}pyrrolo[2,3-d]-pyrimidine 23A
[0581] Prepared from 22 as a pale yellow gum using Method C. MS:
720 (M-H), 744 (M+23). 108
[0582] 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(3,4-bisdiethylphosphono
phenyl)methyl]carboxamido)]pyrrolo[2,3-d]pyrimidine 23B
[0583] Prepared from 22 as a pale yellow gum using Method C. MS:
720 (M-H). 109
[0584]
4-amino-5-(3-methoxyphenyl)-7-{3-[N-(2-(3,4-bisdiethylphosphonophen-
yl)ethyl)]carboxamido)}pyrrolo[2,3-d]-pyrimidine 23C
[0585] Prepared from 22 as a pale yellow gum using Method C. MS:
734 (M-H), 768 (M+23). 110
[0586] 4-amino-5-(3-methoxyphenyl)-7-{4-[N-3-triethyl
bisphosphono-methylenepropyl]phenyl}carboxamido)}pyrrolo[2,3-d]-pyrimidin-
e 23D
[0587] Prepared from 22 as a pale yellow gum. MS: 642 (M-H).
111
[0588] 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(4-bisphosphono
methyl)phenyl]carboxamido)}pyrrolo[2,3-d]pyrimidine 24A
[0589] Prepared from 23A using Method D as a white solid. MS: 608
(M-H), 610 (M+H). 112
[0590] 4-amino-5-(3-methoxyphenyl)-7-{3-[N-(3,4-bisphosphono
phenyl)methyl]carboxamido)}pyrrolo[2,3-d]pyrimidine 24B
[0591] Prepared from 23B using Method D as a white solid. MS: 608
(M-H), 610 (M+H). 113
[0592] 4-amino-5-(3-methoxyphenal)-7-{3-[N-(2-(3,4-bisphosphono
phenyl)ethyl)]carboxamido)}pyrrolo[2,3-d]-pyrimidine 24C
[0593] Prepared from 23C using Method D as a white solid. MS: 622
(M-H), 646 (M+23). 114
[0594] 4-amino-5-(3-methoxyphenyl)-7-{3-[N-3-bisphosphonomethylene
propyl]phenyl}carboxamido)}pyrrolo[2,3-d]pyrimidine 24D
[0595] Prepared from 23D using Method D as a white solid. MS: 558
(M-H).
1 BONE-TARGETED PURINE SERIES Anti Resorption Src Kinase Cell Assay
Example Inhibition % Inhib # R.sub.a R.sub.b R.sub.c IC50 (.mu.M)
(.mu.M) 22 115 116 117 75 @ 20 30 118 Ph 119 0.055 100 @ 20 34 120
3-ClPh 121 0.12 50-70 @ 4
[0596]
2 BONE-TARGETED AMINOPYRIDOPYRIMIDINONES SERIES 122 Anti-
Resorption Src Kinase Cell Assay Example Inhibition % Inhib # Rd Re
IC50 (.mu.M) (.mu.M) i-A 0.002 50 @ 4 i-B 0.008 75-90 @ 20 i-C 0.12
100 @ 20
[0597]
3 BONE-TRAGETED PYRROLOPYRIMIDINE SERIES 123 Anti- Resorption Src
Kinase Cell Assay Inhibition % Inhib Example # Rf Rg IC50 (.mu.M)
(.mu.M) 14 124 125 0.004 25-50 @ 4 21B 126 127 0.87 50 @ 4 21D 128
129 0.13
[0598]
4 BONE_TARGETED PYRRAZOLOPYRIMIDINE SERIES 130 Anti- Resorption Src
Kinase Cell Assay Inhibition % Inhib Example # Rh Ri IV50 (.mu.M)
(.mu.M) 13 131 132 29 50 @ 3
[0599] Assays
[0600] 1. Anti-Resorption Cell Assay (Rabbit Osteoclast)
[0601] Femurs, tibias, and scapulas were isolated from 3-4 day old
New Zealand white rabbits (Millbrook Farms, Amherst, Mass.). Bones
were chopped and minced in a-MEM (Gibco-BRL) containing 0.55 g/L
NaHCO.sub.3, 10 mM HEPES (Gibco-BRL), 50 units/ml penicillin, and
0.05 mg/ml streptomycin, pH 7.1. Bone fragments were allowed to
settle by gravitation, supernatant was collected and centrifuged at
400 RPM (Beckman GS-6KR) for two minutes, and the cell pellet was
resuspended in the same medium supplemented with 10% HIFBS
(Hyclone). For prebinding experiments, 0.75 ml of cell suspension
was added to wells containing sperm whale dentine discs
preincubated for 2 hours with 0.75 ml culture medium containing a
2X concentration of test compound. Alternatively, 0.75 ml of cell
suspension was added to each well containing dentine slices
preincubated with 0.75 ml culture medium alone and test compound
was added after the adhesion phase. Sperm whale dentine was cut as
1 mm.times.6 mm circular discs. The adhesion phase was carried out
for 30 minutes at 37.degree. C. and 5% CO.sub.2 and then the medium
and non-adherent cells and debris were removed by aspiration. Fresh
culture medium containing serially diluted test compounds was added
and cells were incubated on dentine for 24 hours at 37.degree. C.
and 5% CO.sub.2. After the resorption phase, dentine slices were
soaked for 30 seconds in 0.5% sodium hypochlorite, wiped clean of
adherent cells, and then stained for 30-45 seconds with 1%
toluidine blue. Resorption was measured using reflective light
microscopy and automated image analysis. The resorbed area was
measured on the entire 6 mm disc. Remaining cells in the 24-well
plates were stained for tartrate resistant acid phosphatase (TRAP)
and also assessed visually for the presence of fibroblasts.
Experiments were carried out containing triplicate samples for each
concentration of compound tested with five untreated control
samples per plate. IC.sub.50 values were calculated based on the %
resorption in the presence of compound relative to vehicle alone
treated control samples. Data were calculated from at least three
independent experiments each containing triplicate samples.
[0602] 2. Src Kinase Inhibition Assay
[0603] Compounds were tested for their ability to inhibit Src
kinase using the scintillation proximity assay (SPA) technology as
developed by Amersham. Reagents include: Streptavidin SPA beads
from Amersham, 2-[N-morpholino]ethanesulfonic acid from Sigma, ATP
from Boerhinger Mannheim, [.sup.33P]ATP: from NEN (NEG 602H), the
substrate--biotinylated peptide substrate 1 (PKS1) (cdc2 peptide)
from Pierce which is prepared at 12.5 .mu.M (5X solution) in kinase
buffer, and the enzyme, human recombinant c-Src at 135 .mu.g/ml
(stock solution) which is diluted 1/40 in kinase buffer (3.38
.mu.g/ml) before use. Buffers include: (a) Kinase buffer which
contains MES 30 mM pH 6.8, MgCl.sub.2 10 mM, Orthovanadate 0.25 mM,
PMSF 0.1 mM, and DTT 1 mM; (b) ATP buffer which contains ATP 5 mM
in MgCl.sub.2 50 mM buffer (stock solution). Note that before each
use dilute in MES to 100 .mu.M (5X solution) add 100 .mu.Ci/mL
[.sup.33P]ATP; and (c) PBS Stop buffer which contains ATP 0.1 mM,
EDTA 40 mM, Triton 0.1%. Streptavidin beads are suspended at 3.3
mg/ml in stop buffer and mixed by shaking. The Kinase reaction
proceeds by stepwise addition to wells on the 96 well-plate of the
following: (a) 10 .mu.L kinase buffer +10% DMSO or compound to be
tested at different concentration in MES+10% DMSO, (b) 10 .mu.L
kinase buffer, (c) 10 .mu.L substrate 12.5 .mu.M, (d) 10 .mu.L
enzyme 3.38 .mu.g/ml, and (e) 10 .mu.L ATP 100 .mu.M containing 0.2
.mu.Ci [.sup.33P]ATP. Incubation for 2 hours at 30 degrees C. is
followed by addition of 150 .mu.L Stop buffer containing 500 .mu.g
streptavidin beads. Incubation proceeds for 30 min at room
temperature, followed by centrifugation for 5 min at 2000 rpm, and
reading on a Wallac Microbeta Scintillation counter.
[0604] 3. Hydroxyapatite Assay
[0605] Hydroxyapatite is the principal mineral component of bone.
Hydroxyapatite adsorption chromatography is used as an assay to
evaluate the bone-targeting potential of both individual
bone-targeting moieties ("monomers") and of pharmaceuticals
incorporating bone-targeting groups.
[0606] Method: The rentention time of a test compound is measured
using a linear gradient from 10 mM sodium phosphate, 0.15 N NaCl,
pH=6.8 to 500 mM sodium phosphate, 0.15 N NaCl, pH=-6.8 on a
TSK-Gel HA 1000 high pressure liquid chromatography column (7.5
mm.times.75 mm). The rentention time of the compound is expressed
in terms of K=(retention time-void time)/void. This K value is
corrected using two reference compounds to correct from
inter-column and inter-system variation to obtain a K' value.
[0607] Reference Comnpounds: K' values were determined for known
bone targeted compounds, the bisphosphonate, alendronate and
tetracycline. Alendronate gave a K' value of 3.7 and tetracycline
gave a K' value of 2.0.
EXAMPLE 36
[0608] As described previously, the compounds of the present
invention may be provided as pro-drugs. To give but one example,
bone targeting moieities of the following formula: 133
[0609] may be protected using the following Rz groups:
[0610] Atack, J. R. et al. J. of Pharmacology and Experimental
Therapeutics 1994, 270, 70. 134
[0611] Arimilli, M. N., et al. Antiviral Chemistry &
Chemotherapy 1997, 8, 557. 135
[0612] Serafinowska, H. T., et el. J. Med. Chem. 1995, 35,1372.
136
[0613] Ahlmark, M., J. Med. Chem. 1999, 42,1473. 137
[0614] Alternatively, the bone targeting moiety may be provided as
a pro-drug with the formula: 138
[0615] Meier, C., et al. J. Med. Chem. 1998, 41, 1417.
[0616] For a review of pro-drugs such as these, please see Krise,
J. P., Stella, V. J. Advanced Drug Delivery Reviews 1996, 19:287;
incorporated herein by reference.
* * * * *