U.S. patent application number 11/531221 was filed with the patent office on 2007-08-09 for 2-aminopurine analogs having hsp90-inhibiting activity.
This patent application is currently assigned to Conforma Therapeutics Corporation. Invention is credited to Marco A. Biamonte, Marcus F. Boehm, Kevin D. Hong, Srinivas Rao Kasibhatla, Lin Zhang.
Application Number | 20070185064 11/531221 |
Document ID | / |
Family ID | 34381103 |
Filed Date | 2007-08-09 |
United States Patent
Application |
20070185064 |
Kind Code |
A1 |
Kasibhatla; Srinivas Rao ;
et al. |
August 9, 2007 |
2-Aminopurine Analogs Having HSP90-Inhibiting Activity
Abstract
2-Aminopurine analogs are described and demonstrated or
predicted to have utility as Heat Shock Protein 90 (HSP90)
inhibiting agents in the treatment and prevention of various HSP90
mediated disorders, e.g., proliferative disorders. Method of
synthesis and use of such compounds are also described and
claimed.
Inventors: |
Kasibhatla; Srinivas Rao;
(San Diego, CA) ; Hong; Kevin D.; (San Diego,
CA) ; Boehm; Marcus F.; (San Diego, CA) ;
Biamonte; Marco A.; (San Diego, CA) ; Zhang; Lin;
(San Diego, CA) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Assignee: |
Conforma Therapeutics
Corporation
San Diego
CA
|
Family ID: |
34381103 |
Appl. No.: |
11/531221 |
Filed: |
September 12, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10946645 |
Sep 20, 2004 |
7138401 |
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11531221 |
Sep 12, 2006 |
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60504135 |
Sep 18, 2003 |
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60591467 |
Jul 26, 2004 |
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Current U.S.
Class: |
514/81 ; 514/151;
514/263.22; 514/263.4; 544/244; 544/277 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
25/00 20180101; A61P 31/00 20180101; A61P 13/12 20180101; A61P
17/02 20180101; A61P 31/16 20180101; A61P 43/00 20180101; A61P 9/00
20180101; A61P 3/00 20180101; A61P 29/00 20180101; C07D 471/04
20130101; C07D 487/04 20130101; A61P 35/02 20180101; A61P 19/04
20180101; A61P 25/08 20180101; A61P 21/00 20180101; A61P 19/02
20180101; C07D 473/00 20130101; A61P 37/06 20180101; A61P 35/00
20180101; A61P 1/16 20180101; A61P 37/02 20180101; A61P 17/00
20180101; A61P 11/00 20180101 |
Class at
Publication: |
514/081 ;
514/263.22; 514/263.4; 544/244; 544/277; 514/151 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/655 20060101 A61K031/655; A61K 31/52 20060101
A61K031/52; C07D 473/12 20060101 C07D473/12; C07F 9/6512 20060101
C07F009/6512 |
Claims
1. A compound represented by Formula I, or a polymorph, solvate,
ester, tautomer, pharmaceutically acceptable salt or prodrug
thereof: ##STR42## wherein: R.sup.1 is halogen or lower alkyl;
R.sup.2 is --NR.sup.8R.sup.10; R.sup.4 is --CHR.sup.12--; R.sup.3is
hydrogen, halogen, or --CN; R.sup.5 is aryl, heteroaryl, alicyclic,
or heterocyclic, wherein: the aryl group is substituted with 3 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring, the alicyclic group is
substituted with 3 to 5 substituents, the heterocyclic group is
substituted with 3 to 5 substituents, and the substituents are
selected from the group of halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy,
aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,
perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, phosphonate and
phosphonic acid; R.sup.8 is hydrogen, lower alkyl, lower aryl, or
--C(O)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.10R.sup.10 or --OR.sup.11; R.sup.10 is
independently hydrogen or lower alkyl; R.sup.11 is lower alkyl,
lower aryl or lower heteroaryl; R.sup.12 is hydrogen or lower
alkyl; provided that when R.sup.5 is aryl, R.sup.5 is not an
organo-metallic cyclopentadiene; when R.sup.5 is phenyl, the
substituents are not 3,5 di-halo; when R.sup.5 is alicyclic, the
ring system does not contain any tetra-substituted sp.sup.3 ring
carbons; and when R.sup.5 is heterocyclic, the ring system does not
contain any tetra-substituted sp.sup.3 ring carbons or the ring
system is not a tetra-substituted pyrrolidine.
2. The compound of claim 1, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein: R.sup.1 is halogen or methyl; and R.sup.2 is --NHR.sup.8,
where R.sup.8 is hydrogen or --C(O)R.sup.9.
3. The compound of claim 1, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein: R.sup.1 is halogen; R.sup.2 is --NH.sub.2; R.sup.3 is
hydrogen; and R.sup.5 is aryl or heteroaryl, wherein each of said
aryl and heteroaryl groups is monocyclic or bicyclic, the aryl
group is substituted with 4 to 5 substituents, the heteroaryl group
is substituted with 2 to 5 substituents, wherein when the
heteroaryl is substituted with only two substituents, the two
substituents must form part of an optionally substituted fused
ring.
4. The compound of claim 1, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein: R.sup.1 is halogen; R.sup.2 is --NH.sub.2; R.sup.4 is
lower alkyl; R.sup.3 is hydrogen; and R.sup.5 is aryl or
heteroaryl, wherein each of said aryl and heteroaryl groups is
monocyclic or bicyclic, the aryl group is substituted with 4 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring.
5. The compound of claim 1, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R.sup.1 is chloro or bromo, R.sup.2 is --NH.sub.2, and
R.sup.5 is a phenyl having 3 to 5 substituents, a pyridyl having 3
to 5 substituents or an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5
substituents.
6. A compound represented by Formula II, or a polymorph, solvate,
ester, tautomer, pharmaceutically acceptable salt or prodrug
thereof: ##STR43## wherein: R.sup.1 is halogen or lower alkyl;
R.sup.2 is --NR.sup.8R.sup.10; R.sup.3 is hydrogen, halogen, or
--CN; R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic,
wherein the aryl group is substituted with 3 to 5 substituents, the
heteroaryl group is substituted with 2 to 5 substituents, wherein
when the heteroaryl is substituted with only two substituents, the
two substituents must form part of an optionally substituted fused
ring, the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents are selected from the group of halogen, lower
alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic,
arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl,
perhaloalkyloxy, perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8,
--CN, --C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, phosphonate
and phosphonic acid; R.sup.8 is hydrogen, lower alkyl, lower aryl,
or --C(O)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.10R.sup.10 or --OR.sup.11; R.sup.10 is
independently hydrogen or lower alkyl; and R.sup.11 is lower alkyl,
lower aryl or lower heteroaryl; provided that when R.sup.5 is aryl,
R.sup.5 is not an organo-metallic cyclopentadiene; when R.sup.5 is
phenyl, the substituents are not 3,5 di-halo; when R.sup.5 is
alicyclic, the ring system does not contain any tetra-substituted
sp.sup.3 ring carbons; when R.sup.5 is heterocyclic, the ring
system does not contain any tetra-substituted sp.sup.3 ring carbons
or the ring system is not a tetra-substituted pyrrolidine.
7. The compound of claim 6, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein each of said aryl, heteroaryl, alicyclic or heterocyclic
group is monocyclic or bicyclic.
8. The compound of claim 6, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein: R.sup.1 is halogen or methyl; and R.sup.2 is --NHR.sup.8,
where R.sup.8 is hydrogen or --C(O)R.sup.9.
9. The compound of claim 8, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R.sup.1 is halogen.
10. The compound of claim 9, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R.sup.2 is --NH.sub.2 and R.sup.3 is hydrogen.
11. The compound of claim 6, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein: R.sup.1 is halogen; R.sup.2 is --NH.sub.2; R.sup.3 is
hydrogen; and R.sup.5 is aryl or heteroaryl, wherein each of the
aryl and heteroaryl groups is monocyclic or bicyclic, the aryl
group is substituted with 4 to 5 substituents, the heteroaryl group
is substituted with 2 to 5 substituents, wherein when the
heteroaryl is substituted with only two substituents, the two
substituents must form part of an optionally substituted fused
ring.
12. The compound of claim 6, or a polymorph, solvate , ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R.sup.1 is chloro or bromo, R.sup.2 is --NH.sub.2, and
R.sup.5 is a phenyl having 3 to 5 substituents.
13. The compound of claim 6, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R.sup.1 is chloro or bromo, R.sup.2 is --NH.sub.2, and
R.sup.5 is a pyridyl having 3 to 5 substituents.
14. The compound of claim 6, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R.sup.1 is chloro or bromo, R.sup.2 is --NH.sub.2, and
R.sup.5 is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5
substituents.
15. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR44## ##STR45##
16. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR46## ##STR47##
17. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR48##
18. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR49##
19. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR50##
20. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR51##
21. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR52##
22. The compound of claim 11, wherein the compound is a member
selected from the group of compounds below, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof: ##STR53## ##STR54## ##STR55## ##STR56##
23. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR57##
24. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR58##
25. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR59##
26. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR60##
27. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR61##
28. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR62##
29. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR63##
30. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR64##
31. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR65##
32. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR66##
33. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR67##
34. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR68##
35. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR69##
36. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR70##
37. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR71##
38. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR72##
39. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR73##
40. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR74##
41. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR75##
42. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR76##
43. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR77##
44. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR78##
45. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR79##
46. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR80##
47. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR81##
48. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR82##
49. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR83##
50. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR84##
51. The compound of claim 11, wherein said compound is represented
by the formula below, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof: ##STR85##
52. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR86##
53. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR87##
54. The compound of claim 11, wherein said compound is a member
selected from the group below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR88##
55. A pharmaceutical composition comprising one or more
pharmaceutical acceptable excipients and at least one compound
represented by Formula I below, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof:
##STR89## wherein: R.sup.1 is halogen or lower alkyl; R.sup.2 is
--NR.sup.8R.sup.10; R.sup.4 is --CHR.sup.12--; R.sup.3 is hydrogen,
halogen, or --CN; R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, wherein the aryl group is substituted with 3 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring, the alicyclic group is
substituted with 3 to 5 substituents, the heterocyclic group is
substituted with 3 to 5 substituents, and the substituents are
selected from the group of halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy,
aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,
perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, phosphonate and
phosphonic acid; R.sup.8 is hydrogen, lower alkyl, lower aryl, or
--C(O)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.10R.sup.10 or --OR.sup.11; R.sup.10 is
independently hydrogen or lower alkyl; R.sup.11 is lower alkyl,
lower aryl or lower heteroaryl; R.sup.12 is hydrogen or lower
alkyl; and provided that when R.sup.5 is aryl, R.sup.5 is not an
organo-metallic cyclopentadiene; when R.sup.5 is phenyl, the
substituents are not 3,5 di-halo; when R.sup.5 is alicyclic, the
ring system does not contain any tetra-substituted sp.sup.3 ring
carbons; and when R.sup.5 is heterocyclic, the ring system does not
contain any tetra-substituted sp.sup.3 ring carbons or the ring
system is not a tetra-substituted pyrrolidine.
56. The pharmaceutical composition of claim 55 wherein R.sup.4 is
--CH.sub.2--.
57. The pharmaceutical composition of claim 55, wherein: R.sup.1 is
halogen; R.sup.2 is --NH.sub.2; R.sup.3 is hydrogen; and R.sup.5 is
aryl or heteroaryl, wherein each of the aryl and heteroaryl groups
is monocyclic or bicyclic, the aryl group is substituted with 4 to
5 substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring.
58. The pharmaceutical composition of claim 56 wherein, wherein
R.sup.1 is chloro or bromo; R.sup.2 is --NH.sub.2; and R.sup.5 is
selected from a phenyl having 3 to 5 substituents, a pyridyl having
3 to 5 substituents and an 1-oxy-pyridyl (N-oxy-pyridyl) having 3
to 5 substituents.
59. A method of treating an gingival having an HSP90 mediated
disorder comprising administering to said individual a
pharmaceutical composition comprising a pharmaceutically effective
amount of a compound of Formula I: ##STR90## or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: R.sup.1 is halogen, --OR.sup.11,
SR.sup.11, --NHR.sup.8, hydrogen, or lower alkyl; R.sup.2 is
--NR.sup.8R.sup.10; R.sup.3 is hydrogen, halogen, --N.sub.3 or
--CN; R.sup.1 is --(CHR.sup.12).sub.n-- where n=0, 1 or 2,
--C(O)--, --C(S)--, or --S(O)--; R.sup.5 is alkyl, aryl,
heteroaryl, alicyclic, or heterocyclic, all optionally substituted
with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower
aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10; R.sup.8 is hydrogen, lower alkyl, lower aryl,
or --C(O)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.10R.sup.10, or --OR.sup.11; R.sup.10 is
independently hydrogen or lower alkyl; R.sup.11 is lower alkyl,
lower aryl or lower heteroaryl; R.sup.12 is hydrogen or lower
alkyl; and provided that: --R.sup.4R.sup.5 is not a ribose or
derivative thereof, or a sugar or derivative thereof;
--R.sup.4R.sup.5 is not a phosphonate or phosphonic acid, or
substituted with phosphonate or phosphonic acid; and when R.sup.4
is --(CH.sub.2).sub.n-- where n=1 or 2, then R.sup.4 and R.sup.5
are not connected through an ether linkage.
60. The method of claim 59, wherein: R.sup.3 is hydrogen, halogen
or --CN; and R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, all optionally substituted with halogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower alicyclic,
arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl,
perhaloalkyloxy, perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8,
--CN, --C(O)R.sup.9, --NO.sub.2, or --NR.sup.8R.sup.10.
61. The method of claim 59, wherein: R.sup.1 is halogen; R is
--NH.sub.2; R.sup.3 is hydrogen; R.sup.4 is --CH.sub.2; and R.sup.5
is aryl or heteroaryl, wherein: the aryl and heteroaryl groups are
monocyclic or bicyclic, the aryl group is substituted with 4 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with two
substituents, the two substituents must form part of an optionally
substituted fused ring.
62. The method of claim 60, wherein R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a phenyl having 3 to 5
substituents, a pyridyl having 3 to 5 substituents or an
1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
63. The method of claim 60, wherein the HSP90 mediated disorder is
selected from the group of inflammatory diseases, infections,
autoimmune disorders, stroke, ischemia, cardiac disorders,
neurological disorders, fibrogenetic disorders, proliferative
disorders, tumors, leukemias, neoplasms, cancers, carcinomas,
metabolic diseases, and malignant disease.
64. The method of claim 63 wherein the fibrogenetic disorder is
further selected from the group of scleroderma, polymyositis,
systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid
formation, interstitial nephritis and pulmonary fibrosis.
65. The method of claim 60, further comprising administering at
least one therapeutic agent selected from the group of cytotoxic
agents, anti-angiogenesis agents and anti-neoplastic agents.
66. The method of claim 65, wherein the at least one
anti-neoplastic agents is selected from the group of alkylating
agents, anti-metabolites, epidophyllotoxins, antineoplastic
enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones,
platinum coordination complexes, biological response modifiers and
growth inhibitors, hormonal/anti-hormonal therapeutic agents, and
haematopoietic growth factors.
67. A compound, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, prepared by
the process comprising: reacting a compound of formula Y and a
compound of formula Z, wherein: Y is represented by any of the
following formulae, respectively: ##STR91## and Z is
L.sup.1--R.sup.4--R.sup.5; wherein: L.sup.1 is halogen,
NR.sup.8R.sup.10, triflate, tosylate, or mesylate; R.sup.4 is
--CHR.sup.2--, R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, wherein: the aryl group is substituted with 3 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring, the alicyclic group is
substituted with 3 to 5 substituents, the heterocyclic group is
substituted with 3 to 5 substituents, and the substituents are
selected from the group of halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy,
aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,
perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --NO.sub.2, --NR R.sup.8R.sup.10, phosphonate and
phosphonic acid; R.sup.8 is hydrogen, lower alkyl, lower aryl, or
--C(O)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.10R.sup.10 or --OR.sup.11; R.sup.10 is
independently hydrogen or lower alkyl; R.sup.11 is lower alkyl,
lower aryl or lower heteroaryl; R.sup.12 is hydrogen or lower
alkyl; R.sup.21 is halogen, lower alkyl or --OH; R.sup.22 is
--NR.sup.8R.sup.10; R.sup.23 is hydrogen, halogen, or --CN;
R.sup.24 is --NH.sub.2, --NO.sub.2, or --NO; R.sup.25 is halogen or
--OH; R.sup.26 is --C(O)NH.sub.2 or C(O)OEt; and R.sup.27 is
--NH.sub.2, --OH or halogen; provided that: when R.sup.5 is aryl,
R.sup.5 is not an organo-metallic cyclopentadiene; when R.sup.5 is
phenyl, the substituents are not 3, 5 di-halo; when R.sup.5 is
alicyclic, the ring system does not contain any tetra-substituted
sp.sup.3 ring carbons; or when R.sup.5 is heterocyclic, the ring
system does not contain any tetra-substituted sp.sup.3 ring carbons
or the ring system is not a tetra-substituted pyrrolidine.
68. The compound of claim 67 wherein R.sup.4 is --CH.sub.2--.
69. The compound of claim 68, wherein: L.sup.1 is --Cl, --Br or
NH.sub.2; and R.sup.5 is aryl or heteroaryl, wherein the aryl group
is substituted with 4 to 5 substituents, the heteroaryl group is
substituted with 2 to 5 substituents, wherein when the heteroaryl
is substituted with two substituents, the two substituents must
form part of an optionally substituted fused ring.
70. The compound of claim 69, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein Y is a substituted purine.
71. The compound of claim 68, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein said reaction is performed in a solvent comprising a member
selected from the group of DMF, THF, and DMSO.
72. The compound of claim 70, or a polymorph, solvate, ester,
tautomer, pharmaceutically acceptable salt or prodrug thereof,
wherein said reaction is performed in a solvent that comprises DMF.
Description
RELATED APPLICATIONS
[0001] This application relates and claims priority to U.S.
Provisional Application Ser. No. 60/504,135, filed Sept. 18, 2003,
entitled NOVEL HETEROCYCLIC COMPOUNDS AS HSP90 INHIBITORS and U.S.
Provisional Application Ser. No. 60/591,467, filed Jul. 26, 2004,
entitled 2-AMINOPURINE ANALOGS HAVING HSP90-INHIBITING ACTIVITY.
This application also relates to three other United States Utility
Applications, entitled PYRAZOLOPYRIDIMES AND RELATED ANALOGS AS
HSP90 INHIBITORS, PYRROLOPYRIMIDINES AND RELATED ANALOGS AS HSP90
INHIBITORS, and TRIAZOPYRIMIDES AND RELATED ANALOGS AS HSP90
INHIBITORS, which will be filed on the same date by the same
entity. This application further relates to International
Application PCT/US02/35069, filed Oct. 30, 2002, entitled PURINE
ANALOGS HAVING HSP90-INHIBITING ACTIVITY. All the. above cited U.S.
utility applications, provisional applications and international
application are expressly incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The invention relates in general to 2-aminopurine analogs
and their broad-spectrum utility, e.g., in inhibiting heat shock
protein 90 (HSP90) to thereby treat or prevent HSP90-mediated
diseases.
BACKGROUND
[0003] HSP90s are ubiquitous chaperone proteins that are involved
in folding, activation and assembly of a wide range of proteins,
including key proteins involved in signal transduction, cell cycle
control and transcriptional regulation. Researchers have reported
that HSP90 chaperone proteins are associated with important
signaling proteins, such as steroid hormone receptors and protein
kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4,
and ErbB-2 (Buchner J. TIBS 1999,24, 136-141; Stepanova, L. et al.
Genes Dev. 1996,10, 1491-502; Dai, K. et al. J. Biol. Chem. 1996,
271, 22030-4). Studies further indicate that certain co-chaperones,
e.g., HSP70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1,
immunophilins, p23, and p50, may assist HSP90 in its function (see,
e.g., Caplan, A. Trends in Cell Biol 1999, 9, 262-68).
[0004] Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin
(GM), and 17-allylaminogeldanamycin (17-AAG) are thought to exert
their anticancerous effects by tight binding of the N-terminus
pocket of HSP90, thereby destabilizing substrates that normally
interact with HSP90 (Stebbins, C. et al. Cell 1997, 89, 239-250).
This pocket is highly conserved and has weak homology to the
ATP-binding site of DNA gyrase (Stebbins, C. et al., supra;
Grenert, J. P. et al. J. Biol. Chem. 1997, 272, 23843-50). Further,
ATP and ADP have both been shown to bind this pocket with low
affinity and to have weak ATPase activity (Proromou, C. et al. Cell
1997, 90, 65-75; Panaretou, B. et al. EMBO J. 1998, 17, 4829-36).
In vitro and in vivo studies have demonstrated that occupancy of
this N-terminal pocket by ansamycins and other HSP90 inhibitors
alters HSP90 function and inhibits protein folding. At high
concentrations, ansamycins and other HSP90 inhibitors have been
shown to prevent binding of protein substrates to HSP90 (Scheibel,
T. H. et al. Proc. Natl. Acad. Sci. USA 1999, 96, 1297-302;
Schulte, T. W. et al. J. Biol. Chem. 1995, 270, 24585-8; Whitesell,
L., et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).
Ansamycins have also been demonstrated to inhibit the ATP-dependent
release of chaperone-associated protein substrates (Schneider, C.
L. et al. Proc. Natl. Acad. Sci., USA 1996, 93, 14536-41;
Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270, 16580-16587). In
either event, the substrates are degraded by a ubiquitin-dependent
process in the proteasome (Schneider, C. L., supra; Sepp-Lorenzino,
L., et al. J. Biol. Chem. 1995, 270, 16580-16587; Whitesell, L. et
al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).
[0005] HSP90 substrate destabilization occurs in tumor and
non-transformed cells alike and has been shown to be especially
effective on a subset of signaling regulators, e.g., Raf (Schulte,
T. W. et al. Biochem. Biophys. Res. Commun. 1997, 239, 655-9;
Schulte, T. W., et al. J. Biol. Chem. 1995, 270, 24585-8), nuclear
steroid receptors (Segnitz, B.; U. Gehring J. Biol. Chem. 1997,
272, 18694-18701; Smith, D. F. et al. Mol. Cell. Biol. 1995, 15,
6804-12), v-Src (Whitesell, L., et al. Proc. Natl. Acad. Sci. USA
1994, 91, 8324-8328) and certain transmembrane tyrosine kinases
(Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580-16587)
such as EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int.
J. Cancer 1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994, 54,
2724-2730; Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271,
22796-801; Schnur, R. et al. J. Med Chem. 1995, 38, 3806-3812),
CDK4, and mutant p53. Erlichman et al. Proc. AACR 2001, 42,
abstract 4474. The ansamycin-induced loss of these proteins leads
to the selective disruption of certain regulatory pathways and
results in growth arrest at specific phases of the cell cycle
(Muise-Heimericks, R. C. et al. J. Biol. Chem. 1998, 273,
29864-72), and apoptosis, and/or differentiation of cells so
treated (Vasilevskaya, A. et al. Cancer Res., 1999, 59, 3935-40).
Ansamycins thus hold great promise for the treatment and/or
prevention of many types of cancers and proliferative disorders,
and also hold promise as traditional antibiotics. However, their
relative insolubility makes them difficult to formulate and
administer, and they are not easily synthesized and currently must,
at least in part, be generated through fermentation. Further, the
dose limiting toxicity of ansamycins is hepatic.
[0006] In addition to anti-cancer and antitumorgenic activity,
HSP90 inhibitors have also been implicated in a wide variety of
other utilities, including use as anti-inflammation agents,
anti-infectious disease agents, agents for treating autoimmunity,
agents for treating stroke, ischemia, multiple sclerosis, cardiac
disorders, central nervous system related disorders and agents
usefull in promoting nerve regeneration (See, e.g., Rosen et al. WO
02/09696 (PCT/US01/23640); Degranco et al. WO 99/51223
(PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 B1; DeFranco et
al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above,
there are reports in the literature that fibrogenetic disorders
including but not limited to scleroderma, polymyositis, systemic
lupus, rheumatoid arthritis, liver cirrhosis, keloid formation,
interstitial nephritis, and pulmonary fibrosis also may be
treatable with HSP90 inhibitors. Strehlow, WO 02/02123
(PCT/US01/20578). Still further HSP90 modulation, modulators and
uses thereof are reported in Application Nos. PCT/US03/04283,
PCT/US02/35938, PCT/US02/16287, PCT/US02/06518, PCT/US98/09805,
PCT/US00/09512, PCT/US01/09512, PCT/US01/23640, PCT/US01/46303,
PCT/US01/46304, PCT/US02/06518, PCT/US02/29715, PCT/US02/35069,
PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668, 60/335,391,
60/128,593, 60/337,919, 60/340,762, 60/359,484 and 60/331,893.
[0007] Recently, purine derivatives showing HSP90 inhibitory
activity have been reported, e.g., in PCT/US02/35069;
PCT/US02/36075. Purine moieties are well accepted bioisosteres for
a variety of ATP-dependent molecular targets, see, JP 10025294;
U.S. Pat. Nos. 4,748,177; 4,772,606; 6,369,092; WO 00/06573; WO
02/055521; WO 02/055082; WO 02/055083; European Patent 0178178;
Eur. J. Med. Chem. 1994, 29(1), 3-9; and J. Het. Chem. 1990, 27(5),
1409. However, compounds having the desired potency, selectivity
and pharmaceutical properties required for effective HSP90
inhibition in vivo have not been reported. Therefore, a need
remains for additional novel and potent HSP90 inhibitors that meet
the demanding biological and pharmaceutical criteria required to
proceed towards human clinical trials.
SUMMARY OF THE INVENTION
[0008] The present invention is directed towards heterocyclic
compounds, in particular towards 2-aminopures and related compounds
that show broad utility, e.g., in inhibiting HSP90 and/or treating
and preventing diseases that are HSP90-dependent.
[0009] In one aspect, the invention comprises the heterocyclic
compounds as specified below in Formulae A and I, and compounds
that are produced by a process of the invention. Also included in
the scope of the present invention are stereoisomeric forms,
including the individual enantiomers and diastereomers, racemic
mixtures, and diastereomeric mixtures, as well as polymorphs,
solvates, esters, tautomers, pharmaceutically acceptable salts and
prodrugs of these compounds. Stereoisomers of the compounds of the
present invention may be isolated by standard resolution techniques
such as, for example, fractional crystallization and chiral column
chromatography.
[0010] In one embodiment, the invention provides compounds of
Formula A, or a polymorph, solvate, ester, tautomer, diastereomer,
enantiomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility by inhibiting HSP90 and treating and/or
preventing diseases that are HSP90-dependent. ##STR1## wherein:
[0011] X.sup.1 and X.sup.2 are the same or different and each is
nitrogen or --CR.sup.6; [0012] X.sup.3 is nitrogen or --CR.sup.3
wherein R.sup.3 is hydrogen, OH, a keto tautomer, --OR.sup.8, --CN,
halogen, lower alkyl, or --C(O)R.sup.9; [0013] X.sup.4 is nitrogen
or --CR.sup.6 when X.sup.3 is nitrogen, and X.sup.4 is
--CR.sup.6R.sup.7 when X.sup.3 is --CR.sup.3; [0014] R.sup.1 is
halogen, --OR.sup.8, --SR.sup.8, or lower alkyl; [0015] R.sup.2 is
--NR.sup.8R.sup.10; [0016] R.sup.4 is --(CH.sub.2).sub.n-- wherein
n=0-3, --C(O), --C(S), --SO.sub.2--, or --SO.sub.2N--; and [0017]
R.sup.5 is alkyl, aromatic, heteroaromatic, alicyclic, or
heterocyclic, each of which is optionally bi- or tri-cyclic, and
optionally substituted with H, halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, aralkyl, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10.
[0018] In certain embodiments, there are exclusionary provisos with
respect to compounds disclosed in JP 10025294; U.S. Pat. Nos.
4,748,177; 4,748,177; 6,369,092; WO 00/06573; WO 02/055521; WO
02/055082; WO 02/055083; Eur. J. Med. Chem. 1994, 29(1), 3-9; and
J. Het. Chem. 1990, 27(5), 1409, which disclose compounds with
--R.sup.4R.sup.5 comprising ribose or a derivative thereof, or a
sugar or derivative thereof; compounds where --R.sup.4R.sup.5 is a
phosphonate or phosphonic acid, or is substituted with a
phosphonate or phosphonic acid; or compounds where R.sup.4 is
--CH.sub.2-- or --(CH.sub.2).sub.n-- that are connected through an
oxygen atom to another group.
[0019] In another embodiment, the invention provides compounds of
Formula I, or a polymorph, solvate, ester, tautomer, enantiomer,
diastereomer, pharmaceutically acceptable salt or prodrug thereof,
which show utility for inhibiting HSP90 and for treating and/or
preventing diseases that are HSP90-dependent, ##STR2## wherein:
[0020] R.sup.1 is halogen or lower alkyl; [0021] R.sup.2 is
--NR.sup.8R.sup.10; [0022] R.sup.4 is --CHR.sup.12--; [0023]
R.sup.3 is hydrogen, halogen, or --CN; [0024] R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, wherein [0025] the aryl
group is substituted with 3 to 5 substituents, [0026] the
heteroaryl group is substituted with 2 to 5 substituents, wherein
when the heteroaryl is substituted with only two substituents, the
two substituents must form part of an optionally substituted fused
ring, [0027] the alicyclic group is substituted with 3 to 5
substituents, [0028] the heterocyclic group is substituted with 3
to 5 substituents, and [0029] the substituents are selected from
the group of halogen, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10, phosphonate and phosphonic acid; [0030] R.sup.8
is hydrogen, lower alkyl, lower aryl, or --C(O)R.sup.9; [0031]
R.sup.9 is lower alkyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11; [0032] R.sup.10 is
independently hydrogen or lower alkyl; [0033] R.sup.11 is lower
alkyl, lower aryl or lower heteroaryl; [0034] R.sup.12 is hydrogen
or lower alkyl; provided that [0035] when R.sup.5 is aryl, R.sup.5
is not an organo-metallic cyclopentadiene; [0036] when R.sup.5 is
phenyl, the substituents are not 3,5 di-halo; [0037] when R.sup.5
is alicyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons; and [0038] when R.sup.5 is
heterocyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons or the ring system is not a
tetra-substituted pyrrolidine.
[0039] In another embodiment, the invention provides compounds, or
a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,
pharmaceutically acceptable salt or prodrug thereof, which show
utility for inhibiting HSP90 and treating and/or preventing
diseases that are HSP90-dependent, that are prepared by the process
comprising: [0040] reacting a compound of Formula Y and a compound
of Formula Z, wherein: [0041] Y is represented by any of the
following formulae: ##STR3## [0042] Z is L.sup.1--R.sup.4--R.sup.5;
wherein: [0043] L.sup.1 is halogen, NR.sup.8R.sup.10, triflate,
tosylate, or mesylate; [0044] R.sup.4 is --CHR.sup.12--, [0045]
R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
[0046] the aryl group is substituted with 3 to 5 substituents,
[0047] the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring, [0048] the alicyclic group is
substituted with 3 to 5 substituents, [0049] the heterocyclic group
is substituted with 3 to 5 substituents, and [0050] the
substituents are selected from the group of halogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower alicyclic,
arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl,
perhaloalkyloxy, perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8,
--CN, --C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, phosphonate
and phosphonic acid; [0051] R.sup.8 is hydrogen, lower alkyl, lower
aryl, or --C(O)R.sup.9; [0052] R.sup.9 is lower alkyl, lower aryl,
lower heteroaryl, --NR.sup.10OR.sup.10 or --OR.sup.11; [0053]
R.sup.10 is independently hydrogen or lower alkyl; [0054] R.sup.11
is lower alkyl, lower aryl or lower heteroaryl; [0055] R.sup.12 is
hydrogen or lower alkyl; [0056] R.sup.21 is halogen, lower alkyl or
--OH; [0057] R.sup.22 is --NR.sup.8R.sup.10; [0058] R.sup.23 is
hydrogen, halogen, or --CN; [0059] R.sup.24 is --NH.sub.2,
--NO.sub.2 or --NO; [0060] R.sup.25 is halogen or --OH; [0061]
R.sup.26 is --C(O)NH.sub.2 or C(O)OEt; and [0062] R.sup.27 is
--NH2, --OH or halogen; provided that: [0063] when R.sup.5 is aryl,
R.sup.5 is not an organo-metallic cyclopentadiene; [0064] when
R.sup.5 is phenyl, the substituents are not 3, 5 di-halo; [0065]
when R.sup.5 is alicyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons; or [0066] when R.sup.5 is
heterocyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons or the ring system is not a
tetra-substituted pyrrolidine.
[0067] Another aspect of the invention is a method of treating an
individual having an HSP90 mediated disorder comprising
administering to said individual a pharmaceutical composition
comprising a pharmaceutically effective amount of a compound of
Formula I: ##STR4## or a polymorph, solvate, ester, tautomer,
enantiomer, diastereomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: [0068] R.sup.1 is halogen, --OR.sup.11,
--SR.sup.11, --NHR.sup.8, hydrogen, or lower alkyl; [0069] R.sup.2
is --NR.sup.8R.sup.10; [0070] R.sup.3 is hydrogen, halogen,
--N.sub.3, or --CN; [0071] R.sup.4 is --(CHR.sup.12).sub.n-- where
n=0, 1 or 2, --C(O)--, --C(S)--, or --S(O)--; [0072] R.sup.5 is
alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all optionally
substituted with halogen, lower alkyl, lower alkenyl, lower
alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy,
aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,
perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --NO.sub.2, or --NR.sup.8R.sup.10; [0073] R.sup.8 is
hydrogen, lower alkyl, lower aryl, or --C(O)R.sup.9; [0074] R.sup.9
is lower alkyl, lower aryl, lower heteroaryl, --NR.sup.10R.sup.10,
or --OR.sup.11; [0075] R.sup.10 is independently hydrogen or lower
alkyl; [0076] R.sup.11 is lower alkyl, lower aryl or lower
heteroaryl; [0077] R.sup.12 is hydrogen or lower alkyl; provided
that: [0078] --R.sup.4R.sup.5 is not a ribose or derivative
thereof, or a sugar or derivative thereof; [0079] --R.sup.4R.sup.5
is not a phosphonate or phosphonic acid, or substituted with
phosphonate or phosphonic acid; and [0080] when R.sup.4 is
--(CH.sub.2).sub.n-- where n=1 or 2, then R.sup.4 and R.sup.5 are
not connected through an ether linkage.
[0081] In one embodiment, the invention provides a method for
treating an individual having a disorder selected from the group of
inflammatory diseases, infections, autoimmune disorders, stroke,
ischemia, cardiac disorders, neurological disorders, fibrogenetic
disorders, proliferative disorders, tumors, leukemias, neoplasms,
cancers, carcinomas, metabolic diseases, and malignant disease.
[0082] In another embodiment, the invention provides a method for
treating an individual having a fibrogenetic disorder, such as, for
example, scleroderma, polymyositis, systemic lupus, rheumatoid
arthritis, liver cirrhosis, keloid formation, interstitial
nephritis and pulmonary fibrosis.
[0083] In another embodiment, the invention provides a combination
therapy comprising the administration of a pharmaceutically
effective amount of a compound of Formulae A, I or II, or a
solvate, tautomer, pharmaceutically acceptable salt, polymorph, or
prodrug thereof according to any of the preceding aspects or
embodiments, and at least one therapeutic agent selected from the
group of cytotoxic agents, anti-angiogenesis agents and
anti-neoplastic agents. The anti-neoplastic agent may be selected
from the group of alkylating agents, anti-metabolites,
epidophyllotoxins antineoplastic enzymes, topoisomerase inhibitors,
procarbazines, mitoxantrones, platinum coordination complexes,
biological response modifiers and growth inhibitors,
honnonal/anti-hormonal therapeutic agents, and haematopoietic
growth factors.
[0084] In another aspect, the present invention is directed to
pharmaceutical compositions comprising the compounds of the
invention, in particular, the compounds of Formulae A, I and II,
and compounds formed by the process of the invention, and their
polymorphs, solvates, esters, tautomers, diastereomer, enantiomers,
pharmaceutically acceptable salts and prodrugs thereof, and one or
more pharmaceutical excipients, for use in treatment or prevention
of diseases that are HSP90-dependent.
[0085] Any of the above described aspects and embodiments of the
invention can be combined where practical.
[0086] The individual compounds, methods and compositions
prescribed do not preclude the utilization of other, unspecified
steps and agents, and those of ordinary skill in the art will
appreciate that additional steps and compounds may also be combined
usefully within the spirit of various aspects and embodiments of
the invention.
[0087] Advantages of the invention depend on the specific aspect
and embodiment and may include one or more of: ease of synthesis
and/or formulation, solubility, and IC.sub.50 relative to
previously existing compounds in the same or different classes of
HSP90 inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0088] A "pharmaceutically acceptable derivative or prodrug" means
any pharmaceutically acceptable salt, ester, salt of an ester or
other derivative of a compound of this invention, which, upon
administration to a recipient, is capable of providing, either
directly or indirectly, a compound of this invention or a
pharmaceutically active metabolite or residue thereof. Particularly
favored derivatives or prodrugs are those that increase the
bioavailability of the compounds of this invention when such
compounds are administered to a patient (e.g., by allowing orally
administered compound to be more readily absorbed into blood) or
which enhance delivery of the parent compound to a biological
compartment (e.g., the brain or lymphatic system).
[0089] A "pharmaceutically acceptable salt" may be prepared for any
compound of the invention having a functionality capable of forming
a salt, for example, an acid or base functionality.
Pharmaceutically acceptable salts may be derived from organic or
inorganic acids and bases. Compounds of the invention that contain
one or more basic functional groups, e.g., amino or alkylamino, are
capable of forming pharmaceutically acceptable salts with
pharmaceutically acceptable organic and inorganic acids. These
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or by separately
reacting a purified compound of the invention in its free base form
with a suitable organic or inorganic acid, and isolating the salt
thus formed. Examples of suitable acid salts include acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, flimarate, glucoheptanoate,
glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malonate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate,
pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,
pivalate, propionate, salicylate, succinate, sulfate, tartrate,
thiocyanate, tosylate and undeconate. Other acids, such as oxalic,
while not in themselves pharmaceutically acceptable, may be
employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts. See, e.g., Berge et al.
"Pharmaceutical Salts", J. Pharm. Sci. 1977, 66:1-19.
[0090] Compounds of the present invention that contain one or more
acidic functional groups are capable of forming pharmaceutically
acceptable salts with pharmaceutically acceptable bases. The term
"pharmaceutically acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ during the final isolation and purification of the
compounds, or by separately reacting the purified compound in its
free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a pharmaceutically acceptable metal
cation, with ammonia, or with a pharmaceutically acceptable organic
primary, secondary or tertiary amine. Representative alkali or
alkaline earth salts include the lithium, sodium, potassium,
calcium, magnesium, and aluminum salts and the like. Illustrative
examples of some of the bases that can be used include sodium
hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate, N.sup.+(C.sub.1-4 alkyl).sub.4, and the like.
Representative organic amines useful for the formation of base
addition salts include ethylamine, diethylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine and the like. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization. See, for example, Berge et al., supra.
[0091] Pharmaceutically acceptable prodrugs of the compounds of
this invention include, but are not limited to, esters, carbonates,
thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,
quaternary derivatives of tertiary amines, N-Mannich bases, Schiff
bases, aminoacid conjugates, phosphate esters, metal salts and
sulfonate esters.
[0092] Suitable positions for derivatization of the compounds of
the invention to create "prodrugs" include but are not limited,
2-amino substitution. Those of ordinary skill in the art have the
knowledge and means to accomplish this without undue
experimentation. Various forms of prodrugs are well known in the
art. For examples of such prodrug derivatives, see, e.g.,
[0093] a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and
Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.
42, p. 309-396;
[0094] b) Bundgaard, H. "Design and Application of Prodrugs" in A
Textbook of Drug Design and Development, Krosgaard-Larsen and H.
Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and
[0095] c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8,
1-38.
Each of which is incorporated herein by reference.
[0096] The term "prodrugs" as employed herein includes, but is not
limited to, the following groups and combinations of these
groups:
[0097] Hydroxy Prodrugs: [0098] Acyloxyalkyl esters; [0099]
Alcoxycarbonyloxyalkyl esters; [0100] Alkyl esters; [0101] Aryl
esters; [0102] Disulfide containing esters.
[0103] Amine Prodrugs: ##STR5##
[0104] The term "alkyl," alone or in combination, refers to an
optionally substituted straight-chain, or optionally substituted
branched-chain saturated hydrocarbon radical having from one to
about thirty carbons, more preferably one to twelve carbons.
Examples of alkyl radicals include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl,
pentyl, hexyl, heptyl, octyl and the like. The term "cycloalkyl"
embraces cyclic alkyl radicals which include monocyclic, bicyclic,
tricyclic, and higher multicyclic alkyl radicals wherein each
cyclic moiety has from three to about eight carbon atoms. Examples
of cycloalkyl radicals include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and the like. A "lower alkyl" is a shorter
alkyl, e.g., one containing from one to about six carbon atoms.
[0105] The term "alkenyl," alone or in combination, refers to an
optionally substituted straight-chain, or optionally substituted
branched-chain hydrocarbon radical having one or more carbon-carbon
double-bonds and having from two to about thirty carbon atoms, more
preferably two to about eighteen carbons. Examples of alkenyl
radicals include ethenyl, propenyl, butenyl, 1,3-butadienyl and the
like. The term "cycloalkenyl" refers to cyclic alkenyl radicals
which include monocyclic, bicyclic, tricyclic, and higher
multicyclic alkenyl radicals wherein each cyclic moiety has from
three to about eight carbon atoms. A "lower alkenyl" refers to an
alkenyl having from two to about six carbons.
[0106] The term "alkynyl," alone or in combination, refers to an
optionally substituted straight-chain or optionally substituted
branched-chain hydrocarbon radical having one or more carbon-carbon
triple-bonds and having from two to about thirty carbon atoms, more
preferably from two to about twelve carbon atoms, from two to about
six carbon atoms as well as those having from two to about four
carbon atoms. Examples of alkynyl radicals include ethynyl,
2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. The term
"cycloalkynyl" refers to cyclic alkynyl radicals which include
monocyclic, bicyclic, tricyclic, and higher multicyclic alkynyl
radicals wherein each cyclic moiety has from three to about eight
carbon atoms. A "lower alkynyl" refers to an alkynyl having from
two to about six carbons.
[0107] The terms "heteroalkyl, heteroalkenyl and heteroalkynyl"
include optionally substituted alkyl, alkenyl and alkynyl
structures, as described above, and which have one or more skeletal
chain atoms selected from an atom other than carbon, e.g., oxygen,
nitrogen, sulfur, phosphorous or combinations thereof.
[0108] The term "carbon chain" embraces any alkyl, alkenyl,
alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group,
which are linear, cyclic, or any combination thereof. If the chain
is part of a linker and that linker comprises one or more rings as
part of the core backbone, for purposes of calculating chain
length, the "chain" only includes those carbon atoms that compose
the bottom or top of a given ring and not both, and where the top
and bottom of the ring(s) are not equivalent in length, the shorter
distance shall be used in determining the chain length. If the
chain contains heteroatoms as part of the backbone, those atoms are
not calculated as part of the carbon chain length.
[0109] The term "membered ring" can embrace any cyclic structure,
including aromatic, heteroaromatic, alicyclic, heterocyclic and
polycyclic fused ring systems as described below. The term
"membered" is meant to denote the number of skeletal atoms that
constitute the ring. Thus, for example, pyridine, pyran, and
pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and
thiophene are five-membered rings.
[0110] The term "aryl," alone or in combination, refers to an
optionally substituted aromatic hydrocarbon radical of six to about
twenty ring atoms, and includes mono-aromatic rings and fused
aromatic ring. A fused aromatic ring radical contains from two to
four fused rings where the ring of attachment is an aromatic ring,
and the other individual rings within the fused ring may be
aromatic, heteroaromatic, alicyclic or heterocyclic. Further, the
term aryl includes mono-aromatic ring and fused aromatic rings
containing from six to about twelve carbon atoms, as well as those
containing from six to about ten carbon atoms. Examples of aryl
groups include, without limitation, phenyl, naphthyl, anthryl,
chrysenyl, and benzopyrenyl ring systems. The term "lower aryl"
refers to an aryl having six to about ten skeletal ring carbons,
e.g., phenyl and naphthyl ring systems.
[0111] The term "heteroaryl" refers to optionally substituted
aromatic radicals containing from about five to about twenty
skeletal ring atoms and where one or more of the ring atoms is a
heteroatom such as, for example, oxygen, nitrogen, sulfur, selenium
and phosphorus. The term heteroaryl includes optionally substituted
mono-heteroaryl radicals and fused heteroaryl radicals having at
least one heteroatom (e.g., quinoline, benzothiazole). A fused
heteroaryl radical may contain from two to four fused rings and
where the ring of attachment is a heteroaromatic ring, the other
individual rings within the fused ring system may be aromatic,
heteroaromatic, alicyclic or heterocyclic. The term heteroaryl also
includes mono-heteroaryls or fused heteroaryls having from five to
about twelve skeletal ring atoms, as well as those having from five
to about ten skeletal ring atoms. Examples of heteroaryls include,
without limitation, furanyl, benzofuranyl, chromenyl, pyridyl,
pyrrolyl, indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl,
pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
benzothiozole, benzimidazole, benzoxazoles, benzothiadiazole,
benzoxadiazole, benzotriazole, quinolines, isoquinolines, indoles,
purinyl, indolizinyl, thienyl and the like and their oxides. The
term "lower heteroaryl" refers to a heteroaryl having five to about
ten skeletal ring atoms, e.g., pyridyl, thienyl, pyrimidyl,
pyrazinyl, pyrrolyl, or furanyl.
[0112] The term "alicyclic" alone or in combination, refers to an
optionally substituted saturated or unsaturated nonaromatic
hydrocarbon ring system containing from three to about twenty ring
atoms. The term alicyclic includes mono-alicyclic and fused
alicyclic radicals. A fused alicyclic may contain from two to four
fused rings where the ring of attachment is an alicyclic ring, and
the other individual rings within the fused-alicyclic radical may
be aromatic, heteroaromatic, alicyclic and heterocyclic. The term
alicyclic also includes mono-alicyclic and fused alicyclic radicals
containing from three to about twelve carbon atoms, as well as
those containing from three to about ten carbon atoms. Examples of
alicyclics include, without limitation, cyclopropyl, cyclopropenyl,
cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl,
cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The
term "lower alicyclic" refers to an alicyclic having three to about
ten skeletal ring carbons, e.g., cyclopropyl, cyclopropenyl,
cyclobutyl, cyclopentyl, decalinyl, and cyclohexyl.
[0113] The term "heterocyclic" refers to optionally substituted
saturated or unsaturated nonaromatic ring radicals containing from
five to about twenty ring atoms where one or more of the ring atoms
are heteroatoms such as, for example, oxygen, nitrogen, sulfur, and
phosphorus. The term alicyclic includes mono-heterocyclic and fused
heterocyclic ring radicals. A fused heterocyclic radical may
contain from two to four fused rings where the attaching ring is a
heterocyclic, and the other individual rings within the fused
heterocyclic radical may be aromatic, heteroaromatic, alicyclic or
heterocyclic. The term heterocyclic also includes mono-heterocyclic
and fused alicyclic radicals having from five to about twelve
skeletal ring atoms, as well as those having from five to about ten
skeletal ring atoms. Example of heterocyclics include without
limitation, tetrahydrofuranyl, benzodiazepinyl,
tetrahydroindazolyl, dihyroquinolinyl, and the like. The term
"lower heterocyclic" refers to a heterocyclic ring system having
five to about ten skeletal ring atoms, e.g., dihydropyranyl,
pyrrolidinyl, indolyl, piperidinyl, piperazinyl, and the like.
[0114] The term "alkylaryl," alone or in combination, refers to an
aryl radical as defined above in which one H atom is replaced by an
alkyl radical as defined above, such as, for example, tolyl, xylyl
and the like.
[0115] The term "arylalkyl," or "aralkyl," alone or in combination,
refers to an alkyl radical as defined above in which one H atom is
replaced by an aryl radical as defined above, such as, for example,
benzyl, 2-phenylethyl and the like.
[0116] The term "heteroarylalkyl" refers to an alkyl radical as
defined above in which one H atom is replaced by a heteroaryl
radical as defined above, each of which may be optionally
substituted.
[0117] The term "alkoxy," alone or in combination, refers to an
alkyl ether radical, alkyl-O--, wherein the term alkyl is defined
as above. Examples of alkoxy radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy and the like.
[0118] The term "aryloxy," alone or in combination, refers to an
aryl ether radical wherein the term aryl is defined as above.
Examples of aryloxy radicals include phenoxy, benzyloxy and the
like.
[0119] The term "alkylthio," alone or in combination, refers to an
alkyl thio radical, alkyl-S--, wherein the term alkyl is as defined
above.
[0120] The term "arylthio," alone or in combination, refers to an
aryl thio radical, aryl-S--, wherein the term aryl is as defined
above.
[0121] The term "heteroarylthio" refers to the group
heteroaryl-S--, wherein the term heteroaryl is as defined
above.
[0122] The term "acyl" refers to a radical --C(O)R where R includes
alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,
arylalkyl or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl,
aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl
alkyl groups may be optionally substituted.
[0123] The term "acyloxy" refers to the ester group --OC(O)R, where
R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic,
heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl,
alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,
arylalkyl or heteroarylalkyl may be optionally substituted.
[0124] The term "carboxy esters" refers to --C(O)OR where R is
alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl
groups may be optionally substituted.
[0125] The term "carboxamido" refers to ##STR6##
[0126] where each of R and R' are independently selected from the
group consisting of H, alkyl, aryl, heteroaryl, alicyclic,
heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl,
aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may
be optionally substituted.
[0127] The term "oxo" refers to .dbd.O.
[0128] The term "halogen" includes F, Cl, Br and I.
[0129] The terms "haloalkyl, haloalkenyl, haloalkynyl and
haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures,
as described above, that are substituted with one or more
fluorines, chlorines, bromines or iodines, or with combinations
thereof.
[0130] The terms "perhaloalkyl, perhaloalkyloxy and perhaloacyl"
refer to alkyl, alkyloxy and acyl radicals as described above, that
all the H atoms are substituted with fluorines, chlorines, bromines
or iodines, or combinations thereof.
[0131] The terms "cycloalkyl, arylalkyl, aryl, heteroaryl,
alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and
heteroalkyl" include optionally substituted cycloalkyl, arylalkyl,
aryl, heteroaryl, alicyclic, heterocyclic, alkyl alkynyl, alkenyl,
haloalkyl and heteroalkyl groups.
[0132] The terms "alkylamino", refers to the group --NHR where R is
independently selected from alkyl.
[0133] The terms "dialkylamino", refers to the group --NRR' where R
and R' are alkyls.
[0134] The term "sulfide" refers to a sulfur atom covalently linked
to two atoms; the formal oxidation state of said sulfur is (II).
The term "thioether" may be used interchangeably with the term
"sulfide."
[0135] The term "sulfoxide" refers to a sulfur atom covalently
linked to three atoms, at least one of which is an oxygen atom; the
formal oxidation state of said sulfur atom is (IV).
[0136] The term "sulfone" refers to a sulfur atom covalently linked
to four atoms, at least two of which are oxygen atoms; the formal
oxidation state of said sulfur atom is (VI).
[0137] The terms "optional" or "optionally" mean that the
subsequently described event or circumstance may but need not
occur, and that the description includes instances where the event
or circumstance occurs and instances in which it does not. For
example, "aryl optionally mono- or di-substituted with an alkyl"
means that the alkyl may but need not be present, or either one
alkyl or two may be present, and the description includes
situations where the aryl is substituted with one or two alkyls and
situations where the aryl is not substituted with an alkyl.
[0138] "Optionally substituted" groups may be substituted or
unsubstituted. The substituents of an "optionally substituted"
group may include, without limitation, one or more substituents
independently selected from the following groups or designated
subsets thereof: lower alkyl, lower alkenyl, lower alkynyl, lower
aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl,
heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino,
dialkylamino, diarylalkylamino, alkylthio, arylthio,
heteroarylthio, oxo, oxa, carbonyl (--C(O)), carboxyesters
(--C(O)OR), carboxamido (--C(O)NH.sub.2), carboxy, acyloxy, --H,
halo, --CN, --NO.sub.2, --N.sub.3, --SH, --OH, --C(O)CH.sub.3,
perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl,
thiophene, furanyl, indole, indazole, esters, amides, phosphonates,
phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones,
sulfates, sulphonamides, carbamates, ureas, thioureas and
thioamides, thioalkyls. An optionally substituted group may be
unsubstituted (e.g., --CH.sub.2CH.sub.3), fully substituted (e.g.,
--CF.sub.2CF.sub.3), monosubstituted (e.g., --CH.sub.2CH.sub.2F) or
substituted at a level anywhere in-between fully substituted and
monosubstituted (e.g., --CH.sub.2CF.sub.3).
[0139] The term "pyridine-1-oxy" also means "pyridine--N-oxy."
[0140] Some of the compounds of the present invention may contain
one or more chiral centers and therefore may exist in enantiomeric
and diastereomeric forms. The scope of the present invention is
intended to cover all isomers per se, as well as mixtures of cis
and trans isomers, mixtures of diastereomers and racemic mixtures
of enantiomers (optical isomers) as well. Further, it is possible
using well known techniques to separate the various forms, and some
embodiments of the invention may feature purified or enriched
species of a given enantiomer or diastereomer.
[0141] A "pharmacological composition" refers to a mixture of one
or more of the compounds described herein, or pharmaceutically
acceptable salts thereof, with other chemical components, such as
pharmaceutically acceptable carriers and/or excipients. The purpose
of a pharmacological composition is to facilitate administration of
a compound to an organism.
[0142] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or
transporting the subject agent from one organ, or portion of the
body, to another organ, or portion of the body. Each carrier must
be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as
pharmaceutically-acceptable carriers include: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa butter and suppository waxes; (9) oils,
such as peanut oil, cottonseed oil, safflower oil, sesame oil,
olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic compatible substances employed in pharmaceutical
formulations. A physiologically acceptable carrier should not cause
significant irritation to an organism and does not abrogate the
biological activity and properties of the administered
compound.
[0143] An "excipient" refers to an inert substance added to a
pharmacological composition to further facilitate administration of
a compound. Examples of excipients include but are not limited to
calcium carbonate, calcium phosphate, various sugars and types of
starch, cellulose derivatives, gelatin, vegetable oils and
polyethylene glycols.
[0144] A "pharmaceutically effective amount" means an amount which
is capable of providing a therapeutic and/or prophylactic effect.
The specific dose of compound administered according to this
invention to obtain therapeutic and/or prophylactic effect will, of
course, be determined by the particular circumstances surrounding
the case, including, for example, the specific compound
administered, the route of administration, the condition being
treated, and the individual being treated. A typical daily dose
(administered in single or divided doses) will contain a dosage
level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight
of an active compound of the invention. Preferred daily doses
generally will be from about 0.05 mg/kg to about 20 mg/kg and
ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as
clearance rate, half-life and maximum tolerated dose (MTD) have yet
to be determined but one of ordinary skill in the art can determine
these using standard procedures.
[0145] In some method embodiments, the preferred therapeutic effect
is the inhibition, to some extent, of the growth of cells
characteristic of a proliferative disorder, e.g., breast cancer. A
therapeutic effect will also normally, but need not, relieve to
some extent one or more of the symptoms other than cell growth or
size of cell mass. A therapeutic effect may include, for example,
one or more of 1) a reduction in the number of cells; 2) a
reduction in cell size; 3) inhibition (i.e., slowing to some
extent, preferably stopping) of cell infiltration into peripheral
organs, e.g., in the instance of cancer metastasis; 3) inhibition
(i.e., slowing to some extent, preferably stopping) of tumor
metastasis; 4) inhibition, to some extent, of cell growth; and/or
5) relieving to some extent one or more of the symptoms associated
with the disorder.
[0146] As used herein, the term IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response in an assay that measures
such response. In some method embodiments of the invention, the
"IC.sub.50" value of a compound of the invention can be greater for
normal cells than for cells exhibiting a proliferative disorder,
e.g., breast cancer cells. The value depends on the assay used.
[0147] By a "standard" is meant a positive or negative control. A
negative control in the context of HER2 expression levels is, e.g.,
a sample possessing an amount of HER2 protein that correlates with
a normal cell. A negative control may also include a sample that
contains no HER2 protein. By contrast, a positive control does
contain HER2 protein, preferably of an amount that correlates with
overexpression as found in proliferative disorders, e.g., breast
cancers. The controls may be from cell or tissue samples, or else
contain purified ligand (or absent ligand), immobilized or
otherwise. In some embodiments, one or more of the controls may be
in the form of a diagnostic "dipstick."
[0148] By "selectively targeting" is meant affecting one type of
cell to a greater extent than another, e.g., in the case of cells
with high as opposed to relatively low or normal HER2 levels.
II Compounds of the Invention
[0149] Compounds of the invention and their polymorphs, solvates,
esters, tautomers, diastereomers, enantiomers, pharmaceutically
acceptable salts or prodrugs show utility for inhibiting HSP90 and
treating and/or preventing diseases that are HSP90-dependent.
[0150] One embodiment of the compounds of the invention is of
Formula A: ##STR7## or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: [0151] X.sup.1 and X.sup.2 are the same
or different and each is nitrogen or --CR.sup.6; [0152] X.sup.3 is
nitrogen or --CR.sup.3 wherein R.sup.3 is hydrogen, OH, a keto
tautomer, --OR.sup.8, --CN, halogen, lower alkyl, or --C(O)R.sup.9;
[0153] X.sup.4 is nitrogen or a group CR.sup.6 when X.sup.3 is
nitrogen, and X.sup.4 is --CR.sup.6R.sup.7 when X.sub.3 is
--CR.sup.3; [0154] R.sup.1 is halogen, --OR.sup.8, --SR.sup.8, or
lower alkyl; [0155] R.sup.2 is --NR.sup.8R.sup.10; [0156] R.sup.4
is --(CH.sub.2).sub.n-- wherein n=0-3, --C(O), --C(S),
--SO.sub.2--, or --SO.sub.2N--; and [0157] R.sup.5 is alkyl, aryl,
heteroaryl, alicyclic, or heter ocyclic, each of which is
optionally bi- or tricyclic, and optionally substituted with H,
halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,
lower alicyclic, arylalkyl, aryloxyalkyl, alkoxyalkyl,
perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3, --SR.sup.8,
--OR.sup.8, --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10; [0158] with the provisos that: [0159] the one
not found or described in one or more of JP 10025294; U.S. Pat.
Nos. 4,748,177; 4,748,177; 6,369,092; WO 00/06573; WO 02/055521; WO
02/055082; WO 02/055083; Eur. J. Med. Chem., 1994, 29(1), 3-9; and
J. Het. Chem. 1990, 27(5), 1409; [0160] --R.sup.4R.sup.5 is not a
ribose or derivative thereof, or a sugar or derivative thereof;
[0161] --R.sup.4R.sup.5 is not a phosphonate or phosphonic acid, or
substituted with phosphonate or phosphonic acid; and [0162] when
R.sup.4 is (CH.sub.2).sub.n where n=0 or 1, then R.sup.4 and
R.sup.5 are not connected with `O`, e.g., --CH.sub.2--O--CH.sub.2--
or --CH.sub.2--CH.sub.2--O--CH.sub.2--.
[0163] In one embodiment, the compound, tautomer, pharmaceutically
acceptable salt thereof, or prodrug thereof of Formula A, X.sub.1
and X.sub.2 are the same or different and each is nitrogen or
--CR.sup.6; R.sup.1 is halogen, --OR.sup.8, --SR.sup.8, or lower
alkyl; R.sup.2 is --NR.sup.8R.sup.10; R.sup.3 is hydrogen, --OH or
keto tautomer, --OR.sup.8, halogen, --CN, lower alkyl, or
--C(O)R.sup.9; R.sup.4 is --(CH.sub.2).sub.n-- wherein n=0-3,
--C(O), --C(S), --SO.sub.2--, or --SO.sub.2N--; and R.sup.5 is
alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, each of
which is optionally bi- or tricyclic, and optionally substituted
with H, halogen, lower alkyl, --SR.sup.8, --OR.sup.8, --CN,
--CO.sub.2R.sup.9, --NO.sub.2 or --NR.sup.8R.sup.10; R.sup.8 is
hydrogen, lower alkyl, lower aryl or --(CO)R.sup.9; R.sup.9 is
lower alkyl, lower aryl, lower heteroaryl, --NR.sup.8R.sup.10 or
OR.sup.11; R.sup.11 is lower alkyl or lower aryl; and R.sup.10 is
hydrogen or lower alkyl.
[0164] In one embodiment, the compound, tautomer, pharmaceutically
acceptable salt thereof, or prodrug thereof of Formula A, R.sup.1
is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl
and C.sub.1-4 alkyl; and R.sup.2 is --NH.sub.2.
[0165] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3.
[0166] In another embodiment, R.sup.4 is selected from halogen,
hydroxyl, lower alkoxy, lower thioalkyl or C.sub.1-4 alkyl;
optionally wherein R.sup.2 is NH.sub.2.
[0167] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3.
[0168] In another embodiment, R.sup.4 is --(CH.sub.2).sub.n--,
wherein n=0-3, R.sup.1 is selected from halogen, hydroxyl, lower
alkoxy, lower thioalkyl, and C.sub.1-4 alkyl, and R.sup.2 is
optionally NH.sub.2.
[0169] In another embodiment, R.sup.1 is halogen, hydroxyl, lower
alkoxy, lower thioalkyl, or C.sub.1-4 alkyl; and R.sup.2 is
optionally NH.sub.2, R.sup.4 is --(CH.sub.2)--, and R.sup.5 is
phenyl, benzyl, or pyridyl, all optionally substituted with H,
halogen, lower alkyl, --SR.sup.8, --OR.sup.8 (or cyclic ethers such
as methylenedioxy), --CN, --C0.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10; R.sup.8 is hydrogen, lower alkyl, lower aryl or
--(CO)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.8R.sup.10 or --OR.sup.11; R.sup.11 is lower
alkyl or lower aryl; and R.sup.10 is hydrogen or lower alkyl.
[0170] In another embodiment R.sup.1 is halogen, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H or halogen, and
R.sup.5 is phenyl optionally substituted with H, halogen, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, perhaloalkyl,
perhaloalkyloxy, --CN, --NO.sub.2, --NH.sub.2 or
--CO.sub.2R.sup.11.
[0171] In another embodiment, R.sup.1 is halogen, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H, and R.sup.5 is
2-halo-3,5-dimethoxyphenyl optionally substituted with H, halogen,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio,
perhaloalkyl, perhaloalkyloxy, --CN, --NO.sub.2, --NH.sub.2, or
--CO.sub.2R.sup.11 at the para (4-) position.
[0172] In another embodiment, R.sup.1 is chloro, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H and R.sub.5 is
2-chloro-3,4,5-trimethoxyphenyl.
[0173] In another embodiment, R.sup.1 is chloro, R.sup.2 is
--NH.sub.2, R.sup.4 is --CH.sub.2--, R.sup.6 is H and R.sup.5 is
2-bromo-3,4,5-trimethoxyphenyl. In other embodiments, R.sup.5 is
selected from 2-iodo-3,4,5-trimethoxyphenyl,
2-fluoro-3,4,5-trimethoxyphenyl, and
2-bromo-3,4,5-trimethoxyphenyl.
[0174] Any of the forgoing embodiments can be combined where
feasible and appropriate.
[0175] In another embodiment, the invention provides compounds of
Formula A1: ##STR8## or a polymorph, solvate, ester, tautomer,
diastereomer, enantiomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: [0176] X.sup.1 and X.sup.2 are the same
or different and each is nitrogen or --CR.sup.6; [0177] R.sup.1 is
halogen, --OR.sup.8, --SR.sup.8, or lower alkyl; [0178] R.sup.2 is
--NR.sup.8R.sup.10; [0179] R.sup.4 is --(CH.sub.2).sub.n--
wherein=0-3, --C(O), --C(S), --SO.sub.2--, or --SO.sub.2N--; [0180]
R.sup.6 is hydrogen, halogen, lower alkyl, --SR.sup.8, --OR.sup.8,
--NR.sup.8R.sup.10, --N.sub.3, --CN, or --C(O)R.sup.9; [0181]
R.sup.5 is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all
optionally bi- or tri-cyclic, and all optionally substituted with
H, halogen, lower alkyl, --SR.sup.8, --OR.sup.8, --CN,
--CO.sub.2R.sup.9, --NO.sup.2, or --NR.sup.8R.sup.10; [0182]
R.sup.8 is hydrogen, lower alkyl, lower aryl, or --(CO)R.sup.9;
[0183] R.sup.9 is lower alkyl, lower aryl, lower heteroaryl,
--NR.sup.8R.sup.10 or --OR.sup.11; [0184] R.sup.10 is hydrogen or
lower alkyl, [0185] R.sup.11 is lower alkyl or lower aryl.
[0186] In one embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or
C.sub.1-4 alkyl; and R.sup.2 is NH.sub.2.
[0187] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.4 is --(CH.sub.2).sub.n--, where n=0-3.
[0188] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or
C.sub.1-4 alkyl; and R.sup.2 is NH.sub.2; R.sup.4 is
--(CH.sub.2).sub.n--, wherein n=0-3.
[0189] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt thereof, R.sup.1 is
halogen; R.sup.2 is NH.sub.2, R.sup.4 is --CH.sub.2--.
[0190] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.4 is --(CH.sub.2)--; R.sup.5 is phenyl, benzyl, or pyridyl,
and is independently optionally substituted with H, halogen, lower
alkyl, --SR.sup.8, --OR.sup.8 (or cyclic ethers such as
methylenedioxy), --CN, --CO.sub.2R.sup.9, --NO.sub.2, or
--NR.sup.8R.sup.10; R.sup.8 is hydrogen, lower alkyl, lower aryl or
--(CO)R.sup.9; R.sup.9 is lower alkyl, lower aryl, lower
heteroaryl, --NR.sup.8R.sup.10 or --OR.sup.11; R.sup.11 is lower
alkyl or lower aryl; and R.sup.10 is hydrogen or lower alkyl.
[0191] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is halogen, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H or halogen, R.sup.5 is phenyl optionally substituted
with H, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, perhaloalkyl, perhaloalkyloxy, --CN, --NO.sub.2,
--NH.sub.2 or --CO.sub.2R.sup.11.
[0192] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is halogen, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H, wherein R.sup.5 is 2-halo-3,5-dimethoxyphenyl
optionally substituted with H, halogen, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, --CN,
--NO.sub.2, --NH.sub.2, or --CO.sub.2R.sup.11 at the para (4-)
position.
[0193] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is chloro, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H and R.sup.5 is 2-chloro-3,4,5 -trimethoxyphenyl.
[0194] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is chloro, R.sup.2 is --NH.sub.2, R.sup.4is --CH.sub.2--,
R.sup.6 is H and R.sup.5is 2-bromo-3,4,5-trimethoxyphenyl.
[0195] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sub.1 is chloro, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H and R.sup.5 is 2-iodo-3,4,5-trimethoxyphenyl.
[0196] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sub.1 is chloro, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H and R.sup.5 is 2-fluoro-3,4,5-trimethoxyphenyl.
[0197] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sub.1 is bromo, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H, and R.sup.5 is 2-bromo-3,4,5-trimethoxyphenyl.
[0198] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sub.1 is bromo, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H, and R.sup.5 is 2-iodo-3,4,5-trimethoxyphenyl.
[0199] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sub.1 is bromo, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H and R.sup.5 is 2-iodo-3,4,5-trimethoxyphenyl.
[0200] In another embodiment ofthe compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is bromo, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is H and R.sup.5 is 2-fluoro-3,4,5-trimethoxyphenyl.
[0201] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is chloro, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is halo and R.sup.5 is 2-chloro-3,4,5-trimethoxyphenyl.
[0202] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is chloro, R.sup.2 is NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is halo, and R.sup.5 is 2-bromo-3,4,5-trimethoxyphenyl.
[0203] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is bromo, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is halo and R.sup.5 is 2-chloro-3,4,5-trimethoxyphenyl.
[0204] In another embodiment of the compounds of Formula A1, or
tautomer, pharmaceutically acceptable salt, or prodrug thereof,
R.sup.1 is bromo, R.sup.2 is --NH.sub.2, R.sup.4 is --CH.sub.2--,
R.sup.6 is halo and R.sup.5 is 2-bromo-3,4,5-trimethoxyphenyl.
[0205] In another embodiment, the invention provides compounds of
Formula I: ##STR9## or a polymorph, solvate, ester, enantiomer,
diastereomer, tautomer, pharmaceutically acceptable salt or prodrug
thereof, wherein: [0206] R.sup.1 is halogen or lower alkyl; [0207]
R.sup.2 is --NR.sup.8R.sup.10; [0208] R.sup.4 is --CHR.sup.12--;
[0209] R.sup.3 is hydrogen, halogen, or --CN; [0210] R.sup.5 is
aryl, heteroaryl, alicyclic, or heterocyclic, wherein [0211] the
aryl group is substituted with 3 to 5 substituents, [0212] the
heteroaryl group is substituted with 2 to 5 substituents, wherein
when the heteroaryl is substituted with only two substituents, the
two substituents must form part of an optionally substituted fused
ring, [0213] the alicyclic group is substituted with 3 to 5
substituents, [0214] the heterocyclic group is substituted with 3
to 5 substituents, and [0215] the substituents are selected from
the group of halogen, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10 phosphonate and phosphonic acid; [0216] R.sup.8
is hydrogen, lower alkyl, lower aryl, or --C(O)R.sup.9; [0217]
R.sup.9 is lower alkyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11; [0218] R.sup.10 is
independently hydrogen or lower alkyl; [0219] R.sup.11 is lower
alkyl, lower aryl or lower heteroaryl; [0220] R.sup.12 is hydrogen
or lower alkyl; provided that [0221] when R.sup.5 is aryl, R.sup.5
is not an organo-metallic cyclopentadiene; [0222] when R.sup.5 is
phenyl, the substituents are not 3,5 di-halo; [0223] when R.sup.5
is alicyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons; [0224] when R.sup.5 is
heterocyclic, the ring system does not contain any
tetra-substituted sp.sup.3 ring carbons or the ring system is not a
tetra-substituted pyrrolidine.
[0225] In one embodiment of the compounds of Formula I or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, wherein: R.sup.1 is halogen or methyl; and
R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or
--C(O)R.sup.9.
[0226] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is --NH.sub.2
and R.sup.3 is hydrogen.
[0227] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.4 is --(CH.sub.2)--.
[0228] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is --NH.sub.2;
R.sup.4is lower alkyl; R.sup.3 is hydrogen; and R.sup.5 is aryl or
heteroaryl, wherein each of said aryl and heteroaryl groups is
monocyclic or bicyclic, the aryl group is substituted with 4 to 5
substituents, the heteroaryl group is substituted with 2 to 5
substituents, wherein when the heteroaryl is substituted with only
two substituents, the two substituents must form part of an
optionally substituted fused ring.
[0229] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is --NH.sub.2;
R.sup.3 is hydrogen; R.sup.5 is aryl or heteroaryl, wherein each of
said aryl and heteroaryl groups is monocyclic or bicyclic, the aryl
group is substituted with 4 to 5 substituents, the heteroaryl group
is substituted with 2 to 5 substituents, wherein when the
heteroaryl is substituted with only two substituents, the two
substituents must form part of an optionally substituted fused
ring.
[0230] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is chloro or bromo, R.sup.2 is
--NH.sub.2, and R.sup.5 is a phenyl having 3 to 5 substituents.
[0231] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is chloro or bromo, R.sup.2 is
--NH.sub.2, and R.sup.5 is a pyridyl having 3 to 5
substituents.
[0232] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, R.sup.1 is chloro or bromo, R.sup.2 is
--NH.sub.2, and R.sup.5 is an 1-oxy-pyridyl (N-oxy-pyridyl) having
3 to 5 substituents.
[0233] In another embodiment of the compounds of Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, each of the aryl, heteroaryl, alicyclic or
heterocyclic group is monocyclic or bicyclic.
[0234] In another embodiment, the invention provides compounds of
Formula II, which are compounds of Formula I where R.sub.4 is
--CH.sub.2--, ##STR10## or a polymorph, solvate, ester, tautomer,
enantiomer, diastereomer, pharmaceutically acceptable salt or
prodrug thereof, wherein: [0235] R.sup.1 is halogen or lower alkyl;
[0236] R.sup.2 is --NR.sup.8R.sup.10; [0237] R.sup.3 is hydrogen,
halogen, or --CN; [0238] R.sup.5 is aryl, heteroaryl, alicyclic, or
heterocyclic, wherein [0239] the aryl group is substituted with 3
to 5 substituents, [0240] the heteroaryl group is substituted with
2 to 5 substituents, wherein when the heteroaryl is substituted
with only two substituents, the two substituents must form part of
an optionally substituted fused ring, [0241] the alicyclic group is
substituted with 3 to 5 substituents, [0242] the heterocyclic group
is substituted with 3 to 5 substituents, and [0243] the
substituents are selected from the group of halogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower alicyclic,
arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl,
perhaloalkyloxy, perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8,
--CN, --C(O)R.sup.9, --NO.sub.2, --NR.sup.8R.sup.10, phosphonate
and phosphonic acid; [0244] R.sup.8 is hydrogen, lower alkyl, lower
aryl, or --C(O)R.sup.9; [0245] R.sup.9 is lower alkyl, lower aryl,
lower heteroaryl, --NR.sup.10R.sup.10 or --OR.sup.11; [0246]
R.sup.10 is independently hydrogen or lower alkyl; [0247] R.sup.11
is lower alkyl, lower aryl or lower heteroaryl; provided that
[0248] when R.sup.5 is aryl, R.sup.5 is not an organo-metallic
cyclopentadiene; [0249] when R.sup.5 is phenyl, the substituents
are not 3,5 di-halo; [0250] when R.sup.5 is alicyclic, the ring
system does not contain any tetra-substituted sp.sup.3 ring
carbons; [0251] when R.sup.5 is heterocyclic, the ring system does
not contain any tetra-substituted sp.sup.3 ring carbons or the ring
system is not a tetra-substituted pyrrolidine.
[0252] In another embodiment of the compounds of Formula II, each
of the aryl, heteroaryl, alicyclic or heterocyclic group is
monocyclic or bicyclic.
[0253] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen or methyl;
and R.sup.2 is --NHR.sup.8, where R.sup.8 is hydrogen or
--C(O)R.sup.9.
[0254] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen.
[0255] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.2 is --NH.sub.2 and
R.sup.3 is hydrogen.
[0256] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is halogen; R.sup.2 is
--NH.sub.2; R.sup.3 is hydrogen; R.sup.5 is aryl or heteroaryl,
wherein each of the aryl and heteroaryl groups is monocyclic or
bicyclic, the aryl group is substituted with 4 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
wherein when the heteroaryl is substituted with only two
substituents, the two substituents must form part of an optionally
substituted fused ring.
[0257] In another embodiment of the compounds of Formula II, or a
polyrnorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a phenyl having 3 to 5
substituents.
[0258] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is a pyridyl having 3 to 5
substituents.
[0259] In another embodiment of the compounds of Formula II, or a
polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, R.sup.1 is chloro or bromo,
R.sup.2 is --NH.sub.2, and R.sup.5 is an 1-oxy-pyridyl
(N-oxy-pyridyl) having 3 to 5 substituents.
[0260] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0261] In another embodiment, the invention provides compounds, or
polymorphs, solvates, esters, tautomers, pharmaceutically
acceptable salts or prodrugs thereof, prepared by the process
comprising:
[0262] reacting a compound of formula Y and a compound of formula
Z, wherein:
[0263] Y is represented by any of the following formulae: ##STR11##
and [0264] Z is L.sup.1--R.sup.4--R.sup.5; wherein: [0265] L.sup.1
is halogen, NR.sup.8R.sup.10, triflate, tosylate, or mesylate;
[0266] R.sup.4 is --CHR.sup.12--, [0267] R.sup.5 is aryl,
heteroaryl, alicyclic, or heterocyclic, wherein: [0268] the aryl
group is substituted with 3 to 5 substituents, [0269] the
heteroaryl group is substituted with 2 to 5 substituents, wherein
when the heteroaryl is substituted with only two substituents, the
two substituents must form part of an optionally substituted fused
ring, [0270] the alicyclic group is substituted with 3 to 5
substituents, [0271] the heterocyclic group is substituted with 3
to 5 substituents, and [0272] the substituents are selected from
the group of halogen, lower alkyl, lower alkenyl, lower alkynyl,
lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl,
alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, --N.sub.3,
--SR.sup.8, --OR.sup.8, --CN, --C(O)R.sup.9, --NO.sub.2,
--NR.sup.8R.sup.10, phosphonate and phosphonic acid; [0273] R.sup.8
is hydrogen, lower alkyl, lower aryl, or --C(O)R.sup.9; [0274]
R.sup.9 is lower alkyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10 or --OR.sup.11; [0275] R.sup.10 is
independently hydrogen or lower alkyl; [0276] R.sup.11 is lower
alkyl, lower aryl or lower heteroaryl; [0277] R.sup.12 is hydrogen
or lower alkyl; [0278] R.sup.21 is halogen, lower alkyl or --OH;
[0279] R.sup.22 is --NR.sup.8R.sup.10; [0280] R.sup.23 is hydrogen,
halogen, or --CN; [0281] R.sup.24 is --NH.sub.2, --NO.sub.2 or
--NO; [0282] R.sup.25 is halogen or --OH; [0283] R.sup.26 is
--C(O)NH.sub.2 or C(O)OEt; and [0284] R.sup.27 is --NH2, --OH or
halogen; provided that: [0285] when R.sup.5 is aryl, R.sup.5 is not
an organo-metallic cyclopentadiene; [0286] when R.sup.5 is phenyl,
the substituents are not 3,5 di-halo; [0287] when R.sup.5 is
alicyclic, the ring system does not contain any tetra-substituted
sp.sup.3 ring carbons; or [0288] when R.sup.5 is heterocyclic, the
ring system does not contain any tetra-substituted sp.sup.3 ring
carbons or the ring system is not a tetra-substituted
pyrrolidine.
[0289] In one embodiment of the compounds prepared by the process
of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, R.sup.5 is
aryl, heteroaryl, alicyclic, or heterocyclic, each of which is
optionally mono- or bicyclic.
[0290] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, R.sup.4 is
--CH.sub.2--.
[0291] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, L.sup.1 is
--Cl, --Br or NH.sub.2; R.sup.5 is aryl or heteroaryl, wherein the
aryl group is substituted with 4 to 5 substituents and the
heteroaryl group is substituted with 2 to 5 substituents wherein
when the heteroaryl is substituted with only two substituents, the
two substituents must form part of an optionally substituted fused
ring.
[0292] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, Y is a
substituted purine.
[0293] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, the reaction
is performed in a solvent comprising a member selected from the
group of DMF, THF and DMSO.
[0294] In another embodiment of the compounds prepared by the
process of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, the reaction
is performed in a solvent that comprises DMF.
[0295] Compounds for use in the method of treatment of the
invention are HSP90 inhibitors of the following Formula I, or a
polymorph, solvate, ester, tautomer, pharmaceutically acceptable
salt or prodrug thereof, ##STR12## wherein: [0296] R.sup.1 is
halogen, --OR.sup.11, --SR.sup.11, --NHR.sup.8, hydrogen, or lower
alkyl; [0297] R.sup.2 is --NR.sup.8R.sup.10; [0298] R.sup.3 is
hydrogen, halogen, --N.sub.3, or --CN; [0299] R.sup.4 is
--(CHR.sup.12).sub.n-- where n=0, 1 or 2, --C(O)--, --C(S)--, or
--S(O)--; [0300] R.sup.5 is alkyl, aryl, heteroaryl, alicyclic, or
heterocyclic, all optionally substituted with halogen, lower alkyl,
lower alkenyl, lower alkynyl, lower aryl, lower alicyclic,
arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl,
perhaloalkyloxy, perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8,
--CN, --C(O)R.sup.9, --NO.sub.2, or --NR.sup.8R.sup.10; [0301]
R.sup.8 is hydrogen, lower alky, lower aryl, or --C(O)R.sup.9;
[0302] R.sup.9 is lower alkyl, lower aryl, lower heteroaryl,
--NR.sup.10R.sup.10, or --OR.sup.11; [0303] R.sup.10 is
independently hydrogen or lower alkyl; [0304] R.sup.11 is lower
alkyl, lower aryl or lower heteroaryl; [0305] R.sup.12 is hydrogen
or lower alkyl; provided that:
[0306] --R.sup.4R.sup.5 is not a ribose or derivative thereof, or a
sugar or derivative thereof; [0307] --R.sup.4R.sup.5 is not a
phosphonate or phosphonic acid, or substituted with phosphonate or
phosphonic acid; and [0308] when R.sup.4 is --(CH.sub.2).sub.n--
where n=1 or 2, then R.sup.4 and R.sup.5 are not connected through
an ether linkage.
[0309] In one embodiment of the compounds of Formula I for the
method of the invention, R.sup.3 is hydrogen, halogen or --CN;
R.sup.5 is aryl, heteroaryl, alicyclic, or heterocyclic, all
optionally substituted with halogen, lower alkyl, lower alkenyl,
lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy,
aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy,
perhaloacyl, --N.sub.3, --SR.sup.8, --OR.sup.8, --CN,
--C(O)R.sup.9, --NO.sub.2, or --NR.sup.8R.sup.10.
[0310] In another embodiment of the compounds of Formula I for the
method of the invention, or a polymorph, solvate, ester, tautomer,
pharmaceutically acceptable salt or prodrug thereof, R.sup.1 is
halogen or methyl and R.sup.2 is --NHR.sup.8, where R.sup.8 is
hydrogen or --C(O)R.sup.9.
[0311] In another embodiment of the compounds of Formula I for the
method of the invention, R.sup.2 is --NH.sub.2 and R.sup.3 is
hydrogen.
[0312] In another embodiment of the compounds of Formula I for the
method of the invention, R.sup.4 is --CH.sub.2--.
[0313] In another embodiment of the compounds of Formula I for the
method of the invention, R.sup.1 is halogen; R.sup.2 is --NH.sub.2;
R.sup.3 is hydrogen; R.sup.4 is --CH.sub.2--; R.sup.5 is aryl or
heteroaryl, the aryl and heteroaryl groups are monocyclic or
bicyclic, the aryl group is substituted with 4 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
wherein when the heteroaryl is substituted with two substituents,
the two substituents must form part of an optionally substituted
fused ring.
[0314] In another embodiment of the compounds of Formula I for the
method of the invention, R.sup.1 is chloro or bromo, R.sup.2 is
--NH.sub.2, and R.sup.5 is a phenyl having 3 to 5 substituents.
[0315] In another embodiment of the compounds of Formula I for the
method of the invention, R.sup.1 is chloro or bromo, R.sup.2 is
--NH.sub.2, and R.sup.5 is a pyridyl having 3 to 5
substituents.
[0316] In another embodiment of the compounds of Formula I for the
method of the invention, R.sup.1 is chloro or bromo, R.sup.2 is
--NH.sub.2, and R.sup.5 is an 1-oxy-pyridyl (N-oxy-pyridyl) having
3 to 5 substituents.
[0317] It should be understood that any of the foregoing
embodiments can be combined where feasible and appropriate.
[0318] Compounds of the invention that are based on the following
Formula I have illustrative species as described in TABLE 1.
Suitable prodrugs which can be employed by these compounds include,
but are not limited to, those listed in the Definition section.
TABLE-US-00001 TABLE 1 Exemplary Compounds of the Invention of
Formula I I ##STR13## No. Ex. R.sup.1 R.sup.3 R.sup.4 R.sup.5 1 48
Cl H CH.sub.2 3,4,5-Trimethoxyphenyl 2 98 Cl H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 3 51 Cl H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 4 106 Cl H CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 5 Cl H CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 6 Cl H CH.sub.2
3,4,5-Trimethylphenyl 7 Cl H CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 8 Cl H CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 9 Cl H CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 10 Cl H CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 11 43 Cl H CH.sub.2
3,5-Dimethoxy-4-methylphenyl 12 Cl H CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 13 44 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 14 Cl H CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 15 Cl H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 16 Cl H CH.sub.2
3,5-Dichloro-4-methylphenyl 17 Cl H CH.sub.2
2,3,5-Trichloro-4-methylphenyl 18 Cl H CH.sub.2
2-Bromo-3,5-dichloro-4-methylphenyl 19 Cl H CH.sub.2
2-Iodo-3,5-dichloro-4-methylphenyl 20 Cl H CH.sub.2
2-Fluoro-3,5-dichloro-4-methylphenyl 21 Cl H CH.sub.2
3,5-Dibromo-4-methylphenyl 22 Cl H CH.sub.2
2-Chloro-3,5-dibromo-4-methylphenyl 23 Cl H CH.sub.2
2,3,5-Tribromo-4-methylphenylphenyl 24 Cl H CH.sub.2
2-Iodo-3,5-dibromo-4-methylphenyl 25 Cl H CH.sub.2
2-Fluoro-3,5-dibromo-4-methylphenyl 26 Cl H CH.sub.2
3,5-Dichloro-4-methoxyphenyl 27 Cl H CH.sub.2
2,3,5-Trichloro-4-methoxyphenyl 28 Cl H CH.sub.2
2-Bromo-3,5-dichloro-4-methoxyphenyl 29 Cl H CH.sub.2
2-Iodo-3,5-dichloro-4-methoxyphenyl 30 Cl H CH.sub.2
2-Fluoro-3,5-dichloro-4-methoxyphenyl 31 Cl H CH.sub.2
3,5-Dibromo-4-methoxyphenyl 32 Cl H CH.sub.2
2-Chloro-3,5-dibromo-4-methoxyphenyl 33 Cl H CH.sub.2
2,3,5-Tribromo-4-methoxyphenyl 34 Cl H CH.sub.2
2-Iodo-3,5-dibromo-4-methoxyphenyl 35 Cl H CH.sub.2
2-Fluoro-3,5-dibromo-4-methoxyphenyl 36 Cl H CH.sub.2
3-Chloro-5-bromo-4-methylphenyl 37 Cl H CH.sub.2
2,3-Dichloro-5-bromo-4-methylphenyl 38 Cl H CH.sub.2
2,5-Dibromo-3-chloro-4-methylphenyl 39 Cl H CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methylphenyl 40 Cl H CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methylphenyl 41 Cl H CH.sub.2
3-Chloro-5-bromo-4-methoxyphenylphenyl 42 Cl H CH.sub.2
2,3-Dichloro-5-bromo-4-methoxyphenyl 43 Cl H CH.sub.2
2,5-Dibromo-3-chloro-4-methoxyphenyl 44 Cl H CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 45 Cl H CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 46 Cl H CH.sub.2
3-Bromo-5-chloro-4-methylphenyl 47 Cl H CH.sub.2
2,5-Dichloro-3-bromo-4-methylphenyl 48 Cl H CH.sub.2
2,3-Dibromo-5-chloro-4-methylphenyl 49 Cl H CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methylphenyl 50 Cl H CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methylphenyl 51 Cl H CH.sub.2
3-Bromo-5-chloro-4-methoxyphenyl 52 Cl H CH.sub.2
2,5-Dichloro-3-bromo-4-methoxyphenyl 53 Cl H CH.sub.2
2,3-Dibromo-5-chloro-4-methoxyphenyl 54 Cl H CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 55 Cl H CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 56 Cl H CH.sub.2
3,5-Dimethoxy-4-trifluoromethylphenyl 57 Cl H CH.sub.2
2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 58 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 59 Cl H CH.sub.2
2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 60 Cl H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 61 Cl H CH.sub.2
3,5-dibromo-4-trifluoromethoxyphenyl 62 Cl H CH.sub.2
2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 63 Cl H CH.sub.2
2,3,5-Tribromo-4-trifluoromethoxyphenyl 64 Cl H CH.sub.2
2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 65 Cl H CH.sub.2
2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 66 Cl H CH.sub.2
3,5-Dimethyl-4-methoxyphenyl 67 Cl H CH.sub.2
2-Chloro-3,5-dimethyl-4-methoxyphenyl 68 Cl H CH.sub.2
2-Bromo-3,5-dimethyl-4-methoxyphenyl 69 Cl H CH.sub.2
2-Iodo-3,5-dimethyl-4-methoxyphenyl 70 Cl H CH.sub.2
2-Fluoro-3,5-dimethyl-4-methoxyphenyl 71 Cl H CH.sub.2
3,5-Dimethyl-4-bromophenyl 72 Cl H CH.sub.2
2-Chloro-3,5-dimethyl-4-bromophenyl 73 Cl H CH.sub.2
2,4-Dibromo-3,5-dimethylphenyl 74 Cl H CH.sub.2
2-Iodo-3,5-dimethyl-4-bromophenyl 75 Cl H CH.sub.2
2-Fluoro-3,5-dimethyl-4-bromophenyl 76 Cl H CH.sub.2
3,5-Dimethyl-4-chlorophenyl 77 Cl H CH.sub.2
2,4-Dichloro-3,5-dimethylphenyl 78 Cl H CH.sub.2
2-Bromo-3,5-dimethyl-4-chlorophenyl 79 Cl H CH.sub.2
2-Iodo-3,5-dimethyl-4-chlorophenyl 80 Cl H CH.sub.2
2-Fluoro-3,5-dimethyl-4-chlorophenyl 81 101 Br H CH.sub.2
3,4,5-Trimethoxyphenyl 82 77 Br H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 83 102 Br H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 84 Br H CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 85 Br H CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 86 Br H CH.sub.2
3,4,5-Trimethylphenyl 87 Br H CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 88 Br H CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 89 Br H CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 90 Br H CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 91 Br H CH.sub.2
3,5-Dimethoxy-4-methylphenyl 92 Br H CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 93 Br H CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 94 Br H CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 95 Br H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 96 Br H CH.sub.2
3,5-Dichloro-4-methylphenyl 97 Br H CH.sub.2
2,3,5-Trichloro-4-methylphenyl 98 Br H CH.sub.2
2-Bromo-3,5-dichloro-4-methylphenyl 99 Br H CH.sub.2
2-Iodo-3,5-dichloro-4-methylphenyl 100 Br H CH.sub.2
2-Fluoro-3,5-dichloro-4-methylphenyl 101 Br H CH.sub.2
3,5-Dibromo-4-methylphenyl 102 Br H CH.sub.2
2-Chloro-3,5-dibromo-4-methylphenyl 103 Br H CH.sub.2
2,3,5-Tribromo-4-methylphenylphenyl 104 Br H CH.sub.2
2-Iodo-3,5-dibromo-4-methylphenyl 105 Br H CH.sub.2
2-Fluoro-3,5-dibromo-4-methylphenyl 106 Br H CH.sub.2
3,5-Dichloro-4-methoxyphenyl 107 Br H CH.sub.2
2,3,5-Trichloro-4-methoxyphenyl 108 Br H CH.sub.2
2-Bromo-3,5-dichloro-4-methoxyphenyl 109 Br H CH.sub.2
2-Iodo-3,5-dichloro-4-methoxyphenyl 110 Br H CH.sub.2
2-Fluoro-3,5-dichloro-4-methoxyphenyl 111 Br H CH.sub.2
3,5-Dibromo-4-methoxyphenyl 112 Br H CH.sub.2
2-Chloro-3,5-dibromo-4-methoxyphenyl 113 Br H CH.sub.2
2,3,5-Tribromo-4-methoxyphenyl 114 Br H CH.sub.2
2-Iodo-3,5-dibromo-4-methoxyphenyl 115 Br H CH.sub.2
2-Fluoro-3,5-dibromo-4-methoxyphenyl 116 Br H CH.sub.2
3-Chloro-5-bromo-4-methylphenyl 117 Br H CH.sub.2
2,3-Dichloro-5-bromo-4-methylphenyl 118 Br H CH.sub.2
2,5-Dibromo-3-chloro-4-methylphenyl 119 Br H CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methylphenyl 120 Br H CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methylphenyl 121 Br H CH.sub.2
3-Chloro-5-bromo-4-methoxyphenylphenyl 122 Br H CH.sub.2
2,3-Dichloro-5-bromo-4-methoxyphenyl 123 Br H CH.sub.2
2,5-Dibromo-3-chloro-4-methoxyphenyl 124 Br H CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 125 Br H CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 126 Br H CH.sub.2
3-Bromo-5-chloro-4-methylphenyl 127 Br H CH.sub.2
2,5-Dichloro-3-bromo-4-methylphenyl 128 Br H CH.sub.2
2,3-Dibromo-5-chloro-4-methylphenyl 129 Br H CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methylphenyl 130 Br H CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methylphenyl 131 Br H CH.sub.2
3-Bromo-5-chloro-4-methoxyphenyl 132 Br H CH.sub.2
2,5-Dichloro-3-bromo-4-methoxyphenyl 133 Br H CH.sub.2
2,3-Dibromo-5-chloro-4-methoxyphenyl 134 Br H CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 135 Br H CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 136 Br H CH.sub.2
3,5-Dimethoxy-4-trifluoromethylphenyl 137 Br H CH.sub.2
2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 138 Br H CH.sub.2
2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 139 Br H CH.sub.2
2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 140 Br H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 141 Br H CH.sub.2
3,5-Dibromo-4-trifluoromethoxyphenyl 142 Br H CH.sub.2
2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 143 Br H CH.sub.2
2,3,5-Tribromo-4-trifluoromethoxyphenyl 144 Br H CH.sub.2
2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 145 Br H CH.sub.2
2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 146 Br H CH.sub.2
3,5-Dimethyl-4-methoxyphenyl 147 Br H CH.sub.2
2-Chloro-3,5-dimethyl-4-methoxyphenyl 148 Br H CH.sub.2
2-Bromo-3,5-dimethyl-4-methoxyphenyl 149 Br H CH.sub.2
2-Iodo-3,5-dimethyl-4-methoxyphenyl 150 Br H CH.sub.2
2-Fluoro-3,5-dimethyl-4-methoxyphenyl 151 Br H CH.sub.2
3,5-Dimethyl-4-bromophenyl 152 Br H CH.sub.2
2-Chloro-3,5-dimethyl-4-bromophenyl 153 Br H CH.sub.2
2,4-Dibromo-3,5-dimethylphenyl 154 Br H CH.sub.2
2-Iodo-3,5-dimethyl-4-bromophenyl 155 Br H CH.sub.2
2-Fluoro-3,5-dimethyl-4-bromophenyl 156 Br H CH.sub.2
3,5-Dimethyl-4-chlorophenyl 157 Br H CH.sub.2
2,4-Dichloro-3,5-dimethylphenyl 158 Br H CH.sub.2
2-Bromo-3,5-dimethyl-4-chlorophenyl 159 Br H CH.sub.2
2-Iodo-3,5-dimethyl-4-chlorophenyl 160 F H CH.sub.2
3,4,5-Trimethoxyphenyl 161 F H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 162 F H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 163 F H CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 164 F H CH.sub.2
2-Fluoro-3,4,5-trimethoxyphenyl 165 F H CH.sub.2
3,4,5-Trimethylphenyl 166 F H CH.sub.2
2-Chloro-3,4,5-trimethylphenyl 167 F H CH.sub.2
2-Bromo-3,4,5-trimethylphenyl 168 F H CH.sub.2
2-Iodo-3,4,5-trimethylphenyl 169 F H CH.sub.2
2-Fluoro-3,4,5-trimethylphenyl 170 F H CH.sub.2
3,5-Dimethoxy-4-methylphenyl 171 F H CH.sub.2
2-Chloro-3,5-dimethoxy-4-methylphenyl 172 F H CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 173 F H CH.sub.2
2-Iodo-3,5-dimethoxy-4-methylphenyl 174 F H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-methylphenyl 175 F H CH.sub.2
3,5-Dichloro-4-methylphenyl 176 F H CH.sub.2
2,3,5-Trichloro-4-methylphenyl 177 F H CH.sub.2
2-Bromo-3,5-dichloro-4-methylphenyl 178 F H CH.sub.2
2-Iodo-3,5-dichloro-4-methylphenyl 179 F H CH.sub.2
2-Fluoro-3,5-dichloro-4-methylphenyl 180 F H CH.sub.2
3,5-Dibromo-4-methylphenyl 181 F H CH.sub.2
2-Chloro-3,5-dibromo-4-methylphenyl 182 F H CH.sub.2
2,3,5-Tribromo-4-methylphenylphenyl 183 F H CH.sub.2
2-Iodo-3,5-dibromo-4-methylphenyl 184 F H CH.sub.2
2-Fluoro-3,5-dibromo-4-methylphenyl 185 F H CH.sub.2
3,5-Dichloro-4-methoxyphenyl 186 F H CH.sub.2
2,3,5-Trichloro-4-methoxyphenyl 187 F H CH.sub.2
2-Bromo-3,5-dichloro-4-methoxyphenyl 188 F H CH.sub.2
2-Iodo-3,5-dichloro-4-methoxyphenyl 189 F H CH.sub.2
2-Fluoro-3,5-dichloro-4-methoxyphenyl 190 F H CH.sub.2
3,5-Dibromo-4-methoxyphenyl 191 F H CH.sub.2
2-Chloro-3,5-dibromo-4-methoxyphenyl 192 F H CH.sub.2
2,3,5-Tribromo-4-methoxyphenyl 193 F H CH.sub.2
2-Iodo-3,5-dibromo-4-methoxyphenyl 194 F H CH.sub.2
2-Fluoro-3,5-dibromo-4-methoxyphenyl 195 F H CH.sub.2
3-Chloro-5-bromo-4-methylphenyl 196 F H CH.sub.2
2,3-Dichloro-5-bromo-4-methylphenyl 197 F H CH.sub.2
2,5-Dibromo-3-chloro-4-methylphenyl 198 F H CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methylphenyl 199 F H CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methylphenyl 200 F H CH.sub.2
3-Chloro-5-bromo-4-methoxyphenylphenyl 201 F H CH.sub.2
2,3-Dichloro-5-bromo-4-methoxyphenyl 202 F H CH.sub.2
2,5-Dibromo-3-chloro-4-methoxyphenyl 203 F H CH.sub.2
2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 204 F H CH.sub.2
2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 205 F H CH.sub.2
3-Bromo-5-chloro-4-methylphenyl 206 F H CH.sub.2
2,5-Dichloro-3-bromo-4-methylphenyl 207 F H CH.sub.2
2,3-Dibromo-5-chloro-4-methylphenyl 208 F H CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methylphenyl 209 F H CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methylphenyl 210 F H CH.sub.2
3-Bromo-5-chloro-4-methoxyphenyl 211 F H CH.sub.2
2,5-Dichloro-3-bromo-4-methoxyphenyl 212 F H CH.sub.2
2,3-Dibromo-5-chloro-4-methoxyphenyl 213 F H CH.sub.2
2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 214 F H CH.sub.2
2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 215 F H CH.sub.2
3,5-Dimethoxy-4-trifluoromethylphenyl 216 F H CH.sub.2
2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 217 F H CH.sub.2
2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 218 F H CH.sub.2
2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 219 F H CH.sub.2
2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 220 F H CH.sub.2
3,5-Dibromo-4-trifluoromethoxyphenyl 221 F H CH.sub.2
2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 222 F H CH.sub.2
2,3,5-Tribromo-4-trifluoromethoxyphenyl 223 F H CH.sub.2
2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 224 F H CH.sub.2
2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 225 F H CH.sub.2
3,5-Dimethyl-4-methoxyphenyl 226 F H CH.sub.2
2-Chloro-3,5-dimethyl-4-methoxyphenyl 227 F H CH.sub.2
2-Bromo-3,5-dimethyl-4-methoxyphenyl 228 F H CH.sub.2
2-Iodo-3,5-dimethyl-4-methoxyphenyl 229 F H CH.sub.2
2-Fluoro-3,5-dimethyl-4-methoxyphenyl 230 F H CH.sub.2
3,5-Dimethyl-4-bromophenyl 231 F H CH.sub.2
2-Chloro-3,5-dimethyl-4-bromophenyl 232 F H CH.sub.2
2,4-Dibromo-3,5-dimethylphenyl 233 F H CH.sub.2
2-Iodo-3,5-dimethyl-4-bromophenyl 234 F H CH.sub.2
2-Fluoro-3,5-dimethyl-4-bromophenyl 235 F H CH.sub.2
3,5-Dimethyl-4-chlorophenyl 236 F H CH.sub.2
2,4-Dichloro-3,5-dimethylphenyl 237 F H CH.sub.2
2-Bromo-3,5-dimethyl-4-chlorophenyl 238 F H CH.sub.2
2-Iodo-3,5-dimethyl-4-chlorophenyl
239 F H CH.sub.2 2-Fluoro-3,5-dimethyl-4-chlorophenyl 240 25 Cl H
CH.sub.2 3,5-Dimethyl-4-methoxypyridin-2-yl 241 31 Cl H CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 242 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 243 33 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 244 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 245 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 246 1 Cl H
CH.sub.2 3,5-Dimethyl-4-bromopyridin-2-yl 247 4 Cl H CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 248 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 249 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 250 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 251 Cl H CH.sub.2
4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 252 18 Cl H CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 253 19 Cl H CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 254 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 255 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 256 Cl H CH.sub.2
4,6-Dichloro-3,5-dimethyl-1-oxypyridin-2-yl 257 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 258 111 Cl H
CH.sub.2 3,5-Dimethyl-4-iodopyridin-2-yl 259 Cl H CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 260 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 261 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 262 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 263 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 264 115 Cl H CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 265 Cl H CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 266 Cl H CH.sub.2
6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 267 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 268 Cl H CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 269 Cl H
CH.sub.2 6-Bromo-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 270
117 Cl H CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 271 Cl H CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 272 Cl H CH.sub.2
6-Bromo-3,4,5-trimethyl-pyridin-2-yl 273 Cl H CH.sub.2
6-Chloro-3,4,5-trimethyl-pyridin-2-yl 274 Cl H CH.sub.2
6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 275 Cl H CH.sub.2
6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 276 Cl H CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 277 Cl H CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 278 Cl H CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 279 Cl H CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 280 Cl H CH.sub.2
3-Chloro-4,5,6-trimethoxy-1-oxypyridin-2-yl 281 Cl H CH.sub.2
3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 282 Cl H CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 283 Cl H CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 284 Cl H CH.sub.2
3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 285 Cl H CH.sub.2
3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 286 Cl H CH.sub.2
3-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 287 Cl H CH.sub.2
3-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 288 Cl H CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 289 Cl H CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl 290 Cl H CH.sub.2
3-Bromo-4,5,6-trimethyl-pyridin-2-yl 291 Cl H CH.sub.2
3-Chloro-4,5,6-trimethyl-pyridin-2-yl 292 Cl H CH.sub.2
3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 293 Cl H CH.sub.2
3-Bromo-4,5,6-trimethyl-1-oxypyridin-2-yl 294 Cl H CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 295 Cl H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 296 Cl H CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 297 Cl H CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 298 Cl H CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 299 Cl H CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 300 Cl H CH.sub.2
4-Bromo-5,6-dimethoxy-pyridin-2-yl 301 Cl H CH.sub.2
4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 302 Cl H CH.sub.2
3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 303 Cl H CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 304 Cl H CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-1-oxypyridin-2-yl 305 Cl H CH.sub.2
3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 306 41 Cl H CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 307 Cl H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 308 Cl H CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 309 Cl H CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 310 Cl H CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 311 Cl H CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 312 Cl H CH.sub.2
4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 313 Cl H CH.sub.2
4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 314 Cl H CH.sub.2
5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 315 Cl H CH.sub.2
5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 316 Cl H CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 317 Cl H CH.sub.2
2,6-Dimethyl-pyridin-4-yl 318 Cl H CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 319 Cl H CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 320 Cl H CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 321 Cl H CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 322 Cl H CH.sub.2
2,6-Dichloro-3-bromopyridin-4-yl 323 Cl H CH.sub.2
2,6-Dibromo-3-chloropyridin-4-yl 324 Cl H CH.sub.2
2,3,6-Trichloro-pyridin-4-yl 325 Cl H CH.sub.2
2,3,6-Tribromo-pyridin-4-yl 326 Cl H CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 327 Cl H CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 328 Cl H CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 329 Cl H CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 330 Cl H CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 331 Cl H CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 332 Cl H CH.sub.2
2,6-Dichloro-3-bromo-1-oxy-pyridin-4-yl 333 Cl H CH.sub.2
2,6-Dibromo-3-chloro-1-oxy-pyridin-4-yl 334 Cl H CH.sub.2
2,3,6-Trichloro-1-oxy-pyridin-4-yl 335 Cl H CH.sub.2
2,3,6-Tribromo-1-oxy-pyridin-4-yl 336 Cl H CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 337 Cl H CH.sub.2
5,6-Dimethyl-4-iodopyridin-3-yl 338 Cl H CH.sub.2
4,5,6-Trichloropyridin-3-yl 339 Cl H CH.sub.2
4,5,6-Tribromopyridin-3-yl 340 21 Br H CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 341 24 Br H CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 342 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 343 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 344 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 345 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 346 5 Br H
CH.sub.2 3,5-Dimethyl-4-bromopyridin-2-yl 347 6 Br H CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 348 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 349 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 350 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 351 Br H CH.sub.2
4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 352 Br H CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 353 Br H CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 354 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 355 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 356 Br H CH.sub.2
4,6-Dichloro-3,5-dimethyl-1-oxypyridin-2-yl 357 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 358 Br H CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 359 Br H CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 360 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 361 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 362 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 363 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 364 Br H CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 365 Br H CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 366 Br H CH.sub.2
6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 367 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 368 Br H CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 369 Br H
CH.sub.2 6-Bromo-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 370
118 Br H CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 371 119 Br H
CH.sub.2 3,4,5-Trimethyl-1-oxypyridin-2-yl 372 Br H CH.sub.2
6-Bromo-3,4,5-trimethyl-pyridin-2-yl 373 Br H CH.sub.2
6-Chloro-3,4,5-trimethyl-pyridin-2-yl 374 Br H CH.sub.2
6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 375 Br H CH.sub.2
6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 376 Br H CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 377 Br H CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 378 Br H CH.sub.2
6-Bromo-3,4,5-trimethoxy-pyridin-2-yl 379 Br H CH.sub.2
6-Chloro-3,4,5-trimethoxy-pyridin-2-yl 380 Br H CH.sub.2
6-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 381 Br H CH.sub.2
6-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 382 Br H CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 383 Br H CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 384 Br H CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 385 Br H CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 386 Br H CH.sub.2
3-Chloro-4,5,6-trimethoxy-1-oxypyridin-2-yl 387 Br H CH.sub.2
3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 388 Br H CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 389 Br H CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 390 Br H CH.sub.2
3-Bromo-4,5,6-trimethyl-pyridin-2-yl 391 Br H CH.sub.2
3-Chloro-4,5,6-trimethyl-pyridin-2-yl 392 Br H CH.sub.2
3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 393 Br H CH.sub.2
3-Bromo-4,5,6-trimethyl-1-oxypyridin-2-yl 394 Br H CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 395 Br H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 396 Br H CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 397 Br H CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 398 Br H CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 399 Br H CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 400 Br H CH.sub.2
4-Bromo-5,6-dimethoxy-pyridin-2-yl 401 Br H CH.sub.2
4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 402 Br H CH.sub.2
3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 403 Br H CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 404 Br H CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-1-oxypyridin-2-yl 405 Br H CH.sub.2
3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 406 Br H CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 407 Br H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 408 Br H CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 409 Br H CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 410 Br H CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 411 Br H CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 412 Br H CH.sub.2
4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 413 Br H CH.sub.2
4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 414 Br H CH.sub.2
5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 415 Br H CH.sub.2
5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 416 Br H CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 417 Br H CH.sub.2
2,6-Dimethyl-pyridin-4-yl 418 Br H CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 419 Br H CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 420 Br H CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 421 Br H CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 422 Br H CH.sub.2
2,6-Dichloro-3-bromopyridin-4-yl 423 Br H CH.sub.2
2,6-Dibromo-3-chloropyridin-4-yl 424 Br H CH.sub.2
2,3,6-Trichloro-pyridin-4-yl 425 Br H CH.sub.2
2,3,6-Tribromo-pyridin-4-yl 426 Br H CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 427 Br H CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 428 Br H CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 429 Br H CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 430 Br H CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 431 Br H CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 432 Br H CH.sub.2
2,6-Dichloro-3-bromo1-oxy-pyridin-4-yl 433 Br H CH.sub.2
2,6-Dibromo-3-chloro1-oxy-pyridin-4-yl 434 Br H CH.sub.2
2,3,6-Trichloro-1-oxy-pyridin-4-yl 435 Br H CH.sub.2
2,3,6-Tribromo-1-oxy-pyridin-4-yl 436 Br H CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 437 Br H CH.sub.2
5,6-Dimethyl-4-iodopyridin-3-yl 438 Br H CH.sub.2
4,5,6-Trichloropyridin-3-yl 439 Br H CH.sub.2
4,5,6-Tribromopyridin-3-yl 440 F H CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 441 F H CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 442 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 443 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 444 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 445 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 446 F H CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 447 F H CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 448 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 449 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 450 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 451 F H CH.sub.2
4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 452 F H CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 453 F H CH.sub.2
3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 454 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 455 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 456 F H CH.sub.2
4,6-Dichloro-3,5-dimethyl-1-oxypyridin-2-yl 457 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 458 F H CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 459 F H CH.sub.2
3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 460 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 461 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 462 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 463 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 464 F H CH.sub.2
3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 465 F H CH.sub.2
3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 466 F H CH.sub.2
6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 467 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 468 F H CH.sub.2
6-Chloro-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 469 F H
CH.sub.2 6-Bromo-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 470 F
H CH.sub.2 3,4,5-Trimethyl-pyridin-2-yl 471 F H CH.sub.2
3,4,5-Trimethyl-1-oxypyridin-2-yl 472 F H CH.sub.2
6-Bromo-3,4,5-trimethyl-pyridin-2-yl 473 F H CH.sub.2
6-Chloro-3,4,5-trimethyl-pyridin-2-yl 474 F H CH.sub.2
6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 475 F H CH.sub.2
6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 476 F H CH.sub.2
3,4,5-Trimethoxy-pyridin-2-yl 477 F H CH.sub.2
3,4,5-Trimethoxy-1-oxypyridin-2-yl 478 F H CH.sub.2
6-Bromo-3,4,5-trimethoxy-pyridin-2-yl 479 F H CH.sub.2
6-Chloro-3,4,5-trimethoxy-pyridin-2-yl 480 F H CH.sub.2
6-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 481 F H CH.sub.2
6-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 482 F H CH.sub.2
4,5,6-Trimethoxy-pyridin-2-yl 483 F H CH.sub.2
4,5,6-Trimethoxy-1-oxypyridin-2-yl 484 F H CH.sub.2
3-Bromo-4,5,6-trimethoxy-pyridin-2-yl 485 F H CH.sub.2
3-Chloro-4,5,6-trimethoxy-pyridin-2-yl 486 F H CH.sub.2
3-Chloro-4,5,6-trimethoxy-1-oxypyridin-2-yl 487 F H CH.sub.2
3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 488 F H CH.sub.2
4,5,6-Trimethyl-pyridin-2-yl 489 F H CH.sub.2
4,5,6-Trimethyl-1-oxypyridin-2-yl
490 F H CH.sub.2 3-Bromo-4,5,6-trimethyl-pyridin-2-yl 491 F H
CH.sub.2 3-Chloro-4,5,6-trimethyl-pyridin-2-yl 492 F H CH.sub.2
3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 493 F H CH.sub.2
3-Bromo-4,5,6-trimethyl-1-oxypyridin-2-yl 494 F H CH.sub.2
4,6-Dimethyl-5-methoxy-pyridin-2-yl 495 F H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 496 F H CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 497 F H CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 498 F H CH.sub.2
3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 499 F H CH.sub.2
3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 500 F H CH.sub.2
4-Bromo-5,6-dimethoxy-pyridin-2-yl 501 F H CH.sub.2
4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 502 F H CH.sub.2
3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 503 F H CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 504 F H CH.sub.2
3-Chloro-4-bromo-5,6-dimethoxy-1-oxypyridin-2-yl 505 F H CH.sub.2
3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 506 F H CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 507 F H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 508 F H CH.sub.2
4,6-Dimethyl-5-bromopyridin-3-yl 509 F H CH.sub.2
4,6-Dimethyl-5-chloropyridin-3-yl 510 F H CH.sub.2
5,6-Dimethyl-4-bromopyridin-3-yl 511 F H CH.sub.2
5,6-Dimethyl-4-chloropyridin-3-yl 512 F H CH.sub.2
4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 513 F H CH.sub.2
4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 514 F H CH.sub.2
5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 515 F H CH.sub.2
5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 516 F H CH.sub.2
2,6-Dimethyl-3-methoxypyridin-4-yl 517 F H CH.sub.2
2,6-Dimethyl-pyridin-4-yl 518 F H CH.sub.2
2,3,6-Trimethyl-pyridin-4-yl 519 F H CH.sub.2
2,3,6-Trimethoxy-pyridin-4-yl 520 F H CH.sub.2
2,6-Dimethyl-3-bromopyridin-4-yl 521 F H CH.sub.2
2,6-Dimethyl-3-chloropyridin-4-yl 522 F H CH.sub.2
2,6-Dichloro-3-bromopyridin-4-yl 523 F H CH.sub.2
2,6-Dibromo-3-chloropyridin-4-yl 524 F H CH.sub.2
2,3,6-Trichloro-pyridin-4-yl 525 F H CH.sub.2
2,3,6-Tribromo-pyridin-4-yl 526 F H CH.sub.2
2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 527 F H CH.sub.2
2,6-Dimethyl-1-oxy-pyridin-4-yl 528 F H CH.sub.2
2,3,6-Trimethyl-1-oxy-pyridin-4-yl 529 F H CH.sub.2
2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 530 F H CH.sub.2
2,6-Dimethyl-3-bromo1-oxy-pyridin-4-yl 531 F H CH.sub.2
2,6-Dimethyl-3-chloro1-oxy-pyridin-4-yl 532 F H CH.sub.2
2,6-Dichloro-3-bromo1-oxy-pyridin-4-yl 533 F H CH.sub.2
2,6-Dibromo-3-chloro1-oxy-pyridin-4-yl 534 F H CH.sub.2
2,3,6-Trichloro-1-oxy-pyridin-4-yl 536 F H CH.sub.2
2,3,6-Tribromo-1-oxy-pyridin-4-yl 537 F H CH.sub.2
4,6-Dimethyl-5-iodopyridin-3-yl 538 F H CH.sub.2
5,6-Dimethyl-4-iodopyridin-3-yl 539 F H CH.sub.2
4,5,6-Trichloropyridin-3-yl 540 Cl Cl CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 541 Br Cl CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 542 Cl Br CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 543 Br Br CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 544 Cl N.sub.3 CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 545 Br N.sub.3 CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 546 F Cl CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 547 F Br CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 548 Cl CN CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 549 Br CN CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 550 Cl Cl CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 551 Br Cl CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 552 Cl Br CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 553 Br Br CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 554 Cl N.sub.3 CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 555 Br N.sub.3 CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 556 F Cl CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 557 F Br CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 558 Cl CN CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 559 Br CN CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 560 Cl Cl CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 561 Br Cl CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 562 Cl Br CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 563 Br Br CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 564 Cl N.sub.3 CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 565 Br N.sub.3 CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 566 F Cl CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 567 F Br CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 568 Cl CN CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 569 Br CN CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 570 Cl Cl CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 571 Br Cl CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 572 Cl Br CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 573 Br Br CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 574 Cl N.sub.3 CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 575 Br N.sub.3 CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 576 F Cl CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 577 F Br CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 578 Cl CN CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 579 Br CN CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl 580 Cl Cl CH.sub.2
4,5,6-Trimethoxy-3-chloropyridin-2-yl 581 Br Cl CH.sub.2
4,5,6-Trimethoxy-3-chloropyridin-2-yl 582 Cl Br CH.sub.2
4,5,6-Trimethoxy-3-chloropyridin-2-yl 583 Br Br CH.sub.2
4,5,6-Trimethoxy-3-chloropyridin-2-yl 584 Cl Cl CH.sub.2
4,5,6-Trimethoxy-3-bromopyridin-2-yl 585 Br Cl CH.sub.2
4,5,6-Trimethoxy-3-bromopyridin-2-yl 586 Cl Br CH.sub.2
4,5,6-Trimethoxy-3-bromopyridin-2-yl 587 Br Br CH.sub.2
4,5,6-Trimethoxy-3-bromopyridin-2-yl 588 7 Cl H CH.sub.2
3,5-Dimethyl-4-hydroxypyridin-2-yl 589 8 Cl H CH.sub.2
3,5-Dimethyl-4-ethoxypyridin-2-yl 590 9 Cl H CH.sub.2
3,5-Dimethyl-4-allyloxypyridin-2-yl 591 10 Cl H CH.sub.2
3,5-Dimethyl-4-(2-ethoxy-ethoxy)pyridin-2-yl 592 11 Cl H CH.sub.2
3,5-Dimethyl-4isopropoxypyridin-2-yl 593 12 Cl H CH.sub.2
3,5-Dimethyl-4-cyclopropylmethoxypyridin-2-yl 594 13 Cl H CH.sub.2
3,5-Dimethyl-4-(3-methyl-butoxy)pyridin-2-yl 595 14 Cl H CH.sub.2
3,5-Dimethyl-4-isobutoxypyridin-2-yl 596 15 Cl H CH.sub.2
3,5-Dimethyl-4-(2-acetyloxy-ethoxy)pyridin-2-yl 597 16 Cl H
CH.sub.2 3,5-Dimethyl-4-(3-acetyloxy-propoxy)pyridin-2-yl 598 17 Cl
H CH.sub.2 3,5-Dimethyl-4-propoxypyridin-2-yl 599 20 Cl H CH.sub.2
3,5-Dimethylpyridin-2-yl 600 32 Cl H CH.sub.2
3,5-Dimethyl-4-methoxy-1-methoxypyridin-2-yl 601 34 Cl H CH.sub.2
5-Methoxy-4-methoxymethyl-6-methylpyridin-3-yl 602 35 Cl H CH.sub.2
5-Ethoxy-4-hydroxymethyl-6-methylpyridin-3-yl 604 36 Cl H CH.sub.2
3,5-Dimethyl-4-aminopyridin-2-yl 605 37 Cl H CH.sub.2
3-Methoxy-5-methoxymethyl-4-methylpyridin-2-yl 606 38 Cl H CH.sub.2
5-Chloro-6-methoxypyridin-3-yl 607 39 Cl H CH.sub.2
3,4-Dimethoxypyridin-2-yl 608 40 Cl H CH.sub.2
3-Methoxy-6-methylpyridin-2-yl 609 42 H H CH.sub.2
4-Methoxy-3,5-dimethylpyridin-2-yl 610 45 Cl Br CH.sub.2
2-Bromo-3,5-dimethoxy-4-methylphenyl 611 47 Cl Bu CH.sub.2
3,4,5-Trimethoxyphenyl 612 49 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-acetyloxyphenyl 613 50 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-hydroxyphenyl 614 52 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-allyloxyphenyl 615 53 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-chloromethyloxyphenyl 616 54 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-chloroethyloxyphenyl 617 55 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-cyclopropylmethoxyphenyl 618 56 Cl H
CH.sub.2 2-Bromo-3,5-dimethoxy-4-ethoxyphenyl 619 57 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-propoxyphenyl 620 58 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-butoxyphenyl 621 59 Cl H CH.sub.2
3-Methoxymethyloxy-6-imethylpyridin-2-yl 622 60 Cl H CH.sub.2
3H-Benzothiazole-2-thione 623 61 Cl H CH.sub.2 2,5-Dimethylphenyl
624 62 Cl H CH.sub.2 Isoquinolin-1-yl 625 63 Cl H CH.sub.2
Benzo[1,2,5]thiadiazol-5-yl 626 64 Cl H CH.sub.2
1-Methyl-1H-benzotriazol-5-yl 627 65 Cl H CH.sub.2
6-Chloro-benzo[1,2,5]thiadiazol-5-yl 628 66 Cl H CH.sub.2
Benzo[1,2,5]thiadiazol-4-yl 629 67 Cl H CH.sub.2
6-Fluoro-4a,8a-dihydro-4H-benzo[1,3]dioxin-8-yl 630 68 Cl H
CH.sub.2 2-Methoxy-4-acetylphenyl 631 69 Cl H CH.sub.2
3-Trifluoromethoxyphenyl 632 70 Cl H CH.sub.2
2-Fluoro-3-trifluoromethylphenyl 633 71 Cl H CH.sub.2
2-Fluoro-4,5-dimethoxyphenyl 634 72 Cl H CH.sub.2
2,3-Dimethoxyphenyl 635 73 Cl H CH.sub.2 3,4-Dimethoxyphenyl 636 74
Me H CH.sub.2 2-Chloro-3,4,5-trimethoxyphenyl 637 75 Cl H CH.sub.2
2-Chloro-4,5-dimethoxyphenyl 638 76 Cl H CH.sub.2
2-Iodo-4,5-dimethoxyphenyl 639 78 Cl H CH.sub.2
6-Chloro-benzo[1,3]dioxol-5-yl 640 79 Cl H CH.sub.2
2,4-Dimethoxy-3-methylphenyl 641 80 Cl H CH.sub.2
2-Chloro-3,4-dimethoxyphenyl 642 81 Cl H CH.sub.2 3-Methoxyphenyl
643 82 Cl H CH.sub.2 2,6-Dibromo-3,5-dimethoxyphenyl 644 83 Cl H
CH.sub.2 2-Bromo-3,5-dimethoxyphenyl 645 84 Cl H CH.sub.2
3,5-Dimethoxyphenyl 646 86 Cl H CH.sub.2 2,5-Dimethoxyphenyl 647 87
Cl Br CH.sub.2 2,5-Dimethoxyphenyl 648 88 Cl H CH.sub.2
2-Nitro-4,5-dimethoxyphenyl 649 89 Cl Br CH.sub.2
2-Nitro-4,5-dimethoxyphenyl 650 90 Cl H CH.sub.2 2,5-Dichlorophenyl
651 91 Cl H CH.sub.2 2,3,5-Trifluorophenyl 652 92 Cl H C(O)
3,4,5-Trimethoxyphenyl 653 95 Cl H CH.sub.2 3,5-Dichlorophenyl 654
96 Cl H CH.sub.2 3,4-Dichlorophenyl 655 97 Cl Br CH.sub.2
3,4-Dichlorophenyl 656 99 Cl H CH.sub.2
2,6-Dichloro-3,4,5-trimethoxyphenyl 657 100 OH H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 658 103 SEt H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 659 104 OMe H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 660 105 NH.sub.2 H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 661 107 Cl H CH.sub.2
2-Bromo-3,5-dimethoxy-4-methoxymethyloxyphenyl 662 108 Cl H
CH.sub.2 Benzothiazol-2-yl 663 109 Cl H CH.sub.2 4-Methoxyphenyl
664 110 Cl H CH.sub.2 2-Bromo-4,5-dimethoxyphenyl 665 112 Cl H
CH.sub.2 4-Methylquinolin-2-yl 666 113 Br H CH.sub.2
4-Methylquinolin-2-yl 667 114 Br H CH.sub.2
4-Methyl-1-oxy-quinolin-2-yl 668 116 Cl H CH.sub.2
6-Chloro-benzothiazol-2-yl 669 Cl H CH.sub.2
4,5,6-Trimethoxy-pyridin-3-yl 670 Cl H CH.sub.2
4,5,6-Trimethoxy-1-oxy-pyridin-3-yl 671 Cl H CH.sub.2
2-Bromo-4,5,6-trimethoxy-pyridin-3-yl 672 Cl H CH.sub.2
2-Chloro-4,5,6-trimethoxy-pyridin-3-yl 673 Cl H CH.sub.2
2-Chloro-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 674 Cl H CH.sub.2
2-Bromo-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 675 Cl H CH.sub.2
4,5,6-Trimethyl-pyridin-3-yl 676 Cl H CH.sub.2
4,5,6-Trimethyl-1-oxy-pyridin-3-yl 677 Cl H CH.sub.2
2-Bromo-4,5,6-trimethyl-pyridin-3-yl 678 Cl H CH.sub.2
2-Chloro-4,5,6-trimethyl-pyridin-3-yl 679 Cl H CH.sub.2
2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl 680 Cl H CH.sub.2
2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl 681 Cl H CH.sub.2
2-Iodo-4,5,6-trimethyl-pyridin-3-yl 682 Cl H CH.sub.2
2-Iodo-4,5,6-trimethyl-pyridin-3-yl 683 Br H CH.sub.2
4,5,6-Trimethoxy-pyridin-3-yl 684 Br H CH.sub.2
4,5,6-Trimethoxy-1-oxy-pyridin-3-yl 685 Br H CH.sub.2
2-Bromo-4,5,6-trimethoxy-pyridin-3-yl 686 Br H CH.sub.2
2-Chloro-4,5,6-trimethoxy-pyridin-3-yl 687 Br H CH.sub.2
2-Chloro-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 688 Br H CH.sub.2
2-Bromo-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 689 Br H CH.sub.2
4,5,6-Trimethyl-pyridin-3-yl 690 Br H CH.sub.2
4,5,6-Trimethyl-1-oxy-pyridin-3-yl 691 Br H CH.sub.2
2-Bromo-4,5,6-trimethyl-pyridin-3-yl 692 Br H CH.sub.2
2-Chloro-4,5,6-trimethyl-pyridin-3-yl 693 Br H CH.sub.2
2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl 694 Br H CH.sub.2
2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl 695 I H CH.sub.2
3,5-Dimethyl-4-methoxypyridin-2-yl 696 I H CH.sub.2
3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 697 I H CH.sub.2
3-Bromo-4,5,6-trimethoxypyridin-2-yl 698 I H CH.sub.2
4,5,6-Trimethoxypyridin-2-yl 699 I H CH.sub.2
6-Chloro-3,5-dimethyl-4-methoxy-pyridin-2-yl 700 I H CH.sub.2
3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 701 I H CH.sub.2
3,5-Dimethyl-4-bromopyridin-2-yl 702 I H CH.sub.2
3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 703 I H CH.sub.2
3-Chloro-4,5,6-trimethoxypyridin-2-yl 704 I H CH.sub.2
3,4,5-Trimethoxyphenyl 705 I H CH.sub.2
2-Chloro-3,4,5-trimethoxyphenyl 706 I H CH.sub.2
2-Bromo-3,4,5-trimethoxyphenyl 707 I H CH.sub.2
2-Iodo-3,4,5-trimethoxyphenyl 708 I H CH.sub.2
3,4,5-Trimethylpyridin-2-yl 709 I H CH.sub.2
4,5,6-Trimethylpyridin-3-yl 710 I H CH.sub.2
3,5-dimethyl-4-thiomethylpyridin-2-yl 711 I H CH.sub.2
4,6-Dimethyl-5-methoxypyridin-3-yl 712 I H CH.sub.2
4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 713 I H CH.sub.2
3,5-Dimethyl-4-chloropyridin-2-yl 714 I H CH.sub.2
3,5-Dimethyl-4-iodopyridin-2-yl
[0319] compounds of interest in Table 1 are compounds 2, 3, 11, 44,
82, 83, 242, 243, 245, 248, 249, 254, 255, 260, 266, 272, 273, 278,
279, 284, 286, 287, 308, 309, 343, 348, 349, 354, 366, 367, 372,
373, 671 and 697 with those selected being 2, 242, 243, 248, 254,
260, 266, 272, 278, 284, 286, 287, 308, 343, 348, 349, 354, 372,
373, 671 and 697.
III. Synthesis of the Compounds of the Invention
[0320] Synthesis of compounds of the present invention may be
accomplished by various methods the art, including those described
in, for example, Montgomery, J. Med. Pharm. Chem., 1962, 5, 15-24;
Sircar, U.S. Pat. No. 4,772,606 (1988); Sircar, U.S. Pat. No.
4,748,177 (1988); Hans, U.S. Pat. No. 5,110,818 (1992); Gillespie,
WO 02/055521; Matsuda, JP 10025294 A2, (1998). For the synthesis of
compounds of Formulae I and II, a general strategy is outlined in
Scheme 1. It should be understood that other methods can also be
used. ##STR14##
[0321] The starting materials or the intermediates of the Formula
2, or/and 4 can exist in tautomeric forms as shown in FIG. 1. Both
forms are indiscriminately described in the specifications.
Method 1: From Purines:
[0322] The compounds of Formula I (see, Scheme 2) can be
synthesized from the commercially available starting heterocycle,
for example compounds of Formula 2 where R.sup.6 is --Cl, --Br or
--OH, R.sup.7 is --NH.sub.2 and R.sup.8 is --H are commercially
available from Aldrich, AlfaAesar, etc. Accordingly, Formula 2 can
be alkylated in the presence of a base such as K.sub.2CO.sub.3,
NaH, Cs.sub.2CO.sub.3, DBU etc. with/without the presence of halide
such as NaI, KI, (Bu).sub.3NI etc., and in a polar solvent such as
DMF, THF, DMSO etc. using electrophiles such as
L.sup.1--R.sup.4--R.sup.5 where --L.sup.1 is a leaving group.
Leaving groups include but are not limited to, e.g., halogen,
triflate, tosylate , mesylate etc. ##STR15## (See Kasibhatla, WO
03/037860) Compounds of Formula I, wherein R.sup.1 is --OH can be
converted to halides using standard conditions POCl.sub.3,
POBr.sup.3 etc. with/without the presence of base such as
Et.sub.3N, N,N-diethylaniline, (i-Pr).sub.2NEt etc. in polar
solvents such as CH.sub.3CN, CH.sub.2Cl.sub.2 etc.
[0323] The compounds of Formula I wherein R.sup.1 is --OR.sup.11,
--SR.sup.11, or --NHR.sup.8, where R.sup.11 is alkyl, R.sup.8 is
hydrogen, lower alkyl, lower aryl, or --C(O)R.sup.9, where R.sup.9
is lower alkyl, lower aryl, lower heteroaryl, --NR.sup.10R.sup.10,
or --OR.sup.11, where R.sup.10 is independently hydrogen or lower
alkyl, can be prepared from compounds of Formula I wherein R.sup.1
is halogen by reacting with HOR.sup.11, HSR.sup.11 or
NH.sub.2R.sup.8 in presence of a base such as K.sub.2CO.sub.3 or
NaH and a polar solvent such as DMF or THF. Compounds of Formula I
where R.sup.8 is --C(O)R.sup.9 can be prepared when R.sup.1 is
hydroxyl by simple acylation.
[0324] Compounds of Formula I where R.sup.1 is alkyl can be
prepared from compounds of Formula I where R.sup.1 is halogen and
trialkyl aluminum or dialkyl zinc. See Holy, J. Med. Chem. 1999,
42, 2064.
[0325] R.sup.5 especially when it is aryl or heteroaryl, can be
further modified as needed, for example by halogenation, nitration,
palladium coupling of halogen, Friedel-Crafts alkylation/acylation,
etc. or these modifications can also be done before alkylation, see
Jerry March, Advanced Organic Chemistry. The heteroaromatic rings
can also be oxidized to their corresponding N-oxides using various
oxidizing agents such as H.sub.2O.sub.2, O.sub.3, MCPBA etc. in
polar solvents such as CH.sub.2Cl.sub.2, CHCl.sub.3, CF.sub.3COOH
etc. See Jerry March, Advanced Organic Chemistry, 4th edition,
Chapter 19.
[0326] Compounds of Formula I where R.sup.3 is halogen, can be
prepared from Formulae 1 or 2 using halogenating agents such as
Br.sub.2, NBS, NCS, NIS etc. in polar solvents such as DMF, water,
or suitable buffer solution. See Herdewijn, J. Med Chem. 1995, 38,
3838. Alternatively, compounds of Formula 2 where R.sup.8 is iodo
can also be made using procedures known in the literature, e.g.,
Burger, J. Org. Chem. 2000, 65, 7825. These can be further modified
as needed; for example, where R.sup.3 is --N.sub.3, or --CN by
reacting with an azide such as NaN.sub.3, LiN.sub.3 etc. or cynide
such as KCN or NaCN in polar solvents such as DMF, DMSO etc. See
Halbfinger, J. Med. Chem. 1999, 42, 1625; Jacobson, J. Med. Chem.
1999, 42, 5325.
Method 2: From Pyrimidines:
[0327] Compounds of Formula I can also be prepared from the
substituted pyrimidines of Formula 5 (see, Scheme 3). Accordingly,
reaction of commercially available compounds of Formula 5, where
R.sup.16 is hydrogen or --NO.sub.2, (see J. Chem. Soc. 1962,
4186,for the preparation of R.sup.16=--NO.sub.2 compound) with
NH.sub.2--R.sup.4--R.sup.5 in solvents such as EtOH, BuOH etc. in
the presence of organic ##STR16## bases such as Et.sub.3N,
(i-Pr).sub.2NEt etc. followed by nitrosation (when R.sup.16=--H)
using nitrous acid, then reduction with sodium dithionite or
Zn/HCOOH etc. of Formula 6 (R.sup.16=--NO or --NO.sub.2) to yield
compounds of Formula 6 where R.sup.16 is --NH.sub.2. Condensation
of Formula 6,where R.sup.16 is --NH.sub.2 using standard conditions
such as triethylorthoformate, formic acid, cyanogenbromide etc. as
described in J. Chem. Soc. 1963, 4186; Sircar, U.S. Pat. No.
4,748,177, 1988; and Dang, WO 98/39344,followed by reaction with
POCl.sub.3 to give compounds of Formula I, Scheme 3. These
compounds of Formula I can be further modified as necessary.
[0328] Similarly, compounds of Formula I can also be synthesized
from Formula 7, 2-amino-4, 6-dichloro pyrimidine (see Scheme 4).
Reaction of Formula 7 with NH.sub.2--R.sup.4--R.sup.5 in solvents
such as EtOH, BuOH etc. in presence of organic bases such as
Et.sub.3N, (i-Pr).sub.2NEt, etc. followed by reaction with
diazonium salt prepared from 4-chloroaniline ##STR17## and
NaNO.sub.2 in aq. HCl to give compound Formula of 8,where R.sup.16
is azo-(4-chlorobenzene). Reduction of the azo compound with zinc
in acetic acid to give compounds of Formula 8, where R.sup.16 is
--NH.sub.2, see, Meier, U.S. Pat. No. 5,204,353, 1993. Condensation
of these compounds using standard conditions such as
triethylorthoformate, formic acid, cyanogenbromide etc. as
described in J. Chem. Soc. 1963, 4186; Sircar, U.S. Pat. No.
4,748,177, 1988, and Dang, WO 98/39344, followed by reaction with
POCl.sub.3 to give compounds of Formula I, Scheme 4. These
compounds of Formula I can be further modified as necessary.
[0329] Likewise compounds of Formula 8 where R.sup.16 is NH.sub.2
can be made from the commercially available
2,5-diamino-4,6-dihydroxy pyrimidine as described in Daluge, U.S.
Pat. No. 5,917,042, 1999 (see Scheme 5). ##STR18## Method 3: From
Imidazoles:
[0330] Compounds of Formula I can also be prepared from the
substituted imidazoles as shown in Scheme 6. Accordingly, compounds
of Formula 4,wherein R.sup.14 is NH.sub.2, R.sup.13 is C(O)NH.sub.2
and R.sup.15 is H, can be alkylated in the presence of a base such
as KOH, NaOH, K.sub.2CO.sub.3, NaH, Cs.sub.2CO.sub.3, DBU etc.
with/without the presence of halide such as NaI, KI, (Bu).sub.3NI
etc., and in a polar solvent such as DMF, THF, DMSO etc. using
electrophiles such as L.sub.1--R.sup.4--R.sup.5 where L.sub.1 is a
leaving group. Leaving groups include but are not limited to, e.g.,
halogen, triflate, tosylate, mesylate etc. to give compounds of
Formula 10. The ring closure can be achieved using many methods
reported in the literature, Alhede, J. Org. Chem., 1991, 2139 and
references cited therein to give guanines of Formula I, wherein
R.sup.1 is OH. These compounds can be converted to the ##STR19##
compounds of Formula I, wherein R.sup.1 is Cl using POCl.sub.3 as
described earlier. Advantageously, these steps can be reversed as
shown in Scheme 6 via Formula 11. Alternately, we can also
construct these 2-aminopyrimidine rings from Formula 4, wherein
R.sup.14 is --OH or halide, R.sup.13 is --C(O)OEt and R.sup.15 is
--H by reacting with guanidine hydrochoride as described in
Chowdhury, J. Med. Chem. 1999, 42, 4300. Preparation of
Electrophiles L.sup.1--R.sup.4--R.sup.5 wherein L-- is a Leaving
Group and of Nucleophiles NH.sub.2--R.sup.4--R.sup.5 Synthesis of
Benzyl Type Electrophile:
[0331] The electrophiles can be prepared from the substituted
benzene derivatives using various methods reported in the
literature, see Jerry March, Advanced Organic Chemistry, 4.sup.th
edition; Larock, Comprehensive Organic Transformations, 1989, VCH,
New York. For example the L.sub.1 is --Br can be prepared by
reduction followed by halogenation of the benzoic acid or aldehyde
derivatives. These benzyl derivatives can also be prepared by
benzylic oxidation or benzylic halogenation. Further modification
of the benzyl ring can be done before or after the purine
alkylation step, for example the halogenation was done in both
ways. The corresponding amines where L.sup.1 is --NH.sub.2 can be
prepared from the compounds where L.sup.1 is leaving group such as
chloride, bromide, tosylate, mesylate etc. using ammonia.
Synthesis of Pyridyl Methyl Type Electrophile:
[0332] These compounds can be prepared from many methods reported
in the literature. Morisawa et al. J. Med. Chem. 1974, 17, 1083;
Klaus, W. et al. J. Med. Chem. 1992, 35, 438; Abramovitch, R. A.;
Smith, E. M. "Pyridine-1-oxide in Pyridine and its Derivatives" in
The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor,
E. C., Eds.; John Wieley, New York, 1974, Pt. 2, pp 1-261; Jeromin,
G. E. et al. Chem. Ber. 1987, 120, 649. Blanz, E. J., et al. J.
Med. Chem. 1970, 13, 1124; Smith, Kline and French, EP 0184322,
1986; Abblard, J. et al. Bull. Soc. Chim. Fr. 1972, 2466; Fisher,
B. E. et al. "The Structure of Isomaltol" J Org. Chem. 1964, 29,
776. De Cat, A. et al. Bull. Soc. Chim. Belg. 1965, 74, 270;
Looker, J. H. et al. J. Org. Chem. 1979, 44, 3407. Ackerman, J. F.
Ph.D. Dissertation, University of Notre Dame, June, 1949. These
methods can be applied to the synthesis of quinoline and
isoquinolines type compounds.
[0333] Further modification of the pyridyl ring can be done after
the purine alkylation see Scheme 7. ##STR20## ##STR21## IV.
Pharmaceutical Compositions, Dosing, and Modes of
Administration
[0334] The present invention is directed to the clinical use of the
heterocyclics, in particular, 2-aminopurine and related analogs of
Formulae A, I and II, and their polymorphs, solvates, esters,
tautomers, enantiomers, diastereomers, pharmaceutically acceptable
salts and prodrugs thereof, for use in treatment or prevention of
diseases that are HSP90-dependent. For example, a disorder such as
inflammatory diseases, infections, autoimmune disorders, stroke,
ischemia, cardiac disorders, neurological disorders, fibrogenetic
disorders, proliferative disorders, tumors, leukemias, neoplasms,
cancers, carcinomas, metabolic diseases, and malignant disease. The
fibrogenetic disorders include but are not limited to scleroderma,
polymyositis, systemic lupus, rheumatoid arthritis, liver
cirrhosis, keloid formation, interstitial nephritis and pulmonary
fibrosis.
[0335] The present invention features pharmaceutical compositions
comprising the compound of Formulae A, I and II, or a polymorph,
solvate, ester, tautomer, pharmaceutically acceptable salt thereof,
or prodrug thereof, of any of the preceding aspect and embodiments
and one or more pharmaceutical excipients.
[0336] Those of ordinary skill in the art are familiar with
formulation and administration techniques that can be employed with
the compounds and methods of the invention, e.g., as discussed in
Goodman and Gilman, The Pharmacological Basis of Therapeutics,
current ed.; Pergamon; and Remington's, Pharmaceutical Sciences
(current edition), Mack Publishing Co., Easton, Pa.
[0337] The compounds utilized in the methods of the instant
invention may be administered either alone or in combination with
pharmaceutically acceptable carriers, excipients or diluents, in a
pharmaceutical composition, according to standard pharmaceutical
practice. The compounds can be administered orally or parenterally,
including the intravenous, intramuscular, intraperitoneal,
subcutaneous, rectal and topical routes of administration.
[0338] For example, the therapeutic or pharmaceutical compositions
of the invention can be administered locally to the area in need of
treatment. This may be achieved by, for example, but not limited
to, local infusion during surgery, topical application, e.g.,
cream, ointment, injection, catheter, or implant, said implant
made, e.g., out of a porous, non-porous, or gelatinous material,
including membranes, such as sialastic membranes, or fibers. The
administration can also be by direct injection at the site (or
former site) of a tumor or neoplastic or pre-neoplastic tissue.
[0339] Still further, the compounds or compositions of the
invention can be delivered in a vesicle, e.g., a liposome (see, for
example, Langer, Science 1990, 249,1527-1533; Treat et al.,
Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365,
1989).
[0340] The compounds and pharmaceutical compositions used in the
methods of the present invention can also be delivered in a
controlled release system. In one embodiment, a pump may be used
(see, Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et
al. Surgery, 1980 88, 507; Saudek et al. N. Engl. J. Med. 1989,
321, (574). Additionally, a controlled release system can be placed
in proximity of the therapeutic target. (See, Goodson, Medical
Applications of Controlled Release, 1984, Vol. 2, pp. 115-138).
[0341] The pharmaceutical compositions used in the methods of the
instant invention can also contain the active ingredient in a form
suitable for oral use, for example, as tablets, troches, lozenges,
aqueous or oily suspensions, dispersible powders or granules,
emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions, and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients may be, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, such as microcrystalline cellulose, sodium
crosscarmellose, corn starch, or alginic acid; binding agents, for
example starch, gelatin, polyvinyl-pyrrolidone or acacia, and
lubricating agents, for example, magnesium stearate, stearic acid
or talc. The tablets may be un-coated or coated by known techniques
to mask the taste of the drug or delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a water soluble
taste masking material such as hydroxypropylmethyl-cellulose or
hydroxypropylcellulose, or a time delay material such as ethyl
cellulose, or cellulose acetate butyrate may be employed as
appropriate.
[0342] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0343] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethylene-oxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0344] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as butylated
hydroxyanisol or alpha-tocopherol.
[0345] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0346] The compounds and pharmaceutical compositions used in the
methods of the instant invention may also be in the form of an
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example olive oil or arachis oil, or a mineral oil, for example
liquid paraffin or mixtures of these. Suitable emulsifying agents
may be naturally-occurring phosphatides, for example soy bean
lecithin, and esters or partial esters derived from fatty acids and
hexitol anhydrides, for example sorbitan monooleate, and
condensation products of the said partial esters with ethylene
oxide, for example polyoxyethylene sorbitan monooleate. The
emulsions may also contain sweetening agents, flavoring agents,
preservatives and antioxidants.
[0347] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative,
flavoring and coloring agents and antioxidant.
[0348] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous solution. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution.
[0349] The sterile injectable preparation may also be a sterile
injectable oil-in-water microemulsion where the active ingredient
is dissolved in the oily phase. For example, the active ingredient
may be first dissolved in a mixture of soybean oil and lecithin.
The oil solution then introduced into a water and glycerol mixture
and processed to form a microemulsion.
[0350] The injectable solutions or microemulsions may be introduced
into a patient's blood-stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.TM. model 5400 intravenous pump.
[0351] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension for
intramuscular and subcutaneous administration. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0352] The compounds of the present invention used in the methods
of the present invention may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the inhibitors with a
suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
include cocoa butter, glycerinated gelatin, hydrogenated vegetable
oils, mixtures of polyethylene glycols of various molecular weights
and fatty acid esters of polyethylene glycol.
[0353] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing a compound or composition of the
invention can be used. As used herein, topical application can
include mouth washes and gargles.
[0354] The compounds used in the methods of the present invention
can be administered in intranasal form via topical use of suitable
intranasal vehicles and delivery devices, or via transdermal
routes, using those forms of transdermal skin patches well known to
those of ordinary skill in the art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0355] The methods, compounds and compositions of the instant
invention may also be used in conjunction with other well known
therapeutic agents that are selected for their particular
usefulness against the condition that is being treated. For
example, the instant compounds may be useful in combination with
known anti-cancer and cytotoxic agents. Further, the instant
methods and compounds may also be useful in combination with other
inhibitors of parts of the signaling pathway that links cell
surface growth factor receptors to nuclear signals initiating
cellular proliferation.
[0356] The methods of the present invention may also be useful with
other agents that inhibit angiogenesis and thereby inhibit the
growth and invasiveness of tumor cells, including, but not limited
to VEGF receptor inhibitors, including ribozymes and antisense
targeted to VEGF receptors, angiostatin and endostatin.
[0357] Examples of antineoplastic agents that can be used in
combination with the compounds and methods of the present invention
include, in general, and as appropriate, alkylating agents,
anti-metabolites, epidophyllotoxins, an antineoplastic enzyme, a
topoisomerase inhibitor, procarbazine, mitoxantrone, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents and
haematopoietic growth factors. Exemplary classes of antineoplastic
include the anthracyclines, vinca drugs, mitomycins, bleomycins,
cytotoxic nucleosides, epothilones, discodermolide, pteridines,
diynenes and podophyllotoxins. Particularly useful members of those
classes include, for example, carminomycin, daunorubicin,
aminopterin, methotrexate, methopterin, dichloromethotrexate,
mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine,
gemcitabine, cytosine arabinoside, podophyllotoxin or
podo-phyllotoxin derivatives such as etoposide, etoposide phosphate
or teniposide, melphalan, vinblastine, vincristine, leurosidine,
vindesine, leurosine, paclitaxel and the like. Other useful
antineoplastic agents include estramustine, carboplatin,
cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan,
hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate,
dacarbazine, L-asparaginase, canptothecin, CPT-11, topotecan,
ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole
derivatives, interferons and interleukins.
[0358] When a compound or composition of the invention is
administered into a human subject, the daily dosage will normally
be determined by the prescribing physician with the dosage
generally varying according to the age, weight, and response of the
individual patient, as well as the severity of the patient's
symptoms.
[0359] In one exemplary application, a suitable amount of compound
is administered to a mammal undergoing treatment for cancer, for
example, breast cancer. Administration typically occurs in an
anount of between about 0.01 mg/kg of body weight to about 100
mg/kg of body weight per day (administered in single or divided
doses), more preferably at least about 0.1 mg/kg of body weight per
day. A particular therapeutic dosage can include, e.g., from about
0.01 mg to about 1000 mg of compound, and preferably includes,
e.g., from about 1 mg to about 1000 mg. The quantity of active
compound in a unit dose of preparation may be varied or adjusted
from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg,
more preferably 10 mg to 200 mg, according to the particular
application. The amount administered will vary depending on the
particular IC.sub.50 value of the compound used and the judgment of
the attending clinician taking into consideration factors such as
health, weight, and age. In combinational applications in which the
compound is not the sole active ingredient, it may be possible to
administer lesser amounts of compound and still have therapeutic or
prophylactic effect.
[0360] Preferably, the pharmaceutical preparation is in unit dosage
form. In such form, the preparation is subdivided into unit doses
containing appropriate quantities of the active component, e.g., an
effective amount to achieve the desired purpose.
[0361] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
amounts until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired.
[0362] The amount and frequency of administration of the compounds
and compositions of the present invention used in the methods of
the present invention, and if applicable other chemotherapeutic
agents and/or radiation therapy, will be regulated according to the
judgment of the attending clinician (physician) considering such
factors as age, condition and size of the patient as well as
severity of the disease being treated.
[0363] The chemotherapeutic agent and/or radiation therapy can be
administered according to therapeutic protocols well known in the
art. It will be apparent to those skilled in the art that the
administration of the chemotherapeutic agent and/or radiation
therapy can be varied depending on the disease being treated and
the known effects of the chemotherapeutic agent and/or radiation
therapy on that disease. Also, in accordance with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage
amounts and times of administration) can be varied in view of the
observed effects of the administered therapeutic agents (i.e.,
antineoplastic agent or radiation) on the patient, and in view of
the observed responses of the disease to the administered
therapeutic agents.
[0364] Also, in general, the compounds of the invention need not be
administered in the same pharmaceutical composition as a
chemotherapeutic agent, and may, because of different physical and
chemical characteristics, be administered by a different route. For
example, the compounds/compositions may be administered orally to
generate and maintain good blood levels thereof, while the
chemotherapeutic agent may be administered intravenously. The
determination of the mode of administration and the advisability of
administration, where possible, in the same pharmaceutical
composition, is well within the knowledge of the skilled clinician.
The initial administration can be made according to established
protocols known in the art, and then, based upon the observed
effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0365] The particular choice of compound (and where appropriate,
chemotherapeutic agent and/or radiation) will depend upon the
diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment
protocol.
[0366] The compounds/compositions of the invention (and where
appropriate chemotherapeutic agent and/or radiation) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) or
sequentially, depending upon the nature of the proliferative
disease, the condition of the patient, and the actual choice of
chemotherapeutic agent and/or radiation to be administered in
conjunction (i.e., within a single treatment protocol) with the
compound/composition.
[0367] In combinational applications and uses, the
compound/composition and the chemotherapeutic agent and/or
radiation need not be administered simultaneously or essentially
simultaneously, and the initial order of administration of the
compound/composition, and the chemotherapeutic agent and/or
radiation, may not be important. Thus, the compounds/compositions
of the invention may be administered first followed by the
administration of the chemotherapeutic agent and/or radiation; or
the chemotherapeutic agent and/or radiation may be administered
first followed by the administration of the compounds/compositions
of the invention. This alternate administration may be repeated
during a single treatment protocol. The determination of the order
of administration, and the number of repetitions of administration
of each therapeutic agent during a treatment protocol, is well
within the knowledge of the skilled physician after evaluation of
the disease being treated and the condition of the patient. For
example, the chemotherapeutic agent and/or radiation may be
administered first, especially if it is a cytotoxic agent, and then
the treatment continued with the administration of the
compounds/compositions of the invention followed, where determined
advantageous, by the administration of the chemotherapeutic agent
and/or radiation, and so on until the treatment protocol is
complete.
[0368] Thus, in accordance with experience and knowledge, the
practicing physician can modify each protocol for the
administration of a compound/composition for treatment according to
the individual patient's needs, as the treatment proceeds.
[0369] The attending clinician, in judging whether treatment is
effective at the dosage administered, will consider the general
well-being of the patient as well as more definite signs such as
relief of disease-related symptoms, inhibition of tumor growth,
actual shrinkage of the tumor, or inhibition of metastasis. Size of
the tumor can be measured by standard methods such as radiological
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
V. Assays for Determining HSP90 Binding and Downstream Effect
[0370] A variety of in vitro and in vivo assays are available to
test the effect of the compounds of the invention on HSP90. HSP90
competitive binding assays and functional assays can be performed
as known in the art substituting in the compounds of the invention.
Chiosis et al. Chemistry & Biology 2001, 8, 289-299, describe
some of the known ways in which this can be done. For example,
competition binding assays using, e.g., geldanamycin or 17-AAG as a
competitive binding inhibitor of HSP90 can be used to determine
relative HSP90 affinity of the compounds of the invention by
immobilizing the compound of interest or other competitive
inhibitor on a gel or solid matrix, preincubating HSP90 with the
other inhibitor, passing the preincubated mix over the gel or
matrix, and then measuring the amount of HSP90 that retains or does
not retain on the gel or matrix.
[0371] Downstream effects can also be evaluated based on the known
effect of HSP90 inhibition on function and stability of various
steroid receptors and signaling proteins including, e.g., Raf1 and
HER2. Compounds of the present invention induce dose-dependent
degradation of these molecules, which can be measured using
standard techniques. Inhibition of HSP90 also results in
up-regulation of HSP90 and related chaperone proteins that can
similarly be measured. Antiproliferative activity on various cancer
cell lines can also be measured, as can morphological and
functional differentiation related to HSP90 inhibition.
[0372] Many different types of methods are known in the art for
determining protein concentrations and measuring or predicting the
level of proteins within cells and in fluid samples. Indirect
techniques include nucleic acid hybridization and amplification
using, e.g., polymerase chain reaction (PCR). These techniques are
known to the person of skill and are discussed, e.g., in Sambrook,
Fritsch & Maniatis Molecular Cloning: A Laboratory Manual, 2nd
ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989;
Ausubel, et al. Current Protocols in Molecular Biology, John Wiley
& Sons, NY, 1994, and, as specifically applied to the
quantification, detection, and relative activity of HER2/Neu in
patient samples, e.g., in U.S. Pat. No. Nos. 4,699,877, 4,918,162,
4,968,603, and 5,846,749. A brief discussion of two generic
techniques that can be used follows.
[0373] The determination of whether cells overexpress or contain
elevated levels of HER2 can be determined using well known antibody
techniques such as immunoblotting, radioimmunoassays, western
blotting, immunoprecipitation, enzyme-linked immunosorbant assays
(ELISA), and derivative techniques that make use of antibodies
directed against HER2. As an example, HER2 expression in breast
cancer cells can be determined with the use of an
immunohistochemical assay, such as the Dako Hercep.TM. test (Dako
Corp., Carpinteria, Calif.). The Hercep.TM. test is an antibody
staining assay designed to detect HER2 overexpression in tumor
tissue specimens. This particular assay grades HER2 expression into
four levels: 0, 1, 2, and 3, with level 3 representing the highest
level of HER2 expression. Accurate quantitation can be enhanced by
employing an Automated Cellular Imaging System (ACIS) as described,
e.g., by Press, M. et al. Modern Pathology 2000, 13, 225A.
[0374] Antibodies, polyclonal or monoclonal, can be purchased from
a variety of commercial suppliers, or may be manufactured using
well-known methods, e.g., as described in Harlow et al. Antibodies:
A Laboratory Manual, 2nd ed; Cold Spring Harbor Laboratory, Cold
Spring Harbor, N.Y., 1988.
[0375] HER2 overexpression can also be determined at the nucleic
acid level since there is a reported high correlation between
overexpression of the HER2 protein and amplification of the gene
that codes for it. One way to test this is by using RT-PCR. The
genomic and cDNA sequences for HER2 are known. Specific DNA primers
can be generated using standard, well-known techniques, and can
then be used to amplify template already present in the cell. An
example of this is described in Kurokawa, H. et al. Cancer Res.
2000, 60, 5887-5894. PCR can be standardized such that quantitative
differences are observed as between normal and abnormal cells,
e.g., cancerous and noncancerous cells. Well known methods
employing, e.g., densitometry, can be used to quantitate and/or
compare nucleic acid levels amplified using PCR.
[0376] Similarly, fluorescent in situ hybridization (FISH) assays
and other assays can be used, e.g., Northern and/or Southern
blotting. These rely on nucleic acid hybridization between the HER2
gene or mRNA and a corresponding nucleic acid probe that can be
designed in the same or a similar way as for PCR primers, above.
See, e.g., Mitchell MS, and Press M. F. Oncol, Suppl. 1999, 12,
108-116. For FISH, this nucleic acid probe can be conjugated to a
fluorescent molecule, e.g., fluorescein and/or rhodamine, that
preferably does not interfere with hybridization, and which
fluorescence can later be measured following hybridization. See,
e.g., Kurokawa, H et al, Cancer Res. 2000, 60, 5887-5894
(describing a specific nucleic acid probe having sequence
5'-FAM-NucleicAcid-TAMRA-p-3' sequence). ACIS-based approaches as
described above can be employed to make the assay more quantitative
(de la Torre-Bueno, J., et al. Modern Pathology 2000, 13,
221A).
[0377] Immuno and nucleic acid detection can also be directed
against proteins other than HSP90 and HER2, which proteins are
nevertheless affected in response to HSP90 inhibition.
[0378] The following examples are offered by way of illustration
only and are not intended to be limiting of the full scope and
spirit of the invention.
EXAMPLES
I. Materials and Methods
[0379] The chemical reagents used to create the novel products of
the invention below are all available commercially, e.g., from
Aldrich Chemical Co., Milwaukee, Wis., USA. Otherwise their
preparation is facile and known to one of ordinary skill in the
art, or it is referenced or described herein.
[0380] The final compounds were usually purified by preparative TLC
(silica gel 60 .ANG., Whatman Partisil PK6F) or flash
chromatography (silica gel 60 .ANG., EMD) using EtOAc/hexane or
MeOH/CH.sub.2Cl.sub.2 as eluents. Rf's were measured using sicila
gel TLC plates (silica gel 60 .ANG., EMD).
[0381] .sup.1H-NMR spectra were recorded on a Bruker Avance 400 MHz
spectrometer. Analytical HPLC chromatograms were obtained using a
C18 column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm.times.150
mm). A gradient was applied between solvent A (0.1% TFA in
H.sub.2O) and solvent B (0.5% TFA in CH.sub.3CN) increasing the
proportion of A linearly from 5% (t=0) to 100% (t=7.00 min), with a
constant flow rate of 1 mL/min. The samples were diluted to
typically 0.1-1 mg/mL in MeOH or CH.sub.3CN and the injection
volumes were typically 10 .mu.L. The column was not heated, and UV
detection was effected at 254 nm.
[0382] The chemical names were generated using the Beilstein
Autonom 2.1 software.
[0383] 1. General Procedures to Manipulate the Purine Ring
[0384] General Procedure 1.1: Alkylation of Purines at N-9
[0385] A suspension of the purine (3 mmol),
(hetero)aryl-CH.sub.2-halide (3 mmol, if needed it can be added in
batches) and K.sub.2CO.sub.3 (3.3 mmol) in dry DMF (15 mL) was
heated to 40-60.degree. C. for 3 to 10 h. Work-up (EtOAc) and
purification by preparative TLC or flash chromatography
(EtOAc/hexane or MeOH/CH.sub.2Cl.sub.2) yielded the pure N-9
alkylated product.
[0386] General Procedure 1.2: Halogenation of Purines at C-8
[0387] A solution of purine in MeOH/THF/acetate buffer (1N in each
AcOH and AcONa) was treated with Br.sub.2 (1.3-equiv. 1M in
CHCl.sub.3) at room temperature (r.t.) for 16 h. Evaporation,
work-up (EtOAc), drying (MgSO.sub.4) and flash chromatography
afforded the desired 8-bromopurine.
[0388] General Procedure 1.3: Nucleophilic Substitution of Purines
at C-6
[0389] For details, see J Med. Chem. 1999, 42, 2064-2086.
[0390] A) Sulfanyl derivatives: A suspension of 6-chloropurine and
sodium or potassium thiolate in THF was heated to reflux for 6-24
hours. Work-up (EtOAc) and flash chromatography afforded the
desired 6-sulfanylpurine.
[0391] B) Alkoxy derivatives: A suspension of 6-chloropurine and
alkoxide in the appropriate alcohol was heated to reflux for 1-16
hours before quenching with water. Evaporation, work-up (EtOAc),
and flash chromatography afforded the desired 6-alkoxypurine.
[0392] C) Amino derivatives: A solution of 6-chloropurine and
alkylamine in MeOH was heated in a sealed tube to 100.degree. C.
for 16 hours. Evaporation, work-up (EtOAc), and flash
chromatography afforded the desired 6-alkoxypurine.
[0393] General Procedure 1.4: Methylation of Purines at C-6
[0394] A suspension of 6-chloropurine (0.2 mmol) and
tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3
mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol)
under nitrogen. The resulting solution was heated to reflux for 3
h, cooled to r.t., diluted with toluene (5 mL), and quenched with
methanol (0.5 mL) followed by ammonium chloride (1 mmol). The
mixture was heated to reflux for 2 h and filtered while hot through
a Celite plug. Evaporation and purification by prep TLC afforded
the 6-methylpurine. See J. Med. Chem. 1999, 42, 2064-2086.
[0395] General Procedure 1.5: Reductive Dehalogenation of
6-halopurine
[0396] The 6-halo purine derivative was dissolved in acetic acid
and a catalytic amount of 5% Pd/C was added, and the mixture
stirred under H.sub.2 atmosphere (1 psi) at r.t. for 1 h.,
evaporation, and purification afforded the dehalogenated
derivatives.
[0397] General Procedure 1.6: Acetylation of 2-amino-purines
[0398] The 2-amino purine derivative was dissolved in acetic
anhydride, treated with a catalytic amount of concentrated sulfuric
acid at r.t. for 1 hour. Work-up (EtOAc), evaporation, and
purification afforded the 2-acetamido-pyridine.
[0399] 2. General Procedures to Manipulate the Pyridine Ring
[0400] General Procedure 2.1: Preparation of Pyridine N-oxides
[0401] A solution of the pyridine derivative (1.0 mmol) in
dichloromethane or chloroform (5 mL) was cooled by means of an
ice-bath, treated with m-CPBA (1.1 to 3 mmol) in three portions,
and allowed to warm to r.t. The mixture was extracted with
dichloromethane and washed with aqueous NaOH, followed by water.
Drying (Na.sub.2SO.sub.4) and concentration afforded the pyridine
N-oxide.
[0402] General Procedure 2.2: Preparation of
2-(Acetoxymethy)Pyridines
[0403] A solution of the 2-methyl pyridine N-oxide (1.0 mmol) in
acetic anhydride (5 mmol) was heated to reflux for 0.5 h. Work-up
(EtOAc), drying (MgSO.sub.4), evaporation and purification by
preparative TLC or flash chromatography afforded the
2-(acetoxymethyl) pyridine.
[0404] General Procedure 2.3: Preparation of
2-(Hydroxymethyl)Pyridines
[0405] A suspension of 2-acetoxymethyl-pyridine derivative and
solid K.sub.2CO.sub.3 in methanol was heated to 50.degree. C. for
5-30 min. Evaporation, work-up (EtOAc), and drying (MgSO.sub.4)
afforded the 2-(hydroxymethyl)pyridine.
[0406] General Procedure 2.4: Preparation of
2-(Chloromethyl)Pyridines
[0407] A suspension of 2-hydroxymethyl-pyridine (10 g) in
POCl.sub.3 (30 mL) was stirred at 110.degree. C. for 1.5 h. The
resulting viscous oil was cooled to r.t. and poured onto ice water
(500 g). The pH was adjusted to 10 with solid KOH. Work-up
(CHCl.sub.3), drying (MgSO.sub.4) and evaporation gave the
2-(chloromethyl)pyridine, usually as a purple oil or solid, which
was used without purification.
[0408] General Procedure 2.5: Preparation of
2-(Bromomethyl)Pyridines
[0409] A solution of 2-(hydroxymethyl)pyridine (1.0 mmol) and
triphenyl phosphine (1.2 mmol) in dichloromethane or chloroform (5
mL) was cooled to 0.degree. C. A solution of CBr.sub.4 (1.5 mmol)
in dichloromethane or chloroform was added dropwise, and the
resulting mixture was stirred at 0.degree. C. for 0.5-1 h. Work up
followed and purification by flash chromatography afforded the
2-(bromomethyl)pyridine.
[0410] General Procedure 2.6: O-alkylation of 3- or
4-hydroxypyridines
[0411] A mixture of hydroxypyridine, alkyl halide (1.1 equiv.),
base (K.sub.2CO.sub.3, KOH or NaH 1.2-2 equiv.) and solvent (THF or
DMF) was stirred at 23-80.degree. C. for 5-30 min. Work-up (EtOAc),
drying (Na.sub.2SO.sub.4) and evaporation gave the crude
4-(alkoxy)pyridine, which was purified by preparative TLC or flash
chromatography.
[0412] General Procedure 2.7: Preparation of Salts.
[0413] Method 1: The free base (40 mmol) was heated in MeOH (1:6,
300 mL) until it dissolved. A solution of H.sub.3PO.sub.4 in MeOH
(40 mmol) was added dropwise at r.t. The mixture was stirred for 10
min., and the solvent was evaporated to give the pyridinium
phosphate as a glassy white solid. The following solvents could
also be used: THF, EtOH, or i-PrOH.
[0414] Method 2: The free base (50 mmol) was heated in i-PrOH (6 L)
until it dissolved. The solution was allowed to cool to r.t. and a
solution of HCl in i-PrOH (75 mmol) was added slowly dropwise. The
hydrochloride crystallized out of solution within a few minutes,
and was collected by filtration, washed (acetone) and dried. The
sulfate and mesylate salts were also prepared in this manner.
[0415] The hydrochloride salts can also be made by adding
CH.sub.3COCl to the alcoholic solution of the pyridine or free base
derivative.
[0416] Method 3: To a suspension of free base (5 mmol) in MeOH (50
mL) was added a solution of methane sulfonic acid in MeOH (75 mmol)
was added slowly dropwise. The mixture became clear within a few
minutes, upon addition of i-PrOH (50-100 mL) the salt precipitated
out and was collected by filtration, washed with i-PrOH, ether and
dried.
[0417] These methods can be applied to prepare all other salts.
[0418] 3. General Procedure to Manipulate Benzene Rings
[0419] General Procedure 3.1: Halogenation of Benzene Rings.
[0420] Variant 1: A solution of the aromatic compound in
MeOH/THF/acetate buffer (1N in each AcOH and AcONa) was treated
with Br.sub.2 (1.3 equiv) at r.t. for 5 min. The excess bromine and
solvent were removed on a rotary evaporator. Work-up (CHCl.sub.3)
and flash chromatography afforded the desired bromobenzene.
[0421] Variant 2: A solution of the aromatic compound (7 mmol) and
N-halosuccinimide (NCS, NBS, or NIS, 1.06 equiv) in acetic acid (40
mL) was heated to 40-90.degree. C. for 0.3-1 h. Evaporation,
work-up (EtOAc) and flash chromatography afforded the desired
halogenated benzene.
[0422] General Procedure 3.2: Preparation of Benzylic Alcohols
[0423] Benzoic acid derivatives were reduced to the corresponding
benzylic alcohols according to the procedure given by Bhaskar et
al. J. Org. Chem. 1991, 56, 5964-5965.
4. SPECIFIC EXAMPLES
Example 1
9-(4-Bromo-3,5-dimethyl-pyridin-2-yl)-6-chloro-9H-purin-2-ylamine
[0424] The title compound was obtained by alkylating
2-amino-6-chloropurine with
4-bromo-2-bromomethyl-3,5-dimethyl-pyridine according to the
general procedure 1.1. HPLC Rt: 5.301 min.
[0425] .sup.1H-NMR (CDCl.sub.3): .delta. 8.19 (s, 1H), 7.88 (s,
1H), 5.41 (s, 2H), 5.06 (s, 2H), 2.53 (s, 3H), 2.39 (s, 3H). m/z
(%) 367.1 (M+1, 75%), 369.1 (M+3, 100%), 371.1 (M+5, 25%).
[0426] The alkylating agent,
4-bromo-2-bromomethyl-3,5-dimethyl-pyridine, could itself be
prepared by any of the following three methods:
Method 1
Step 1: 2,3,5-Collidine-N-oxide
[0427] Oxidation of 2,3,5-collidine according to the general
procedure 2.1 gave 2,3,5-collidine-N-oxide. Yield: 70%. HPLC Rt:
3.96 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.03 (s, 1H), 6.90 (s,
1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z (%) 138.2 (M+1,
100%). Rf (20% MeOH/EtOAc): 0.35.
Step 2: 4-Bromo-2,3,5-collidine-N-oxide
[0428] 2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K.sub.2CO.sub.3
(2.9 g, 20 mmol) were suspended in 10 mL of CCl.sub.4. Bromine (1
mL, 20 mmol) was added dropwise, and the reaction mixture was
heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography
(10% MeOH/EtOAc) afforded the product as a solid (1.05 g, 51%
yield). HPLC Rt: 5.239 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.06
(s, .sup.1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%)
216.2 (M+1, 100%), 218.2 (M+3, 100%). Rf(20% MeOH/EtOAc): 0.45.
Step 3: Acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl
ester
[0429] 4-Bromo-2,3,5-collidine-N-oxide (0.25 g, 11 mmol) was
dissolved in acetic anhydride (5 mL) and the solution was heated to
reflux for 30 min. Work-up and flash chromatography (50%
Hexane/EtOAc) afforded the product (0.27 g, 96% yield). Rf (50%
Hexane/EtOAc): 0.70. HPLC Rt: 4.759 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.26 (s, 1H), 5.27 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H),
2.14 (s, 3H).
Step 4: 4-Bromo-3,5-dimethyl-pyridin-2-yl methanol
[0430] A suspension of acetic acid
4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester (0.26 g, 1.0 mmol)
and K.sub.2CO.sub.3 (excess) in MeOH (5 mL) was heated to
50.degree. C. for 15 min. Work-up (CHCl.sub.3), filtration through
a silica gel pad (eluent: 100% EtOAc) and evaporation gave the
title compound as a white solid (0.19 g, 88% yield). Rf (50%
Hexane/EtOAc): 0.5. HPLC Rt: 3.80 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.23 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
Step 5: 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
[0431] The title compound was obtained from
4-bromo-3,5-dimethyl-pyridin-2-yl methanol according to the general
procedure 2.5. HPLC Rt: 6.323 min. .sup.1H-NMR (CDCl.sub.13):
.delta. 8.22 (s, 1H), 4.63 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H).
Method 2
Step 1: 2-chloromethyl-3,5-dimethyl-pyridin-4-ol
[0432] The title compound was obtained by following the procedure
described in the patent by Tarbit, et al. WO 99/10326.
Step 2: 4-bromo-2-chloromethyl-3,5-dimethyl pyridine
[0433] A neat mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol
(8.2 g, 47.8 mmol) and POBr.sub.3 (60 g, 209 mmol) was stirred at
130.degree. C. for 3 h. The resulting viscous oil was cooled to
r.t. and poured onto ice water. The pH was adjusted to 10 with
solid KOH. Work-up (CHCl.sub.3), drying (MgSO.sub.4) and
evaporation afforded the title compound as a purple solid (8.7 g,
78% yield) which was used without purification. HPLC Rt: 6.028 min.
.sup.1H-NMR (CDCl.sub.3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H),
2.38 (s, 3H).
Method 3
Step 1: 4-bromo-2-chloromethyl-3,5-dimethyl pyridine
[0434] A suspension of
2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14.6 mmol)
in PBr.sub.3 (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to
80.degree. C. under nitrogen. A catalytic amount of DMF (0.50 ml,
6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly
turned into an orange solution. After 40 min., the reaction was
still incomplete as judged by HPLC. The temperature was raised to
110.degree. C. and the reaction was prolonged for 30 min, at which
point it was complete. The mixture was poured over ice, made basic
with conc. aq. NH.sub.4OH and extracted into EtOAc. Washing with
water, drying (brine, MgSO.sub.4) and concentration gave the title
compound as a pink solid (1.51 g, 44%) containing 10% of an
impurity by .sup.1H-NMR. The crude was used without further
purification. .sup.1H-NMR (CDCl.sub.3) .delta. 8.19 (s, 1H), 4.59
(s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
Example 2
9-(4-bromo-3,5-dimethyl-pyridin-2-yl
methyl)-6-chloro-9H-purin-2-ylamine, phosphate salt
[0435] The title compound was obtained by treating
9-(4-bromo-3,5-dimethyl-pyridin-2-yl
methyl)-6-chloro-9H-purin-2-ylamine with H.sub.3PO.sub.4 according
to the general procedure 2.7. HPLC Rt: 5.294 min. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.12 (s, 1H), 8.09 (s, 1H), 6.83 (s, 2H),
5.47 (s, 2H), 2.49 (s, 3H), 2.29 (s, 3H)
Example 3
9-(4-bromo-3,5-dimethyl-pyridin-2-yl
methyl)-6-chloro-9H-purin-2-ylamine, hydrochloric acid salt
[0436] The title compound was obtained by treating
9-(4-bromo-3,5-dimethyl-pyridin-2-yl
methyl)-6-chloro-9H-purin-2-ylamine with HCl according to the
general procedure 2.7. HPLC Rt: 5.294 min. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.13 (s, 1H), 8.12 (s, 1H), 5.47 (s, 2H),
5.47 (s, 2H), 2.49 (s, 3H), 2.30 (s, 3H).
Example 4
9-(4-bromo-3,5-dimethyl-1-oxy-pyridin-2-yl
methyl)-6-chloro-9H-purin-2-ylamine
[0437] The title compound was obtained by oxidation of
9-(4-bromo-3,5-dimethyl-pyridin-2-yl)-6-chloro-9H-purin-2-ylamine
according to the general procedure 2.1. HPLC Rt: 4.916 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.46 (s, 1H), 8.07 (s, 1H), 5.57
(s, 2H), 5.03 (s, 2H), 2.81 (s, 3H), 2.35 (s, 3H).
Example 5
6-bromo-9-(4-bromo-3,5-dimethyl-pyridin-2-yl
methyl)-9H-purin-2-ylamine
[0438] A mixture of 6-bromo-9H-purin-2-ylamine (2.4 g, 11 mmol),
4-bromo-2-chloromethyl-3,5-dimethyl pyridine (3.5 g, 15 mmol),
K.sub.2CO.sub.3 (2.07 g, 15 mmol) and DMF (50 mL) was stirred at
50.degree. C. for 2 h. Work-up and flash chromatography gave the
title compound as a white solid (2.6 g, 56%). HPLC Rt: 5.415 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.17 (s, 1H), 7.88 (s, 1H), 5.38
(s, 2H), 5.05 (s, 2H), 2.51(s, 3H), 2.37 (s, 3H).
Example 6
6-bromo-9-(4-bromo-3,5-dimethyl-1-oxy-pyridin-2-yl methyl)
-9H-purin-2-ylamine
[0439] The title compound was obtained by oxidation of
6-bromo-9-(4-bromo-3,5-dimethyl-pyridin-2-yl methyl) according to
the general procedure 2.1 (52% yield). Rf (100% EtOAc): 0.1. HPLC
Rt: 4.978 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.47 (s, 1H), 8.07
(s, 1H), 5.56 (s, 2H), 5.06 (s, 2H), 2.81(s, 3H), 2.35 (s, 3H).
Example 7
2-(2-Amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
[0440] The title compound was obtained by alkylating
6-chloro-9H-purin-2-ylamine with
2-chloromethyl-3,5-dimethylpyridin-4-ol according to the general
procedure 1.1. HPLC Rt: 3.624 min. .sup.1H-NMR (d.sub.6-DMSO):
.delta. 8.07 (s, 1H), 7.47 (s, 1H), 6.90 (s, 2H), 5.20 (s, 2H),
2.00 (s, 3H), 1.86 (s, 3H).
Example 8
6-Chloro-9-(4-ethoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0441] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with ethyl iodide using the general procedure 2.6. HPLC Rt: 4.321
min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.90 (s, 1H),
5.34 (s, 2H), 5.12 (s, 2H), 3.90 (q, 2H), 2.31 (s, 3H) 2.26 (s,
3H), 1.44 (t, 3H).
Example 9
9-(4-Allyloxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-chloro-9H-purin-2-ylamine
[0442] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with allyll chloride using the general procedure 2.6. HPLC Rt:
4.417 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.20 (s, 1H), 7.90 (s,
1H), 6.03-6.10 (m, 1H), 5.40-5.44 (dd, 1H), 5.34 (s, 2H), 5.29-5.32
(dd, 1H), 5.19 (s, 2H), 4.34-4.36 (m, 2H), 2.30 (s, 3H) 2.25 (s,
3H).
Example 10
6-Chloro-9-[4-(2-ethoxy-ethoxy)-3,5-dimethyl-pyridin-2-ylmethyl]-9H-purin--
2-ylamine
[0443] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with ethoxyethyl chloride, using the general procedure 2.6. HPLC
Rt: 4.388 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.19 (s, 1H), 7.89
(s, 1H), 5.33 (s, 2H), 5.14 (s, 2H), 3.97-4.00 (t, 2H), 3.73-3.76
(t, 2H), 3.56-3.61 (q, 2H), 2.33 (s, 3H), 2.26 (s, 3H), 1.22-1.26
(t, 3H).
Example 11
6-Chloro-9-(4-isopropoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylami-
ne
[0444] The title compound was obtained by 0-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with isopropyl iodide using the general procedure 2.6. HPLC Rt:
4.571 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.17 (s, 1H), 7.89 (s,
1H), 5.32 (s, 2H), 5.06 (s, 2H), 4.20 (m, 1H), 2.26 (s, 3H) 2.22
(s, 3H), 1.28-1.30 (d, 3H).
Example 12
6-Chloro-9-(4-cyclopropylmethoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-
-2-ylamine
[0445] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with cyclopropylmethyl iodide using the general procedure 2.6. HPLC
Rt: 4.709 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.20 (s, 1H), 7.90
(s, 1H), 5.34 (s, 2H) 5.09 (s, 2H), 3.68-3.70 (d, 2H), 2.32(s, 3H)
2.27 (s, 3H), 1.23-1.31 (m, 1H), 0.63-0.68 (m, 2H), 0.30-0.33 (m,
2H).
Example 13
6-Chloro-9-[3,5-dimethyl-4-(3-methyl-butoxy)-pyridin-2-ylmethyl]-9H-purin--
2-ylamine
[0446] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with 3-methylbutyl bromide using the general procedure 2.6. HPLC
Rt: 5.425 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.90
(s, 1H), 5.34 (s, 2H), 5.07 (s, 2H), 3.82-3.86 (t, 2H), 2.31 (s,
3H) 2.26 (s, 3H), 1.84-1.91 (m, 1H), 1.71-1.74 (q, 2H), 1.00 (s,
3H), 0.98 (s, 3H).
Example 14
6-Chloro-9-(4-isobutoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamin-
e
[0447] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with isobutyl bromide using the general procedure 2.6. HPLC Rt:
4.321 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.90 (s,
1H), 5.34 (s, 2H), 5.12 (s, 2H), 3.58-3.56 (d, 2H), 2.30 (s, 3H)
2.26 (s, 3H), 1.09 (s, 3H), 1.08 (s, 3H).
Example 15
Acetic acid
2-[2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-yloxy]-et-
hyl ester
[0448] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
with 2-bromoethyl acetate using the general procedure 2.6. HPLC Rt:
4.103 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.90 (s,
1H), 5.35 (s, 2H), 5.10 (s, 2H), 4.42 (t, 2H), 4.05 (t, 2H), 2.34
(s, 3H) 2.27 (s, 3H), 2.13 (s, 3H).
Example 16
Acetic acid
3-[2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-yloxy]-pr-
opyl ester
[0449] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)3,5-dimethyl-pyridin-4-ol with
2-chloropropyl acetate the general procedure 2.6. HPLC Rt: 4.414
min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.91 (s, 1H),
5.34 (s, 2H), 5.12 (s, 2H), 4.34 (t, 2H), 3.90 (t, 2H), 2.31 (s,
3H), 2.25 (s, 3H), 2.15 (m, 1H), 2.09 (s, 3H).
Example 17
6-Chloro-9-(3,5-dimethyl-4-propoxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0450] The title compound was obtained by O-alkylation of
2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol
according to the general procedure 2.6. HPLC Rt: 4.644 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.91 (s, 1H), 5.34
(s, 2H), 5.12 (s, 2H), 3.80-3.76 (t, 2H), 2.31 (s, 3H), 2.26 (s,
3H), 1.85 (m, 2H), 1.07-1.10 (t, 3H).
Example 18
6-Chloro-9-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Step 1: 4-Chloro-2-chloromethyl-3,5-dimethyl pyridine
[0451] The title compound was obtained by treating
2-chloromethyl-3,5-dimethyl-pyridin-4-ol with POCl.sub.3 according
to the general procedure 2.4 (74% yield). HPLC Rt: 5.543 min.
.sup.1H-NMR (CDCl.sub.3): 8.24 (s, 1H), 4.71 (s, 2H), 2.48 (s, 3H),
2.36 (s, 3H).
Step 2: 6-chloro-9-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-yl
methyl) -9H-purin-2-ylamine
[0452] A mixture of 6-chloro-9H-purin-2-ylamine (7 g, 41 mmol),
4-chloro-2-chloromethyl-3,5-dimethyl pyridine (8.2 g, 43 mmol),
K.sub.2CO.sub.3 (10 g, 72 mmol) and DMF (200 mL) was heated to
50.degree. C. for 2 h. The reaction mixture was diluted with water
(200 mL) and the resulting precipitate was collected by filtration,
washed with water, and dried to give the title compound as a beige
solid (11.7 g, 88% yield, 90% purity). HPLC Rt: 5.167 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.24 (s, 1H), 7.90 (s, 1H), 5.40
(s, 2H), 5.07 (s, 2H), 2.49 (s, 3H), 2.37 (s, 3H).
Example 19
6-Chloro-9-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-yl methyl)
-9H-purin-2-ylamine
[0453] The title compound was obtained by oxidation of
6-chloro-9-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
according to the general procedure 2.1 (56% yield). HPLC Rt: 4.813
min. .sup.1H-NMR (d.sub.6-DMSO): .delta. 8.31 (s, 1H), 8.20 (s,
1H), 6.91 (s, 2H), 5.41 (s, 2H), 2.73 (s, 3H), 2.26 (s, 3H).
Examples 20
6-Chloro-9-(3,5-dimethyl-pyridin-2-yl
methyl)-9H-purin-2-ylamine
Step 1: Acetic acid 3,5-dimethyl-pyridin-2-yl methyl ester
[0454] The title compound was prepared from 2,3,5-collidine-N-oxide
(see example 1) according to the general procedure 2.2. HPLC Rt:
2.916 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.30 (s, 1H), 7.33 (s,
1H), 5.22 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H).
Step 2: 3,5-Dimethyl-pyridin-2-yl methanol
[0455] The title compound was obtained by deacetylation of acetic
acid 3,5-dimethyl-pyridin-2-yl methyl ester according to the
general procedure 2.3. HPLC Rt: 2.909 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.24 (s, 1H), 7.30 (s, 1H), 4.85 (broad s,
1H), 4.67 (s, 2H), 2.33 (s, 3H), 2.20 (s, 3H).
Step 3: 2-Bromomethyl-3,5-dimethyl pyridine
[0456] The title compound was obtained from
3,5-dimethyl-pyridin-2-yl methanol according to the general
procedure 2.5. HPLC Rt: 3.895 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.3 (s, 1H), 7.3 (s, 1H), 4.61 (s, 2H), 2.41 (s, 3H), 2.33
(s, 3H).
Step 4:
6-Chloro-9-(3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0457] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 2-bromomethyl-3,5-dimethyl pyridine
according to the general procedure 1.1. HPLC Rt: 3.760 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.21 (s, 1H), 7.89 (s, 1H), 7.30
(s, 1H), 5.32 (s, 2H), 5.05 (s, 2H), 2.36 (s, 3H), 2.29 (s,
3H).
Example 21
6-Bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0458] The title compound was obtained by alkylation of
6-bromo-9H-purin-2-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethylpyridine according to the
general procedure 1.1. PLC Rt: 4.138. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.21 (s, 1H), 7.91 (s, 1H), 5.34 (s, 2H), 5.12 (s, 2H),
3.77 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H).). m/z (%) 363.2 (M+1,
100%), 365.2 (M+3, 100%).
Example 22
6-Bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine,
phosphate salt
[0459] The title compound was obtained by treating
6-bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with H.sub.3PO.sub.4 according to the general procedure 2.7. HPLC
Rt: 4.138. .sup.1H-NMR (d.sub.6-DMSO): .delta. 8.07 (s, 1H), 8.02
(s, 1H), 6.84 (s, 2H), 5.35 (s, 2H), 3.73 (s, 3H), 2.29 (s, 3H),
2.15 (s, 3H). ). m/z (%) 363.2(M+1, 100%), 365.2 (M+3, 100%).
Example 23
6-Bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine,
hydrochloride salt
[0460] The title compound was obtained by treating
6-bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with HCl according to the general procedure 2.7. HPLC Rt: 4.138.
.sup.1H-NMR (d.sub.6-DMSO): .delta. 8.44 (s, 1H), 8.26 (s, 1H),
5.57 (s, 2H), 3.96 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H).
Example 24
6-Bromo-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-yla-
mine
[0461] The title compound was obtained by oxidation of
6-bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
according to the general procedure 2.1. HPLC Rt: 4.439 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.55 (s, 1H), 8.06 (s, 1H), 5.50
(s, 2H), 5.12 (s, 2H), 3.76 (s, 3H), 2.60 (s, 3H), 2.25 (s, 3H).
m/z (%) 379.1 (M+1, 100%), 381.1 (M+3, 100%).
Example 25
6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)
9H-purin-2-ylamine
Method 1
[0462] The title compound was obtained by alkylating
6-chloro-9H-purin-2-ylamine with
2-chloromethyl-4-methoxy-3,5-dimethylpyridine (or its HCl salt)
according to the general procedure 1.1.
Method 2
[0463] The title compound could also be obtained by O-methylation
of
6-chloro-9-(4-hydroxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
according to the procedure 2.6 (KOH, MeI, DMF, 80.degree. C., 5
min). HPLC Rt: 3.980 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.19
(s, 1H), 7.88 (s, 1H), 5.32 (s, 2H), 5.07 (s, 2H), 3.75 (s, 3H),
2.29 (s, 3H), 2.24 (s, 3H).
Method 3
Step 1: (4-Methoxy-3,5-dimethyl-pyridin-2-yl)-methylamine
[0464] A solution of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine
hydrochloride in 7N methanolic ammonia was placed in a pressure
vessel and to 100.degree. C. for 16 h. Concentration and flash
chromatography gave the title compound as a greenish solid (76%
yield). HPLC Rt: 3.773 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.19
(s, 1H), 4.35 (s, 2H), 3.76 (s, 3H), 2.24 (s, 3H), 2.18 (s,
3H).
Step 2:
6-Chloro-4-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine--
2,4,5-triamine
[0465] A solution of 4,6-dichloro-pyrimidine-2,5-diamine (see Seela
et al. Helv. Chim. Acta. 1986, 69, 1602-1613 and U.S. Pat. No.
5,917,042), 4-methoxy-3,5-dimethyl-pyridin-2-yl)-methylamine, and
Et.sub.3N in butanol was heated to reflux for 1 h to give the title
compound. HPLC Rt: 3.761 min. .sup.1H-NMR (CDCl.sub.3): .delta.
8.24 (s, 1H), 7.15 (s, 1H), 4.60 (s, 2H), 4.56-4.55 (d, 2H), 3.80
(s, 3H), 3.00 (s, 2H), 2.28 (s, 3H), 2.27 (s, 3H).
Step 3: Synthesis of
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0466] The cyclization with trimethylorthoformate in presence of
acid to prepare purines can be done. See similar reaction, example
48.
Example 26
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine,
phosphate salt
[0467] The title compound was obtained treating
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with H.sub.3PO.sub.4 according to the general procedure 2.7. HPLC
Rt: 4.003 min. .sup.1H-NMR (d.sub.6-DMSO): .delta. 8.06 (s, 1H),
8.03 (s, 1H), 6.83 (s, 2H), 5.36 (s, 2H), 3.74 (s, 3H), 2.29 (s,
3H), 2.16 (s, 3H).
Example 27
6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine,
sulphate salt
[0468] The title compound was obtained treating
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with H.sub.2SO.sub.4 according to the general procedure 2.7. HPLC
Rt: 3.999 min. .sup.1H-NMR (d.sub.6-DMSO): .delta. 8.36 (s, 1H),
8.15 (s, 1H), 5.52 (s, 2H), 3.93 (s, 3H), 2.31 (s, 3H), 2.30 (s,
3H).
Example 28
6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine,
hydrochloride salt
[0469] The title compound was obtained treating
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with HCl according to the general procedure 2.7. HPLC Rt: 4.093
min. .sup.1H-NMR (d.sub.6-DMSO): .delta. 8.38 (s, 1H), 8.23 (s,
1H), 5.55 (s, 2H), 3.93 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H).
Example 29:
6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine-
, mesylate salt
[0470] The title compound was obtained treating
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with MeSO.sub.3H according to the general procedure 2.7. HPLC Rt:
4.093 min. .sup.1H-NMR (d.sub.6-DMSO): .delta. 8.38 (s, 1H), 8.17
(s, 1H), 5.54 (s, 2H), 3.95 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H),
2.33 (s, 3H).
Example 30
N-[6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2yl]-ac-
etamide
[0471] A suspension of
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
(80 mg, 0.25 mmol) in acetic acid anhydride (2.2 g) was treated
with one drop of concentrated H.sub.2SO.sub.4 and stirred at r.t.
for 5 min. Work-up (EtOAc), drying (MgSO.sub.4) and evaporation
gave the title compound as a white solid. HPLC Rt: 4.093 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.20 (s, 1H), 8.10 (s, 1H), 5.46
(s, 2H), 3.78 (s, 3H), 2.54 (s, 3H), 2.38 (s, 3H), 2.27 (s,
3H).
Example 31
6-Chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-yl-
amine
[0472] The title compound was obtained by oxidation of
6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
according to the general procedure 2.1. HPLC Rt: 4.435 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.55 (s, 1H), 8.06 (s, 1H), 5.52
(s, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 2.61 (s, 3H), 2.25 (s, 3H).).
m/z (%) 335.1 (M+1, 100%), 337.1 (M+3, 34%).
Example 32
6-Chloro-9-(4-methoy-3,5-dimethyl-1-methoxy-pyridinium-2-methyl)-9H-purin--
2-ylamine methyl sulfate salt
[0473] A suspension of
6-chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-y-
lamine (0.2 g, 0.56 mmol) in DCM (10 ml) was heated to reflux.
Dimethyl sulfate (1.12 mmol) was added dropwise (Tarbit WO
99/10326) and heating was continued for 3 h. Filtration and washing
(hot acetone) gave the title compound as a beige solid. HPLC Rt:
3.379 min. .sup.1H-NMR (d.sub.6-DMSO): .delta. 9.68 (s, 1H), 9.40
(s, 1H), 5.85 (s, 2H), 4.42 (s, 3H), 4.15 (s, 3H), 4.12 (s, 3H),
2.70 (s, 3H), 2.47 (s, 3H).
Example 33
6-Chloro-9-(6-chloro-4-metho-3,5-dimethyl-pyridin-2ylmethyl)-9H-purin-2-yl-
amine
Method 1
[0474]
6-Chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-pu-
rin-2-ylamine was treated with POCl.sub.3 according to the general
procedure 2.4. Flash chromatography gave the title compound as a
white solid. HPLC Rt: 5.741 min. .sup.1H-NMR (CDCl.sub.3): .delta.
7.94 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 3.74 (s, 3H), 2.30 (s,
3H), 2.28 (s, 3H).
Method 2
Step 1: 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine-1-oxide
[0475] The title compound was obtained by oxidation of
2-chloromethyl-4-methoxy-3,5-dimethylpyridine according to the
general procedure 2.1. HPLC Rt: 4.462 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.05 (s, 1H), 4.93 (s, 2H), 3.77 (s, 3H),
2.37 (s, 3H), 2.24 (s, 3H).
Step 2: 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethylpyridine
[0476] The title compound was obtained by treating
2-chloromethyl-4-methoxy-3,5-dimethylpyridine-1-oxide with
POCl.sub.3 according to the general procedure 2.4. HPLC Rt: 6.757
min. .sup.1H-NMR (CDCl.sub.3): .delta. 4.64 (s, 2H), 3.79 (s, 3H),
2.35 (s, 3H), 2.33 (s, 3H).
Step 3:
6-Chloro-9-(6-chloro-4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-
-purin-2-ylamine
[0477] The title compound was obtained by alkylation of
6-chloro-9H-purin-2-ylamine with
2-chloro-6-chloromethyl-4-methoxy-3,5-dimethylpyridine according to
the general procedure 1.1.
Example 34
6-Chloro-9-(5-methoxy4-methoxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-
-2-ylamine
Step 1: Acetic acid
3-acetoxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl ester
[0478] The title compound was obtained by following the procedure
reported by Morisawa et al. J. Med. Chem. 1974, 17, 1083-1086. HPLC
Rt: 3.08 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.41 (s, 1H), 5.20
(s, 2H), 4.80 (s, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.03 (s,
3H).
Step 2: Acetic acid
3-acetoxy-5-bromomethyl-2-methyl-pyridin-4-ylmethyl ester
[0479] The title compound was obtained from Acetic acid
3-acetoxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl ester
according to the general procedure 2.5. HPLC Rt: 5.332 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.43 (s, 1H), 5.22 (s, 2H), 4.70
(s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.06 (s, 3H).
Step 3:
6-Chloro-9-(5-acetoxy-4-acetoxymethyl-6-methyl-pyridin-3-ylmethyl)-
-9H-purin-2-ylamine
[0480] The title compound was obtained by alkylation of
2-amino-6-chloropurine with acetic acid
3-acetoxy-5-bromomethyl-2-methyl-pyridin-4-ylmethyl ester according
to the general procedure 1.1. HPLC Rt: 4.498 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.42 (s, 1H), 7.74 (s, 1H), 5.43 (s, 2H),
5.10 (s, 2H), 5.07 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.96 (s,
3H).
Step 4:
6-Chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-
-9H-purin-2-ylamine
[0481] A suspension of
6-chloro-9-(5-acetoxy-4-acetoxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-pur-
in-2-ylamine and K.sub.2CO.sub.3 (excess) in MeOH was heated to
50.degree. C. for 15 min. Filtration, work-up (EtOAc) and
purification by preparative TLC gave the title compound. HPLC Rt:
4.498 min. .sup.1H-NMR (d.sub.6-DMSO) .delta. 8.08 (s, 1H), 7.74
(s, 1H), 6.95 (s, 1H), 5.31 (s, 2H), 4.74 (s, 2H), 2.31 (s,
3H).
Step 5:
6-Chloro-9-(5-methoxy-4-methoxymethyl-6-methyl-pyridin-3-ylmethyl)-
-9H-purin-2ylamine
[0482] A mixture of
6-chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-pur-
in-2-ylamine, MeI, K.sub.2CO.sub.3 (excess) and DMF was heated to
50.degree. C. for 15 min. Work-up (EtOAc), drying (MgSO.sub.4),
evaporation, and purification by preparative TLC gave the title
compound. HPLC Rt: 5.446 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.35
(s, 1H), 7.70 (s, 1H), 5.35 (s, 2H), 5.25 (s, 2H), 5.15 (s, 2H),
3.80 (s, 3H) 2.59 (s, 3H), 1.970 (s, 3H).
Example 35
Synthesis of
6-Chloro-9-(5-ethoxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-puri-
n-2-ylamine
[0483] A mixture of
6-chloro-9-(5-hydroxy4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-puri-
n-2-ylamine (see previous example), EtI (excess), K.sub.2CO.sub.3
(excess) and DMF was heated to 50.degree. C. for 15 min. Work-up
(EtOAc), drying (MgSO4), evaporation, and purification by
preparative TLC gave the title compound. HPLC Rt: 3.720 min.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.27 (s, 1H), 7.90 (s, 1H), 5.40
(s, 2H), 5.11 (s, 2H), 4.85 (d, 2H), 4.50 (t, 1H), 3.95 (q, 2H),
2.51 (s, 3H) 1.45 (t, 3H).
Example 36
6-Chloro-9-(3,5-dimethyl-4-amino-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Step 1: 2-Bromomethyl-3,5-dimethyl-4-nitro-pyridine
[0484] The title compound was obtained from
(3,5-dimethyl-4-nitro-pyridin-2-yl)-methanol according to the
general procedure 2.5. HPLC Rt: 6.206 min. .sup.1H-NMR (CDCl.sub.3)
.delta. 8.46 (s, 1H), 4.64 (s, 2H), 2.38 (s, 3H), 2.33 (s, 3H).
Step 2:
6-Chloro-9-(3,5-dimethyl-4-nitro-pyridin-2-ylmethyl)-9H-purin-2-yl-
amine
[0485] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-bromomethyl-3,5-dimethyl-4-nitro-pyridine according to the
general procedure 1.1 HPLC Rt: 6.206 min. .sup.1H-NMR (CDCl.sub.3)
.delta. 8.40 (s, 1H), 7.94 (s, 1H), 5.40 (s, 2H), 5.05 (s, 2H),
2.40 (s, 3H), 2.27 (s, 3H).
Step 3:
6-Chloro-9-(3,5-dimethyl-4-amino-pyridin-2-ylmethyl)-9H-purin-2-yl-
amine
[0486] A suspension of
6-chloro-9-(4,6-dimethyl-5-nitro-pyridine-3-ylmethyl)-9H-purin-2-ylamine
and excess of sodium hydrosulfite (Na.sub.2S.sub.2O.sub.4) in
methanol was stirred for 2 days at r.t. The MeOH was evaporated
before extracting with EtOAc. Evaporation and purification by
preparative TLC (100% EtOAc) gave the title compound. HPLC Rt:
3.544 min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.05 (s, 1H), 7.83 (s,
1H), 5.31 (s, 2H), 5.05 (s, 2H), 4.08 (s, 2H), 2.12 (s, 6H).
Example 37
6-Chloro-9-(3-methoxy-5-methoxymethyl-4-methyl-pyridin-2-ylmethyl)-9H-puri-
n-2-ylamine
Step 1: 3-Methoxy-5-methoxymethyl-2,4-dimethyl-pyridine
[0487] The title compound was obtained by treating a solution of
5-hydroxymethyl-2,4-dimethyl-pyridin-3-ol hydrochloride (1 g, 5.2
mmol) in DMF with Mel (2.28 g, 15 mmol) and NaH (0.6 g, 50 mmol)
for 1 h at 0.degree. C. HPLC Rt: 2.835 min. .sup.1H-NMR
(CDCl.sub.3) .delta. 8.16 (s, 1H), 4.44 (s, 2H), 3.75 (s, 3H), 3.41
(s, 3H), 2.53 (s, 3H), 2.32 (s, 3H).
Step 2: 3-Methoxy-5-methoxymethyl-2,4-dimethyl-pyridine 1-oxide
[0488] The title compound was obtained by oxidation of
3-methoxy-5-methoxymethyl-2,4-dimethyl-pyridine according to the
general procedure 2.1. HPLC Rt: 4.181 min. .sup.1H-NMR (CDCl.sub.3)
.delta. 8.18 (s, 1H), 4.39 (s, 2H), 3.76 (s, 3H), 3.43 (s, 3H),
2.52 (s, 3H), 2.46 (s, 3H).
Step 3: Acetic acid
3-methoxy-5-methoxymethyl-4-methyl-pyridin-2-ylmethyl ester
[0489] The title compound was obtained by treating
3-methoxy-5-methoxymethyl-2,4-dimethyl-pyridine 1-oxide with
Ac.sub.2O according to the general procedure 2.2. HPLC Rt: 4.062
min. .sup.1H-NMR (CDCl.sub.3) .delta. 8.32 (s, 1H), 5.27 (s, 2H),
4.47 (s, 2H), 3.80 (s, 3H), 3.43 (s, 3H), 2.34 (s, 3H), 2.25 (s,
3H).
Step 4:
(3-Methoxy-5-methoxymethyl-4-methyl-pyridin-2-yl)-methanol
[0490] The title compound was obtained from acetic acid
3-methoxy-5-methoxymethyl-4-methyl-pyridin-2-ylmethyl ester
according to the general procedure 2.3. HPLC Rt: 3.465 min.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.22(s, 1H), 4.75 (d, 2H), 4.47
(s, 2H), 4.20 (t, 1H), 3.77 (s, 3H), 3.43 (s, 3H), 2.34 (s,
3H).
Step 5:
2-Bromomethyl-3-methoxy-5-methoxymethyl-4-methyl-pyridine
[0491] The title compound was obtained from
(3-methoxy-5-methoxymehtyl-4-methyl-pyridine-2-yl)-methanol
according to the general procedure 2.5. HPLC Rt: 4.498 min.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.22 (s, 1H), 4.695 (s, 2H), 4.42
(s, 2H), 3.86 (s, 3H), 3.40 (s, 3H), 2.31 (s, 3H).
Step 6:
6-Chloro-9-(3-methoxy-5-methoxymethyl-4-methyl-pyridin-2-ylmethyl)-
-9H-purin-2-ylamine
[0492] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-bromomethyl-3-methoxy-5-methoxymethyl-4-methyl-pyridine according
to the general procedure 1.1. HPLC Rt: 4.254 min. .sup.1H-NMR
(CDCl.sub.3) .delta. 8.210 (s, 1H), 7.96 (s, 1H), 5.40 (s, 2H) 5.05
(s, 2H), 4.42 (s, 2H ), 3.78 (s, 3H), 3.40 (s, 3H), 2.31 (s,
3H).
Example 38
6-Chloro-9-(5-chloro-6-methoxy-pyridin-3-ylmethyl)-9H-purin-2-ylamine
Step 1: (5-Chloro-6-methoxy-pyridin-3-yl)-methanol
[0493] (5,6-Dichloro-pyridin-3-yl)-methanol was dissolved in a
saturated solution of NaOMe in MeOH and heated to reflux overnight.
Evaporation of MeOH, work-up (EtOAc) and evaporation gave the title
compound. .sup.1H-NMR (CDCl.sub.3) .delta. 8.03 (d, 1H), 7.72 (d,
1H), 4.65 (s, 2H), 4.04 (s, 3H).
Step 2: 5-Bromomethyl-3-chloro-2-methoxy-pyridine
[0494] The title compound was obtained from
(5-chloro-6-methoxy-pyridine-3-yl)-methanol according to the
general procedure 2.5. .sup.1H-NMR (CDCl.sub.3) .delta. 8.05 (d,
1H), 7.70 (d, 1H), 4.42 (s, 2H), 4.02 (s, 3H).
Step 3:
6-Chloro-9-(5-chloro-6-methoxy-pyridin-3-ylmethyl)-9H-purin-2-ylam-
ine
[0495] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
5-bromomethyl-3-chloro-2-methoxy-pyridine according to the general
procedure 1.1. HPLC Rt: 5.256 min. .sup.1H-NMR (CDCl.sub.3) .delta.
8.11 (d, 1H), 7.78 (s, 1H), 7.63 (d, 1H), 5.19 (s, 2H), 4.04 (s,
3H).
Example 39
6-chloro-9-(3,4-dimethoxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0496] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 2-chloromethyl-3,4-dimethoxylpyridine
hydrochloride according to the general procedure 1.1. HPLC Rt:
3.777 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.19 (d, 1H), 7.95 (s,
1H), 6.82 (d, 1H) 5.39 (s, 2H), 5.09 (s, 2H), 3.92 (s, 3H), 3.87
(s, 3H).
Example 40
6-chloro-9-(3-methoxy-6-methyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Step 1: (3-Methoxy-6-methyl-pyridin-2-yl) -methanol
[0497] The title compound was obtained by O-methylation of
2-hydroxymethyl-6-methyl-pyridin-3-ol according to the general
procedure 2.6. HPLC Rt: 2.304 min. .sup.1H-NMR (CDCl.sub.3) .delta.
7.05-7.11 (m, 2H), 4.72-4.71 (d, 2H), 4.47-4.49 (t, 1H), 3.84 (s,
3H), 2.51 (s, 3H).
Step 2: 2-Bromomethyl-3-methoxy-6-methyl-pyridine
[0498] The title compound was obtained from
(3-Methoxy-6-methyl-pyridine-2-yl)-methanol according to the
general procedure 2.5. HPLC Rt: 4.361. .sup.1H-NMR (CDCl.sub.3)
.delta. 7.06-7.12 (m, 2H), 4.61 (s, 2H), 3.89 (s, 3H), 2.49 (s,
3H).
Step 3:
6-chloro-9-(3-methoxy-6-methyl-pyridin-2-ylmethyl)-9H-purin-2-ylam-
ine
[0499] The title compound was obtained by alkylation of
2amino-6-chloropurine with 2bromomethyl-3-methoxy-6-methylpyridine
according to the general procedure 1.1. HPLC Rt: 3.777 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.92 (s, 1H), 7.11 (m, 2H), 5.39
(s, 2H), 5.15 (s, 2H), 3.85 (s, 3H), 2.45 (s, 3H).
Example 41
6-Chloro-9-(5-methoxy-4,6-dimethyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine
Step 1: (5-Methoxy-4,6-dimethyl-pyridin-3-yl)-methanol
[0500] The title compound was obtained by O-methylation of
5-hydroxymethyl-2,4-dimethyl-pyridin-3-ol according to the general
procedure 2.6. HPLC Rt: 3.114 min. .sup.1H-NMR (CDCl.sub.3) .delta.
8.08 (s, 1H), 4.67 (s, 2H), 3.74 (s, 3H), 2.49 (s, 3H), 2.33 (s,
3H).
Step 2: 5-Bromomethyl-3-methoxy-2,4-dimethyl-pyridine
[0501] The title compound was obtained from
(5-methoxy-4,6-dimethyl-pyridine-3-yl)-methanol according to the
general procedure 2.5. HPLC Rt: 2.873. .sup.1H-NMR (CDCl.sub.3)
.delta. 8.22 (s, 1H), 4.50 (s, 2H), 3.764 (s, 3H), 2.54 (s, 3H),
2.37 (s, 3H).
Step 3:
6-Chloro-9-(5-methoxy-4,6-dimethyl-pyridin-3-ylmethyl)-9H-purin-2--
ylamine
[0502] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
5-bromomethyl-3-methoxy-2,4-methylpyridine according to the general
procedure 1.1. HPLC Rt: 3.7387 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.25 (s, 1H), 7.63 (s, 1H), 5.39 (s, 2H), 5.11 (s, 2H),
3.73 (s, 3H), 2.55 (s, 3H), 2.22 (s, 3H).
Example 42
9-Methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0503] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride
according to the general procedure 1.1. HPLC Rt: 3.434 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.75 (s, 1H), 8.25 (s, 1H), 7.90
(s, 1H), 5.37 (s, 2H), 5.07 (s, 2H), 3.77 (s, 3H), 2.32 (s, 3H),
2.26 (s, 3H).
Example 43
6-Chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine
Step 1: (3,5-Dimethoxy-4-methyl-phenyl)-methanol
[0504] The title compound was obtained by reducing
3,5-dimethoxy-4-methyl-benzoic acid as described by Bhaskar et al.
J. Org. Chem. 1991, 56, 5964-5965. HPLC Rt: 5.352. .sup.1H-NMR
(CDCl.sub.3): .delta. 6.58 (s, 2H), 4.68 (s, 2H), 3.85 (s, 6H),
2.10 (s, 3H).
Step 2: 5-Bromomethyl-1,3-dimethoxy-2-methyl-benzene
[0505] The title compound was obtained from
(3,5-dimethoxy-4-methyl-phenyl)-methanol according to the general
procedure 2.5. HPLC Rt: 7.200. .sup.1H-NMR (CDCl.sub.3): .delta.
6.59 (s, 2H), 4.51 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.22 (s,
3H).
Step 3:
6-Chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine
[0506] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 5-bromomethyl-1,3-dimethoxy-4-methyl
benzene according to the general procedure 1.1. HPLC Rt: 5.841 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.75 (s, 1H), 6.46 (s, 1H), 5.21
(s, 2H), 5.07(s, 2H), 3.80 (s, 6H), 2.09 (s, 3H).
Example 44
9-(2-Bromo-3,5-dimethoxy-4-methyl-benzyl)-6-chloro-9H-purin-2-ylamine
[0507] The title compound was obtained by brominating
6-chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine with
bromine according to the general procedure 3.1. HPLC Rt: 6.222 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.85 (s, 1H), 6.60 (s, 1H), 5.36
(s, 2H), 5.07 (s, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.20 (s,
3H).
Example 45
8-Bromo-9-(2-bromo-3,5-dimethoxy-4-methyl-benzyl)-6-chloro-9H-purin-2-ylam-
ine
[0508] The title compound was obtained by brominating
6-chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine with
excess bromine according to the general procedure 3.1. HPLC Rt:
7.040 min. .sup.1H-NMR (CDCl.sub.3): .delta. 5.88 (s, 1H), 5.38 (s,
2H), 5.14 (s, 2H), 3.83 (s, 3H), 3.57 (s, 3H), 2.19 (s, 3H).
Example 46
2,6-Dichloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purine
[0509] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-chloromethyl-4-methoxy-3,5-dimethylpyridine (or its HCl salt)
according to the general procedure 1.1. HPLC Rt: 5.081 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.30 (s, 1H), 8.17 (s, 1H), 5.50
(s, 2H) 3.80 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H).
Example 47
8-butyl-6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
Step 1:
6-Chloro-N4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triamine
[0510] The title compound was obtained by refluxing
4,6-dichloro-pyrimidine-2,5-diamine (see Seela et al. Helv. Chim.
Acta. 1986, 69, 1602-1613 and U.S. Pat. No. 5,917,042),
3,4,-5-trimethoxybenzylamine, and Et.sub.3N in butanol or ethanol
for 1 to 14 h. HPLC Rt: 4.327 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 6.57 (s, 2H), 5.65 (t, 1H), 4.75 (s, 2H), 4.54 (d, 2H),
3.86-3.87 (d, 9H).
Step 2:
8-Butyl-6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0511] The title compound was obtained by following the procedure
given in WO 98/39344. HPLC Rt: 5.971 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 6.34 (s, 2H), 5.19 (s, 2H), 5.04 (s, 2H), 3.81 (s, 3H),
3.77 (s, 6H), 2.71-2.75 (t, 2H), 1.68-1.74 (m, 2H), 1.35-1.41 (m,
2H), 0.88-0.92 (t, 2H).
Example 48
6-Chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0512] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 3,4,5-trimethoxybenzyl according to the
general procedure 1.1. The title compound was also obtained by
treating a solution of
6-chloro-N-4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triamine in
triethyl orthoformate with a catalytic amount of conc. HCl at r.t.
for 20 min. HPLC Rt: 4.906 min. .sup.1H-NMR (CDCl.sub.3): .delta.
7.76 (s, 1H), 6.51 (s, 2H), 5.18 (s, 2H), 5.12 (s, 2H), 3.85 (s,
3H), 3.84 (s, 6H).
Example 49
Acetic acid
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenyl
ester
Step 1: Acetic acid 4-hydroxymethyl-2,6-dimethoxy-phenyl ester
[0513] A solution of acetic acid 4-formyl-2,6-dimethoxy-phenyl
ester (25 mmol) in MeOH (100 mL) was treated with NaBH.sub.4 (1
equiv.) at 0.degree. C. for 15 min. After quenching with acetone
and evaporating the solvent, work-up (CH.sub.2Cl.sub.2) and
evaporation gave the title compound as a white solid (85% yield).
Rf (in EtOAc/Hexane 1:1): 0.5. .sup.1H-NMR (CDCl.sub.3): .delta.
6.66 (s, 1H), 4.68-4.70 (d, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 1.74
(t, 1H).
Step 2: Acetic acid 3-bromo-4-hydroxymethyl-2,6-dimethoxy-phenyl
ester
[0514] The title compound was obtained by bromination of acetic
acid 4-hydroxymethyl-2,6-dimethoxy-phenyl ester in AcOH/AcONa
buffer according to the general procedure 3.1. Rf (EtOAc/Hexane
1:3): 0.2. .sup.1H-NMR (CDCl.sub.3): .delta. 7.01 (s, 1H),
4.75-4.76 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H ), 2.38 (s, 3H), 2.05
(t, 1H).
Step 3: Acetic acid 3-bromo-4-bromomethyl-2,6-dimethoxy-phenyl
ester
[0515] The title compound was obtained from Acetic acid
3-bromo-4-hydroxymethyl-2,6-dimethoxy-phenyl ester according to the
general procedure 2.5. Rf (EtOAc/Hexane 1:3): 0.8. .sup.1H-NMR
(CDCl.sub.3): .delta. 6.87 (s, 1H), 4.60 (s, 2H), 3.84 (s, 3H),
3.83 (s, 3H ), 2.36 (s, 3H).
Step 4: Acetic acid
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenyl
ester
[0516] The title compound was obtained by alkylation of
2-amino-6-chloropurine with acetic acid
3-bromo-4-bromomethyl-2,6-dimethoxy-phenyl ester according to the
general procedure 1.1. HPLC Rt: 5.081 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.30 (s, 1H), 8.17 (s, 1H), 5.50 (s, 2H),
3.80 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H).
Example 50
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
[0517] The title compound was obtained by deacetylation of Acetic
acid
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenyl
ester (see previous example) in NH.sub.3/MeOH at r.t. for 0.5 h or
K.sub.2CO.sub.3 in methanol according to the general procedure 2.3.
HPLC Rt: 4.912 min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.85 (s, 1H),
6.72 (s, 1H), 5.70 (s, 1H), 5.33 (s, 1H), 5.07 (s, 2H), 3.94 (s,
3H), 3.82 (s, 3H).
Example 51
9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0518] The title compound was obtained by O-methylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see previous example) according to the general procedure 2.6. The
title compound could also be obtained by bromination of
6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see
example 48) in acetate buffer according to the general procedure
3.1. HPLC Rt: 5.742 min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.85 (s,
1H), 6.66 (s, 1H), 5.32 (s, 2H), 5.11 (s, 2H), 3.90 (s, 3H), 3.87
(s, 3H), 3.76 (s, 3H).
Example 52
9-(4-allyloxy-2-bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0519] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with 3-bromo-propene in DMF in the presence of
K.sub.2CO.sub.3 at 70.degree. C. for 0.25-1 h. HPLC Rt: 6.309 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.84 (s, 1H), 6.64 (s, 1H),
6.00-6.10 (m, 2H), 5.36-5.36 (m, 1H), 5.31 (s, 2H), 5.20-5.21 (m,
2H), 4.52-4.54 (m, 2H), 3.90 (s, 3H), 3.74 (s, 2H).
Example 53
9-(2-bromo-4-chloromethoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylami-
ne
[0520] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with chloroiodomethane in DMF in the presence of
K.sub.2CO.sub.3 at 70.degree. C. for 0.25-1 h. HPLC Rt: 6.109 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.87 (s, 1H), 6.66 (s, 1H), 5.91
(s, 2H), 5.34 (s, 2H), 5.08 (s, 2H), 3.90 (s, 3H), 3.76 (s,
3H).
Example 54
9-[2-bromo-4-(2-chloro-ethoxy)-3,5-dimethoxy-benzyl]-6-chloro-9H-purin-2-y-
lamine
[0521] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with 1-bromo-2-chloro-ethane in DMF in the
presence of K.sub.2CO.sub.3 at 70.degree. C. for 0.25-1 h. HPLC Rt:
6.285 min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.86 (s, 1H), 6.67 (s,
1H), 5.37 (s, 2H), 5.32 (s, 2H), 4.22-4.25 (t, 2H), 3.91 (s, 3H),
3.77-3.78 (t, 2H), 3.75 (s, 3H).
Example 55
9-(2-bromo-4-cyclopropylmethoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2--
ylamine
[0522] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with bromomethyl-cyclopropane in DMF in the
presence of K.sub.2CO.sub.3 at 70.degree. C. for 0.25-1 h. HPLC Rt:
6.512 min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.86 (s, 1H), 6.67 (s,
1H), 5.34 (s, 2H), 5.17 (s, 2H), 3.95 (s, 3H), 3.83-3.84 (d, 2H),
3.77 (s, 3H), 1.27 (m, 1H), 0.58-0.62 (m, 2H), 0.28-0.32 (m,
2H).
Example 56
9-(2-bromo-4-ethoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0523] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with EtI in DMF in the presence of K.sub.2CO.sub.3
at 70.degree. C. for 0.25-1 h. HPLC Rt: 6.112 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.84 (s, 1H), 6.65 (s, 1H), 5.31 (s, 2H),
5.13 (s, 2H), 4.04-4.09 (q, 2H), 3.90(s, 3H), 3.82 (s, 3H),
1.32-1.38 (t, 3H).
Example 57
9-(2-bromo-3,5-dimethoxy-4-propoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0524] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with PrI in DMF in the presence of K.sub.2CO.sub.3
at 70.degree. C. for 0.25-1 h. HPLC Rt: 6.594 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.84 (s, 1H), 6.65 (s, 1H), 5.30 (s, 2H),
5.14 (s, 2H), 3.93-3.97 (t, 2H), 3.89 (s, 3H), 3.74 (s, 3H),
1.72-1.81 (m, 2H), 1.00-1.04 (t, 3H).
Example 58
9-(2-bromo-4-butoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0525] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) with BuI in DMF in the presence of K.sub.2CO.sub.3
at 70.degree. C. for 0.25-1 h. HPLC Rt: 6.594 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.84 (s, 1H), 6.65 (s, 1H), 5.30 (s, 2H),
5.14 (s, 2H), 3.97-4.00 (t, 2H), 3.89 (s, 3H), 3.74 (s, 3H),
1.68-1.76 (m, 2H), 1.44-1.53 (m,
Example 59
6-chloro-9-(3-methoxymethoxy-6-methyl-pyridin-2-ylmethyl)-9H-purin-2-ylami-
ne
Step 1: (3-methoxymethoxy-6-methyl-pyridin-2-yl)-methanol
[0526] The title compound was obtained by O-alkylation of
2-hydroxymethyl-6-methyl-pyridin-3-ol with chloromethyl methyl
ether according to the general procedure 2.6. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.28-7.30 (d, 1H), 6.98-7.00 (d, 1H), 5.17 (s,
2H), 4.71 (s, 2H), 4.50 (s, 2H), 3.45 (s, 3H), 2.49 (s, 3H).
Step 2: 2-Bromomethyl-3-methoxymethoxy-6-methyl-pyridine
[0527] The title compound was obtained from
(3-methoxymethyl-6-methyl-pyridine-2-yl)-methanol according to the
general procedure 2.5. .sup.1H-NMR (CDCl.sub.3) .delta. 7.32-7.40
(d 1H), 7.08-7.10 (d, 1H), 5.30 (s, 2H), 4.67 (s, 2H), 3.55 (s,
3H), 2.54 (s, 3H).
Step 3:
6-Chloro-9-(3-methoxymethoxy-6-methyl-pyridin-2-ylmethyl)-9H-purin-
-2-ylamine
[0528] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-bromomethyl-3-methoxymethoxy-6-methyl-pyridine according to the
general procedure 1.1. HPLC Rt: 3.884 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.92 (s, 1H), 7.34-7.36 (d, 1H), 7.05-7.07
(d, 1H), 5.39 (s, 2H), 5.17 (s, 2H), 5.06 (s, 2H), 3.40 (s, 3H),
2.44 (s, 3H).
Example 60
3-(2-Amino-6-chloro-purin-9-ylmethyl)-3H-benzothiazole-2-thione
[0529] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
3-chloromethyl-3H-benzothiazole-2-thione according to the general
procedure 1.1. HPLC Rt: 5.982 min. .sup.1H-NMR (d.sub.6-DMSO):
.delta. 8.37 (s, 1H), 8.25-8.28 (d, 1H) 7.79-7.81 (d, 1H),
7.54-7.56 (t, 1H), 7.39-7.43 (m 1H), 7.20 (s, 2H), 6.62 (s, 2H),
3.34 (s, 3H).
Example 61
6-Chloro-9-(2,5-dimethyl-benzyl)-9H-purin-2-ylamine
[0530] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 2-chloromethyl-1,4-dimethyl-benzene
according to the general procedure 1.1. HPLC Rt: 5.920 min.
.sup.1H-NMR (d.sub.6-DMSO): .delta. 8.10 (s, 1H), 7.10 (d, 1H) 7.04
(d, 1H), 6.95 (s, 2H), 6.65 (s, 1H), 5.23, (s, 2H), 3.34 (s, 3H),
2.30 (s, 3H), 2.17 (s, 3H).
Example 62
6-Chloro-9-isoquinolin-1-ylmethyl-9H-purin-2-ylamine
[0531] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-bromomethyl-isoquinoline according to
the general procedure 1.1. HPLC Rt: 4.306 min. .sup.1H-NMR
(d6-DMSO): .delta. 8.43-8.45 (d, 1H) 8.27-8.28 (d, 1H), 8.20 (s,
1H), 8.03-8.05 (d 1H), 7.85-7.89 (m, 1H), 7.77-7.82 (m, 2H), 6.83
(s, 2H), 6.04 (s, 2H).
Example 63
9-benzo[1,2,5]thiadiazol-5-ylmethyl-6-chloro-9H-purin-2-ylamine
[0532] The title compound was obtained by alkylation of
.sup.2-amino-6-chloropurine with
5-bromomethyl-benzo[1,2,5]thiadiazole according to the general
procedure 1.1. HPLC Rt: 4.931 min. .sup.1H-NMR (d.sub.6-DMSO):
.delta. 8.31 (s, 1H), 8.11 (d, 1H), 7.87 (br. s, 1H), 7.70-7.67
(dd, 1H), 6.98 (br, s, 2H), 5.52 (s, 2H).
Example 64
9-(1-methyl-1H-benzotriazol-5-ylmethyl)-6-chloro-9H-purin-2-ylamine
[0533] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 6-bromomethyl-1-methyl-1H-benzotriazole
according to the general procedure 1.1. HPLC Rt: 4.295 min.
.sup.1H-NMR (d.sub.6-DMSO): .delta. 8.29 (s, 1H), 7.95 (s, 1H),
7.86-7.84 (d, 1H), 7.55-7.53 (dd, 1H), 6.97 (s, 2H), 5.45 (s, 2H),
4.3 (s, 3H).
Example 65
6-chloro-9-(6-chloro-benzo[1,2,5]thiadiazol-5-ylmethyl)-9H-purin-2-ylamine
[0534] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
5-bromomethyl-6-chloro-benzo[1,2,5]thiadiazole according to the
general procedure 1.1. HPLC Rt: 5.400 min. .sup.1H-NMR
(d.sub.6-DMSO): .delta. 8.45 (s, 1H), 8.20 (s, 1H), 7.64 (s, 1H),
6.97 (s, 2H), 5.55 (s, 2H).
Example 66
9-benzo[1,2,5]thiadiazol-4-ylmethyl-6-chloro-9H-purin-2-ylamine
[0535] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 4-bromomethyl-benzo[1,2,5]thiadiazole
according to the general procedure 1.1. HPLC Rt: 5.027 min.
.sup.1H-NMR (d.sub.6-DMSO): .delta. 8.26 (s, 1H), 8.04-8.07 (d,
1H), 7.68-7.64 (dd, 1H), 7.22-7.20 (dd, 1H), 6.93 (s, 2H), 5.79 (s,
2H).
Example 67
6-chloro-9-(6-fluoro-4a,8a-dihydro-4H-benzo
[1,3]dioxin-8-ylmethyl)-9H-purin-2-ylamine
[0536] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
8-chloromethyl-6-fluoro-4a,8a-dihydro-4H-benzo[1,3]dioxine
according to the general procedure 1.1. HPLC Rt: 5.172 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.84 (s, 1H), 6.92-6.89 (dd, 1H),
6.70-6.67 (dd, 1H), 5.31 (s, 2H), 5.22 (s, 2H), 5.07 (s, 2H), 4.90
(s, 2H).
Example 68
1-[3-(2-Amino-6-chloro-purin-9-ylmethyl)-4-methoxy-phenyl]-ethanone
[0537] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-(3-chloromethyl-4-methoxy-phenyl)-ethanone according to the
general procedure 1.1. HPLC Rt: 4.887 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.03-8.02 (d, 1H), 7.97-7.95 (dd, 1H), 7.81
(s, 1H), 6.96-6.93 (d, 1H), 5.25 (s, 2H), 5.08 (s, 2H), 3.93 (s,
3H), 2.54 (s, 3H).
Example 69
6-chloro-9-(3-trifluoromethoxy-benzyl)-9H-purin-2-ylamine
[0538] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-chloromethyl-3-trifluoromethoxy-benzene according to the general
procedure 1.1. HPLC Rt: 5.965 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 7.76 (s, 1H), 7.39-7.37 (t, 1H), 7.21-7.15 (m, 3H), 5.27
(s, 2H), 5.12 (s, 2H).
Example 70
6-chloro-9-(2-fluoro-3-trifluoromethyl-benzyl)-9H-purin-2-ylamine
[0539] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2-fluoro-3-trifluoromethyl-benzene according to the
general procedure 1.1. HPLC Rt: 4.841 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.83 (s, 1H), 7.63-7.59 (t, 1H), 7.48-7.45
(t, 1H), 7.25-7.22 (t, 1H), 5.36 (s, 2H), 5.12 (s, 2H).
Example 71
6-Chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: (2-Fluoro-4,5-dimethoxy-phenyl)-methanol
[0540] A solution of 2-fluoro-4,5-dimethoxy-benzaldehyde (6.0 mmol)
in MeOH (10 mL) was treated with NaBH.sub.4 (1.2 equiv.) at
0-23.degree. C. for 0.5 h. After quenching with acetone and
evaporating the solvent, work-up (CH.sub.2Cl.sub.2), drying
(MgSO.sub.4) and evaporation gave the title compound as a crude
oily product (94% yield). .sup.1H-NMR (CDCl.sub.3): .delta.
6.90-6.88 (d, 1H), 6.61-6.64 (d, 1H), 4.65-4.63 (d, 2H), 3.86 (s,
3H), 3.84 (s, 3H), 2.00-1.94 (t, 1H).
Step 2: 1-Bromomethyl-2-fluoro-4,5-dimethoxy-benzene
[0541] The title compound was obtained from
(2-fluoro-4,5-dimethoxy-phenyl)-methanol according to the general
procedure 2.5. .sup.1H-NMR (CDCl.sub.3): .delta. 6.84-6.81 (d, 1H),
6.64-6.61 (d, 1H), 4.52 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
Step 3:
6-Chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0542] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2-fluoro-4,5-dimethoxy-benzene according to the
general procedure 1.1. HPLC Rt: 4.939 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.79 (s, 1H), 6.88-6.85 (d, 1H), 6.69-6.66
(d, 1H), 5.22 (s, 2H), 5.12 (s, 2H), 3.89 (s, 3H), 3.82 (s,
3H).
Example 72
6-chloro-9-(2,3-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 1-Bromomethyl-2,3-dimethoxy-benzene
[0543] The title compound was obtained from
(2,3-dimethoxy-phenyl)-methanol according to the general procedure
2.5. .sup.1H-NMR (CDCl.sub.3): .delta. 7.02-7.08 (t, 1H), 6.95-6.98
(dd, 1H), 6.87-6.91 (dd, 1H), 4.57 (s, 2H), 3.92 (s, 3H), 3.86 (s,
3H).
Step 2: 6-Chloro-9-(2,3-dimethoxy-benzyl)-9H-purin-2-ylamine
[0544] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-bromomethyl-2,3-dimethoxy-benzene
according to the general procedure 1.1. HPLC Rt: 5.200. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.81 (s, 1H), 7.02-7.08 (t, 1H), 6.95-6.98
(dd, 1H), 6.87-6.91 (dd, 1H), 5.28 (s, 2H), 5.12 (s, 2H), 3.92 (s,
3H), 3.87 (s, 3H).
Example 73
6-chloro-9-(3,4-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 4-Bromomethyl-1,2-dimethoxy-benzene
[0545] The title compound was obtained from
(3,4-dimethoxy-phenyl)-methanol according to the general procedure
2.5. .sup.1H-NMR (CDCl.sub.3): .delta. 6.95-6.98 (dd, 1H),
6.92-6.94 (d, 1H), 6.78-6.81 (d, 1H), 4.51 (s, 2H), 3.92 (s, 3H),
3.86 (s, 3H).
Step 2: 6-Chloro-9-(3,4-dimethoxy-benzy1)-9H-purin-2-ylamine
[0546] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 4-bromomethyl-1,2-dimethoxy-benzene
according to the general procedure 1.1. HPLC Rt: 4.753.
[0547] .sup.1H-NMR (CDCl.sub.3): .delta. 7.71 (s, 1H), 6.87 (s,
2H), 6.82 (s, 1H), 5.20 (s, 2H), 5.12 (s, 2H), 3.92 (s, 3H), 3.87
(s, 3H).
Example 74
9-(2-chloro-3,4,5-trimethoxy-benzyl)-6-methyl-9H-purin-2-ylamine
[0548] A suspension of
6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine,
see example 97) (0.2 mmol) and
tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3
mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol)
under nitrogen and heated to reflux for 3 h. The reaction mixture
was cooled to r.t., diluted with toluene (5 mL) and quenched with
methanol (0.5 mL) followed by ammonium chloride (1 mmol). The
mixture was heated to reflux for 2 h and filtered, while hot, on
Celite. See J. Med. Chem. 1999, 42, 2064-2086. TLC (100% EtOAc) Rf
was 0.2. HPLC Rt: 4.800 min.
Example 75
6-chloro-9-(2-chloro-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: (2-Chloro-4,5-dimethoxy-phenyl)-methanol
[0549] The title compound was obtained by chlorination of
(3,4-dimethoxy-phenyl)-methanol according to the general procedure
3.1. .sup.1H-NMR (CDCl.sub.3): .delta. 7.01 (s, 1H), 6.88 (s, 1H),
4.75-4.73 (d, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 1.95-1.92 (t,
1H).
Step 2: 1-Bromomethyl-2-chloro-4, 5-dimethoxy-benzene
[0550] The title compound was obtained from
(2-chloro-4,5-dimethoxy-phenyl)-methanol according to the general
procedure 2.5. .sup.1H-NMR (CDCl.sub.3): .delta. 6.92 (s, 1H), 6.88
(s, 1H), 4.60 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).
Step 3:
6-Chloro-9-(2-chloro-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0551] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2-chloro-4,5-dimethoxy-benzene according to the
general procedure 1.1. HPLC Rt: 5.366 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.81 (s, 1H), 7.28 (s, 1H), 6.92 (s, 1H),
5.30 (s, 2H), 5.15 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H).
Example 76
6-chloro-9-(2-iodo-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 4-Bromomethyl-1,2-dimethoxy-benzene
[0552] The title compound was obtained from
(3,4-dimethoxy-phenyl)-methanol according to the general procedure
2.5. .sup.1H-NMR (CDCl.sub.3): .delta. 6.95-6.98 (dd, 1H),
6.92-6.94 (d, 1H), 6.78-6.81 (d, 1H), 4.51 (s, 2H), 3.92 (s, 3H),
3.86 (s, 3H).
Step 2: 1-Bromomethyl-2-iodo-4, 5-dimethoxy-benzene
[0553] The title compound was obtained by iodination of
4-bromomethyl-1,2-dimethoxy-benzene according to the general
procedure 3.1. .sup.1H-NMR (CDCl.sub.3): .delta. 7.04 (s, 1H), 6.95
(s, 1H), 4.61 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).
Step 3:
6-Chloro-9-(2-iodo-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0554] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2-iodo-4,5-dimethoxy-benzene according to the general
procedure 1.1. HPLC Rt: 5.470 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 7.84 (s, 1H), 7.08 (s, 1H), 6.93 (s, 1H), 5.30 (s, 2H),
5.15 (s, 2H), 3.91 (s, 3H), 3.82 (s, 3H).
Example 77
6-Bromo-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 2-Chloro-1-chloromethyl-3,4,5-trimethoxy-benzene
[0555] The title compound was obtained by chlorination of
5-chloromethyl-1,2,3-trimethoxy-benzene according to the general
procedure 3.1. .sup.1H-NMR (CDCl.sub.3): .delta. 6.82 (s, 1H), 4.70
(s, 1H), 3.93 (s, 3H), 3.90 (s, 3H) 3.87 (s, 3H).
Step 2: Synthesis of
6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0556] The title compound was obtained by alkylation of
6-bromoguanine with
2-chloro-1-chloromethyl-3,4,5-trimethoxy-benzene according to the
general procedure 1.1. HPLC Rt: 5.676 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.82 (s, 1H), 6.70 (s, 1H), 5.32 (s, 2H),
5.15 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H) 3.79 (s, 3H).
Example 78
6-chloro-9-(6-chloro-benzol[1,3]dioxol-5-ylmethyl)-9H-purin-2-ylamine
[0557] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
5-chloro-6-chloromethyl-benzo[1,3]dioxole according to the general
procedure 1.1. HPLC Rt: 5.506 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 7.81 (s, 1H), 6.88 (s, 1H), 6.79 (s, 1H), 5.98 (s, 2H),
5.25 (s, 2H), 5.13 (s, 2H).
Example 79
6-chloro-9-(2,4-dimethoxy-3-methyl-benzyl)-9H-purin-2-ylamine
Step 1: 1-Bromomethyl-2,4-dimethoxy-3-methyl-benzene
[0558] The title compound was obtained from
(2,4-dimethoxy-3-methyl-phenyl)-methanol according to the general
procedure 2.5.
Step 2:
6-Chloro-9-(2,4-dimethoxy-3-methyl-benzyl)-9H-purin-2-ylamine
[0559] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2,4-dimethoxy-3-methyl-benzene according to the
general procedure 1.1. HPLC Rt: 5.433 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.76 (s, 1H), 7.08-7.06 (d, 1H), 6.60-6.62
(d, 1H), 5.20 (s, 2H), 5.07 (s, 2H), 3.82 (s, 3H), 3.72 (s, 3H),
2.17 (s, 3H).
Example 80
6-Chloro-9-(2-chloro-3,4-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 1-Bromomethyl-2-chloro-3, 4-dimethoxy-benzene
[0560] The title compound was obtained from
(2-chloro-3,4-dimethoxy-phenyl)-methanol according to the general
procedure 2.5.
Step 2:
6-Chloro-9-(2-chloro-3,4-dimethoxy-benzyl)-9H-purin-2-ylamine
[0561] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2-chloro-3,4-dimethoxy-benzene according to the
general procedure 1.1. HPLC Rt: 5.633 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.80 (s, 1H), 7.00-6.98 (d, 1H), 6.82-6.79
(d, 1H), 5,31 (s, 2H), 5.08 (s, 2H), 3.88 (s, 3H), 3.88 (s,
3H).
Example 81
6-chloro-9-(3-methoxy-benzyl)-9H-purin-2-ylamine
[0562] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-bromomethyl-3-methoxybenzene
according to the general procedure 1.1. HPLC Rt: 5.136 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.75 (s, 1H), 7.30-7.28 (m. 1H),
6.88-6.85 (dd, 1H), 6.84-6.82 (dd, 1H), 6.80-6.79 (m, 1H), 5.28 (s,
2H), 5.15 (s, 2H), 3.78 (s, 3H).
Example 82
6-Chloro-9-(2,6-dibromo-3,5-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 2-Bromo-1-chloromethyl-3,5-dimethoxy-benzene and
2,4-dibromo-3-chloromethyl-1,5-dimethoxy-benzene
[0563] Bromination of 1-chloromethyl-3,5-dimethoxy-benzene
according to the general procedure 3.1 gave a mixture of the two
title compounds, which were separated by flash chromatography.
.sup.1H-NMR of 2,4-dibromo-3-chloromethyl-1,5-dimethoxy-benzene
(CDCl.sub.3): .delta. 6.52 (s, 1H), 5.02 (s, 2H), 3.93 (s, 6H).
2-bromo-1-chloromethyl-3,5-dimethoxy-benzene .sup.1H-NMR
(CDCl.sub.3): .delta. 6.67-6.67 (d, 1H), 6.47-6.46 (d, 1H), 4.80
(s, 2H), 3.85 (s, 3H), 3.82 (s, 3H).
Step 2:
6-Chloro-9-(2,6-dibromo-3,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0564] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2,4-dibromo-3-chloromethyl-1,5-dimethoxy-benzene according to the
general procedure 1.1. HPLC Rt: 6.022 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.46 (s, 1H), 6.64 (s, 1H), 5.64 (s, 2H),
5.14 (s, 2H), 3.99 (s, 6H).
Example 83
9-(2-Bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0565] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-bromo-1-chloromethyl-3,5-dimethoxy-benzene (see previous example,
step 1) according to the general procedure 1.1. HPLC Rt: 6.026 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.82 (s, 1H), 6.48-6.47 (d, 1H),
6.32-6.32 (d, 1H), 5.35 (s, 2H), 5.09 (s, 2H), 3.90 (s, 3H), 3.73
(s, 3H).
Example 84
6-chloro-9-(3,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0566] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-chloromethyl-3,5-dimethoxy-benzene
according to the general procedure 1.1. HPLC Rt: 5.257 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.79 (s, 1H), 6.44-6.42 (t, 1H),
6.41-6.39 (d, 2H), 5.22 (s, 2H), 5.15 (s, 2H), 3.80 (s, 6H).
Example 85
N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yl]-acetamide
[0567] A solution of
6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine in acetic
acid was treated with fuming HNO.sub.3 at 0.degree. C. for 15 min.
Work-up and preparative TLC (EtOAc:hexane 1:1) gave
N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yl]-acetamide.
HPLC Rt: 5.744 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.09 (s, 1H),
6.58 (s, 2H), 5.33 (s, 2H), 3.85 (s, 3H), 3.85 (s, 6H), 2.43 (s,
3H).
Example 86
6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0568] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-chloromethyl-2,5-dimethoxy-benzene
according to the general procedure 1.1. HPLC Rt: 5.291 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.82 (s, 1H), 6.85-6.84 (d, 1H),
6.82-6.82 (d, 2H), 5.18 (s, 2H), 5.16 (s, 2H), 3.80 (s, 3H), 3.75
(s, 3H).
Example 87
8-bromo-6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine
[0569] The title compound was obtained by bromination of
6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine according to
the general procedure 1.2. HPLC Rt: 6.150 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 6.83-6.78 (m, 2H), 6.37-6.36 (d, 1H), 5.31
(s, 2H), 5.13 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H).
Example 88
6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purin-2-ylamine
[0570] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-4,5-dimethoxy-2-nitro-benzene according to the
general procedure 1.1. HPLC Rt: 5.194 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.98 (s, 1H), 7.74 (s, 1H), 6.79 (s, 1H),
5.67 (s, 2H), 5.15 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H).
Example 89
8-bromo-6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purin-2-ylamine
[0571] The title compound was obtained by brominating
6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purin-2-ylamine (see
previous example) according to the general procedure 1.2. HPLC Rt:
6.040 min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.74 (s, 1H), 6.13 (s,
1H), 5.78 (s, 2H), 5.16 (s, 2H), 3.99 (s, 3H), 3.71 (s, 3H).
Example 90
6-chloro-9-(2,5-dichloro-benzyl)-9H-purin-2-ylamine
[0572] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 2-bromomethyl-1,4-dichloro-benzene
according to the general procedure 1.1. HPLC Rt: 5.846 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.82 (s, 1H), 7.38-7.36 (d, 1H),
7.28-7.26 (dd, 1H), 7.18-7.18 (d, 1H), 5.32 (s, 2H), 5.17 (s,
2H).
Example 91
6-chloro-9-(2,3,5-trifluoro-benzyl)-9H-purin-2-ylamine
[0573] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-bromomethyl-2,3,5-trifluoro-benzene
according to the general procedure 1.1. HPLC Rt: 5.414 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.82 (s, 1H), 6.98-6.89 (m, 1H),
6.82-6.75 (m, 1H), 5.30 (s, 2H), 5.13 (s, 2H).
Example 92
(2-amino-6-chloro-purin-9-yl)-(3,4,5-trimethoxy-phenyl)-methanone
[0574] A solution of 6-chloro-9H-purin-2-ylamine in pyridine was
treated with 3,4,5-trimethoxybenzoyl chloride at r.t. for 2 h.
Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave
the title compound. HPLC Rt: 5.305 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.24 (s, 1H), 7.13 (s, 2H), 5.36 (s, 2H), 3.99 (s, 3H),
3.88 (s, 6H).
Example 93
N-[9-(2-Bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-acetamide
[0575] A suspension of
9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
(example 51) in acetic anhydride was treated with a catalytic
amount of conc. H.sub.2SO.sub.4 at r.t. for 3 h. Work-up and
purification by preparative TLC (EtOAc:hexane 9:1) gave the title
compound. HPLC Rt: 5.603 min. .sup.1H-NMR (CDCl.sub.3): .delta.
8.20 (s, 1H), 8.10 (s, 1H), 7.00 (s, 1H), 5.47 (s, 2H), 3.92 (s,
3H), 3.90 (s, 3H), 3.86 (s, 3H), 2.51 (s, 3H).
Example 94
N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2yl]-N-methyl-ace-
tamide
[0576] A mixture of
N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-acetamide
and NaH in DMF was stirred at r.t. for 15 min, before adding MeI.
Stirring was prolonged for 2 h at 50.degree. C. Work-up and
purification by preparative TLC (EtOAc:hexane 1:1) gave the title
compound. HPLC Rt: 6.422 min. .sup.1H-NMR (CDCl.sub.3): .delta.
8.20 (s, 1H), 6.80 (s, 1H), 5.45 (s, 2H), 3.93 (s, 3H), 3.90 (s,
3H), 3.82 (s, 3H), 3.57 (s, 3H), 2.51 (s, 3H).
Example 95
6-chloro-9-(3,5-dichloro-benzyl)-9H-purin-2-ylamine
Step 1: 1-Bromomethyl-3,5-dichloro-benzene
[0577] The title compound was obtained from
(3,5-dichloro-phenyl)-methanol according to the general procedure
2.5.
Step 2: 6-chloro-9-(3,5-dichloro-benzyl)-9H-purin-2-ylamine
[0578] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-bromomethyl-3,5-dichloro-benzene.
HPLC Rt: 6.074 min. .sup.1H-NMR (Acetone-d.sub.6): .delta. 8.12 (s,
1H), 7.45-7.43 (t, 1H), 7.72-7.42 (d, 2H), 6.30 (s, 2H), 5.40 (s,
2H).
Example 96
6-chloro-9-(3,4-dichloro-benzyl)-9H-purin-2-ylamine
[0579] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 4-bromomethyl-1,2-dichloro-benzene
according to the general procedure 1.1. HPLC Rt: 5.982 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.76 (s, 1H), 7.48-7.45 (d, 1H),
7.40-7.39 (d, 1H), 7.12-7.10 (dd, 1H), 5.23 (s, 2H), 5.12 (s,
2H).
Example 97
8-bromo-6-chloro-9-(3,4-dichloro-benzyl)-9H-purin-2-ylamine
[0580] The title compound was obtained by bromination of
6-chloro-9-(3,4-dichloro-benzyl)-9H-purin-2-ylamine (see previous
example) according to the general procedure 1.2. HPLC Rt: 6.878
min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.45-7.43 (m, 2H), 7.17-7.14
(dd, 1H), 5.23 (s, 2H), 5.12 (s, 2H).
Example 98
6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0581] Chlorination of
6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine according
to the general procedure 3.1 gave a mixture of the title compound
and of
6-chloro-9-(2,6-dichloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine.
The two compounds were isolated by preparative TLC. HPLC Rt: 5.626
min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.83 (s, 1H), 6.68 (s, 1H),
5.51 (s, 2H), 5.23 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.80 (s,
3H).
Example 99
6-chloro-9-(2,6-dichloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0582] See the previous example. HPLC Rt: 6.099 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.57 (s, 1H), 5.48 (s, 2H), 5.12 (s, 2H),
3.99 (s, 3H), 3.92 (s, 6H).
Example 100
2-amino-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-6-ol
[0583] The title compound was obtained by heating a solution of
6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
(see example 98in 1N HCl for 4 h. Solvent was evaporated and the
residue was washed with EtOAc to give the title compound. HPLC Rt:
4.603 min. .sup.1H-NMR (DMSO-d6): .delta. 7.82 (s, 1H), 6.65 (s,
1H), 6.60 (s, 2H), 5.15 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.69
(s, 3H).
Example 101
6-bromo-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0584] The title compound was obtained by alkylation of
6-bromoguanine with 3-chloromethyl-3,4,5-trimethoxy benzene
according to the general procedure 1.1. HPLC Rt: 4.947 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.80 (s, 1H), 6.50 (s, 2H), 5.20
(s, 2H), 5.18 (s, 2H), 3.85 (s, 3H), 3.84 (s, 6H).
Example 102
6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0585] The title compound was obtained by bromination of
6-bromo-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see
previous example) according to the general procedure 3.1. HPLC Rt:
5.793 min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.88 (s, 1H), 6.68 (s,
1H), 5.33 (s, 2H), 5.19 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.79
(s, 3H).
Example 103
9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-ethylsulfanyl-9H-purin-2-ylamine
[0586] A mixture of
6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see
previous example), EtSH, K.sub.2CO.sub.3 and THF was placed in a
pressure vessel and heated to 70.degree. C. for 6 h. Work-up and
purification by preparative TLC (EtOAc:hexane 1:1) gave the title
compound. HPLC Rt: 6.039 min. .sup.1H-NMR (CDCl.sub.3): .delta.
7.72 (s, 1H), 6.62 (s, 1H), 5.30 (s, 2H), 4.98 (s, 2H), 3.91 (s,
3H), 3.88 (s, 3H), 3.74 (s, 3H), 3.35-3.29 (q, 2H), 1.44-1.41 (t,
3H).
Example 104
9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxy-9H-purin-2-ylamine
[0587] A solution of
9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
(see example 51) in MeOH was treated with MeONa at reflux for 1 h.
Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave
the title compound. HPLC Rt: 5.229 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 7.69 (s, 1H), 6.58 (s, 1H), 5.33 (s, 2H), 4.88 (s, 2H),
4.11 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H).
Example 105
9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2,6-diamine
[0588] A solution of
9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
(see example 51) in MeOH was treated with NH.sub.3 (7N in MeOH) in
a pressure vessel at 90.degree. C. for 16 h. Work-up and
purification by preparative TLC (EtOAc:hexane 3:1) gave the title
compound. HPLC Rt: 4.884 min. .sup.1H-NMR (DMSO-d.sub.6): .delta.
7.67 (s, 1H), 6.71 (s, 2H), 6.60 (s, 1H), 5.84 (s, 2H), 5.17 (s,
2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.66 (s, 3H).
Example 106
6-chloro-9-(2-iodo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
[0589] The title compound was obtained by iodination of
6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see
example 48) according to the general procedure 3.1. HPLC Rt: 5.887
min. .sup.1H-NMR (CDCl.sub.3): .delta. 7.87 (s, 1H), 6.67 (s, 1H),
5.33 (s, 2H), 5.22 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.77 (s,
3H).
Example 107
9-(2-bromo-3,5-dimethoxy-4-methoxymethoxy-benzyl)-6-chloro-9H-purin-2-ylam-
ine
[0590] The title compound was obtained by alkylation of
4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol
(see example 50) chloromethyl methyl ether according to the general
procedure 2.6 (NaOH, THF, r.t.) HPLC Rt: 5.817 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.90 (s, 1H), 6.70 (s, 1H), 5.35 (s, 2H),
5.32 (s, 2H), 5.17 (s, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.62 (s,
3H).
Example 108
9-benzothiazol-2-ylmethyl-6-chloro-9H-purin-2-ylamine
[0591] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 2-bromomethyl-benzothiazole according
to the general procedure 1.1. HPLC Rt: 5.055 min. .sup.1H-NMR
(DMSO-d.sub.6): .delta. 8.34 (s,1H), 8.09-8.07 (dd, 1H), 7.98-7.96
(d, 1H), 7.53-7.50 (m, 1H), 7.47-7.43 (m, 1H), 7.01 (s, 2H), 5.81
(s, 2H).
Example 109
6-chloro-9-(4-methoxy-benzyl)-9H-purin-2-ylamine
[0592] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 1-chloromethyl-4-methoxy-benzene
according to the general procedure 1.1. HPLC Rt: 5.067 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 7.69 (s, 1H), 7.22-7.20 (d, 2H),
6.88-6.86 (d, 2H), 5.22 (s, 2H), 5.17 (s, 2H), 3.79 (s, 3H).
Example 110
9-(2-bromo-4,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
Step 1: (2-Bromo-4,5-dimethoxy-phenyl)-methanol
[0593] The title compound was obtained by bromination of
(3,4-dimethoxy-phenyl)-methanol according to the general procedure
3.1. .sup.1H-NMR (CDCl.sub.3): .delta. 7.03 (s, 1H), 7.03 (s, 1H),
4.70 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H)
Step 2: 1-Bromomethyl-2-chloro-4,5-dimethoxy-benzene
[0594] The title compound was obtained from
(2-bromo-4,5-dimethoxy-phenyl)-methanol according to the general
procedure 2.5. .sup.1H-NMR (CDCl.sub.3): .delta. 7.03 (s, 1H), 6.94
(s, 1H), 4.60 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H)
Step 3:
9-(2-Bromo-4,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
[0595] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
1-bromomethyl-2-chloro-4,5-dimethoxy-benzene according to the
general procedure 1.1. HPLC Rt: 5.458 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 7.84 (s, 1H), 7.08 (s, 1H), 6.93 (s, 1H),
5.30 (s, 2H), 5.15 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H).
Example 111
6-Chloro-9-(4-iodo-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Step 1: 2,3,5-Collidine-N-oxide
[0596] The title compound was obtained by oxidation of
2,3,5-collidine according to the general procedure 2.1 (yield 70%).
HPLC Rt: 3.964 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.03 (s, 1H),
6.90 (s, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z (%)
138.2 (M+1, 100%). Rf(20% MeOH/EtOAc) was 0.35.
Step 2: 2,3,5-Trimethyl-4-nitro-pyridine 1-oxide
[0597] A suspension of 2,3,5-collidine-N-oxide (3.77 g, 28 mmol) in
conc. H.sub.2SO.sub.4 (8 mL) was cooled to 0.degree. C. and fuming
HNO.sub.3 (5 mL, 100 mmol) was added dropwise. The resulting
transparent solution was stirred at 100.degree. C. for 24 h, cooled
to r.t., poured onto ice, and the pH was adjusted to 10. Work-up
(CHCl.sub.3), drying (MgSO.sub.4), and evaporation gave the title
compound, (97% yield, 97% purity). Rf (MeOH/EtOAc 1:9): 0.7. HPLC
Rt: 4.756 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.08 (s, 1H), 2.50
(s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). m/z (%) 183.1 (M+1, 100%).
Step 3: 2,3,5-Trimethyl-pyridin-4-ylamine-1-oxide hydrochloride
[0598] A suspension of 2,3,5-trimethyl-4-nitro-pyridine 1-oxide
(4.2 g, 23 mmol) and 10% Pd/C (0.42 g) in conc. aq. HCl/EtOH (1
:11) was treated with H2 (60 psi) at r.t. for 3 h. Filtration and
evaporation gave the title compound as a slightly yellow solid.
HPLC Rt: 4.756 min. .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.28 (s,
1H), 7.24 (s, 2H), 2.50 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H). m/z
(%) 153.2 (M+1, 100%).
Step 4: 4-Iodo-23,5-trimethyl-pyridine-1-oxide
[0599] A solution of 2,3,5-Trimethyl-pyridin-4-ylamine-1-oxide
hydrochloride (1.9 g, 10 mmol) HBF.sub.4 (20 mmol) in water (50 mL)
was cooled to 0.degree. C. A solution of NaNO.sub.2 (0.76 g, 11
mmol) in water (5 mL) was added dropwise to give a dark yellow
solution which gradually gave a precipitate within 15 min.
Potassium iodide (2.3 g, 1.39.times.10.sup.-2 mol) was added slowly
in several portion to give a dark brown precipitate. The reaction
mixture was stirred at r.t. for 5 min, and then heated to
60.degree. C. for 10 min. The mixture was cooled to r.t. and the pH
was adjusted to 10. Work-up (CHCl.sub.3), drying (MgSO.sub.4),
evaporation, and flash chromatography gave the title compound. HPLC
Rt: 5.579 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.07 (s, 1H), 2.62
(s, 3H), 2.56 (s, 3H), 2.38 (s,3H). m/z (%) 264.1 (M+1, 100%).
Step 5: Acetic acid 4-iodo-3,5-dimethyl-pyridin-2-ylmethyl
ester
[0600] The title compound was obtained by treating
4-iodo-3,5-dimethyl-pyridine 1-oxide was with Ac.sub.2O according
to the general procedure 2.2. HPLC Rt: 2.913 min. .sup.1H-NMR
(CDCl3): .delta. 8.26 (s, 1H), 5.32 (s, 2H), 2.47 (s, 3H), 2.41 (s,
3H), 2.24 (s, 3H). m/z (%) 306.0 (M+1, 100%).
Step 6: (4-Iodo-3,5-dimethyl-pyridin-2-yl)-methanol
[0601] The title compound was obtained by deacetylation of
4-iodo-3,5-dimethyl-pyridin-2-ylmethyl ester according to the
general procedure 2.3. HPLC Rt: 3.773 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.15 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H),
2.40 (s, 3H). m/z (%) 264.1 (M+1, 100%).
Step 7: 2-Bromomethyl-4-iodo-3, 5-dimethyl-pyridine
[0602] The title compound was obtained from
(4-Iodo-3,5-dimethyl-pyridin-2-yl)-methanol according to the
general procedure 2.5. HPLC Rt: 5.957 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.14 (s, 1H), 4.67 (s, 2H), 2.59 (s, 3H),
2.45 (s, 3H). m/z (%) 326.07 (M+1, 100%), 328.07 (M+1, 100%).
Step 8: 6-Chloro-9-(4-iodo-3,
S-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0603] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-bromomethyl-4-iodo-3,5-dimethyl-pyridine according to the general
procedure 1.1. HPLC Rt: 5.361 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.08 (s, 1H), 7.86 (s, 1H), 5.41 (s, 2H), 5.04 (s, 2H),
2.57 (s, 3H), 2.41 (s, 3H).
Example 112
6-chloro-9-(4-methyl-quinolin-2-ylmethyl)-9H-purin-2-ylamine
Step 1: 2,4-Dimethyl-quinoline 1-oxide
[0604] The title compound was obtained by oxidation of
2,4-dimethyl-quinoline according to the general procedure 2.1. HPLC
Rt: 4.489 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.89-8.07 (dd,
1H), 8.00-7.97 (dd, 1H), 7.82-7.79 (m, 1H), 7.69-7.65 (m, 1H), 7.20
(s, 1H), 2.73 (s, 3H), 2.69 (s, 3H).
Step 2: Acetic acid 4-methyl-quinolin-2-ylmethyl ester
[0605] The title compound was obtained by treating
2,4-dimethyl-quinoline-1-oxide with Ac.sub.2O according to the
general procedure 2.2. HPLC Rt: 3.158 min. Rf (EtOAc/Hexane 1:1):
0.8.
Step 3: (4-Methyl-quinolin-2-yl)-methanol
[0606] The title compound was obtained by deacetylation of acetic
acid 4-methyl-quinolin-2-ylmethyl ester according to the general
procedure 2.3. HPLC Rt: 3.715 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.08-8.06 (dd, 1H), 8.00-7.97 (dd, 1H), 7.73-7.69 (m, 1H),
7.57-7.54 (m, 1H), 7.12 (s, 1H), 4.87 (s, 2H), 4.52 (s, 1H), 2.70
(s, 3H).
Step 4: 2-bromomethyl-4-methyl-quinoline
[0607] The title compound was obtained from
(4-methyl-quinolin-2-yl)-methanol according to the general
procedure 2.5. HPLC Rt: 4.516 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.07-8.05 (dd, 1H), 7.98-7.96 (dd, 1H), 7.73-7.69 (m, 1H),
7.58-7.54 (m, 1H), 7.40 (d, 1H), 4.66 (s, 2H), 2.70 (s, 3H).
Step 5:
6-chloro-9-(4-methyl-quinolin-2-ylmethyl)-9H-purin-2-ylamine
[0608] The title compound was obtained by alkylation of
2-amino-6-chloropurine with 2-bromomethyl-4-methyl-quinoline
according to the general procedure 1.1. HPLC Rt: 4.387 min.
.sup.1H-NMR (DMSO-d6): .delta. 8.31 (s, 1H), 8.11-8.09 (dd, 1H),
7.90-7.88 (dd, 1H), 7.77-7.74 (m, 1H), 7.66-7.62 (m, 1H), 7.27 (s,
1H), 6.91 (s, 2H) 5.58 (s, 2H), 2.68 (s, 3H).
Example 113
6-bromo-9-(4-methyl-quinolin-2-ylmethyl)-9H-purin-2-ylamine
[0609] The title compound was obtained by alkylation of
6-bromoguanine with 2-bromomethyl-4-methyl-quinoline (see previous
example) according to the general procedure 1.1. HPLC Rt: 4.489
min. .sup.1H-NMR (DMSO-d6): .delta. 8.27 (s, 1H), 8.06-8.04 (dd,
1H), 7.85-7.83 (dd, 1H), 7.73-7.69 (m, 1H), 7.61-7.57 (m, 1H), 7.22
(s, 1H), 6.89 (s, 2H), 5.52 (s, 2H), 2.64 (s, 3H)
Example 114
6-bromo-9-(4-methyl-1-oxy-quinolin-2-ylmethyl)-9H-purin-2-ylamine
[0610] The title compound was obtained by oxidation of
6-bromo-9-(4-methyl-quinolin-2-ylmethyl)-9H-purin-2-ylamine (see
previous example) according to the general procedure 2.1. HPLC Rt:
4.698 min. .sup.1H-NMR (DMSO-d6): .delta. 8.62-8.60 (dd, 1H), 8.27
(s, 1H), 8.12-8.10 (dd, 1H), 7.88-7.85 (m, 1H), 7.79-7.75 (m, 1H),
6.93 (s, 2H), 6.89 (s, 1H) 5.57 (s, 2H), 2.64 (s, 3H).
Example 115
6-chloro-9-(3,5-dimethyl-4-methylsulfanyl-pyridin-2-ylmethyl)-9H-purin-2-y-
lamine
Step 1: 2,3,5-Trimethyl-4-methylsulfanyl-pyridine 1-oxide
[0611] A solution of 4-bromo-2,3,5-trimethyl-pyridine 1-oxide in
THF was treated in a pressure vessel with NaSMe at 110.degree. C.
for 16 h. HPLC Rt: 5.303 min. .sup.1H-NMR (CDCl.sub.3): .delta.
8.07 (s, 1H), 2.57 (s, 3H), 2.52 (s, 3H), 2.42 (s, 3H), 2.23 (s,
3H).
Step 2: Acetic acid
3,5-dimethyl-4-methylsulfanyl-pyridin-2-ylmethyl ester
[0612] The title compound was obtained by treating
2,3,5-trimethyl-4-methylsulfanyl-pyridine 1-oxide with Ac.sub.2O
according to the general procedure 2.2. HPLC Rt: 4.341 min.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.27 (s, 1H), 5.20 (s, 2H), 2.57
(s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 2.10 (s, 3H).
Step 3: (3,5-Dimethyl-4-methylsulfanyl-pyridin-2-yl)-methanol
[0613] The title compound was obtained by deacetylation of acetic
acid 3,5-dimethyl-4-methylsulfanyl-pyridin-2-ylmethyl ester
according to the general procedure 2.3. HPLC Rt: 3.921 min.
Step 4: 2-Bromomethyl-3,5-dimethyl-4-methylsulfanyl-pyridine
[0614] The compound was obtained from
(3,5-dimethyl-4-methylsulfanyl-pyridin-2-yl)-methanol according to
the general procedure 2.5. HPLC Rt: 4.905 min. .sup.1HNMR
(CDCl.sub.3): .delta. 8.26 (s, 1H), 4.59 (s, 2H), 2.62 (s, 3H),
2.47 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H). m/z (%): 246.13 (M+1,
96%), 248.09 (M+3, 100%).
Step 5:
6-Chloro-9-(3,5-dimethyl-4-methylsulfanyl-pyridin-2-ylmethyl)-9H-p-
urin-2-ylamine
[0615] The title compound was obtained by alkylation of
2-amino-6-chloropurine with
2-bromomethyl-3,5-dimethyl-4-methylsulfanyl-pyridine according to
the general procedure 1.1. HPLC Rt: 4.611 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.24 (s, 1H), 7.87 (s, 1H), 5.36 (s, 2H),
5.00 (s, 2H), 2.61 (s, 3H), 2.47 (s, 3H), 2.26 (s, 3H).
Example 116
6-chloro-9-(7-chloro-benzothiazol-2-ylmethyl)-9H-purin-2-ylamine
Step 1: (2,3-dichloro-phenyl)-acetamide
[0616] A solution of 2,3-dichloroaniline (5.00 g, 30.86 mmol) in
pyridine (20 ml) was cooled to 0.degree. C. and treated with AcCl
(4.85 g, 62 mmol). The reaction mixture was stirred at r.t. for 1 h
and then concentrated under reduced pressure. The residue was
dissolved in ethyl acetate, washed with 1% aqueous hydrochloric
acid, water and brine, and dried over MgSO.sub.4. The solution was
concentrated and recrystallized from EtOAc/hexane to give
(2,3-dichloro-phenyl)-acetamide (4.50 g, 22 mmol). HPLC Rt: 5.52
min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.35 (br. s, 1H), 7.7 (1H),
7.24 (1H), 7.23 (1H), 2.28 (s, 3H).
Step 2: (2,3-dichloro-phenyl)-thioacetamide
[0617] A solution of (2,3-dichloro-phenyl)-acetamide (4.50 g, 22
mmol,) in toluene (50 ml) was treated at r.t. with P.sub.2S.sub.5
(9.80 g, 22 mmol). The reaction mixture was heated to 90.degree. C.
for 1.5 h, cooled to r.t., and filtered. The solid was washed with
ether and the washings were combined with the filtrate. The
combined solutions were extracted twice with 10% aq. NaOH. The
combined aqueous extracts were acidified at 0.degree. C. with HCl.
The precipitate was collected and recrystallized from ethyl
acetate/hexane to afford (2,3-dichloro-phenyl)-thioacetamide (3.40
g, 16 mmol). HPLC Rt: 5.91 min. .sup.1H-NMR (CDCl.sub.3): .delta.
8.80 (br. s, 1H, NH), 8.5 (d, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 2.82
(s, 3H).
Step 3: 7-Chloro-2-methyl-benzothiazole
[0618] A solution of (2,3-dichloro-phenyl)-thioacetamide (3.4 g, 15
mmol) in N-methyl-2-pyrrolidinone (25 ml) was treated with NaH (60%
oil suspension, 0.74 g, 19 mmol) at r.t. The reaction mixture was
heated to 150.degree. C. for 30 min. Work-up (EtOAc), drying
(brine, MgSO.sub.4), evaporation, and purification by flash
chromatography afforded the title compound (2.4 g, 13 mmol). HPLC
Rt: 6.65 min. .sup.1H-NMR (CDCl3): .delta. 7.87 (d, 1H, J=7.9 Hz,
ph-H), 7.44 (t, 1H, J=7.9 Hz, ph-H), 7.35 (d, 1H, J=8.0 Hz, ph-H),
2.87 (s, 3H, CH.sub.3).
Step 4: 2-Bromomethyl-7-chloro-benzothiazole
[0619] A mixture of 7-chloro-2-methyl-benzothiazole (1.00 g, 5.45
mmol), N-bromosuccinimide (1.26 g, 7.08 mmol), benzoyl peroxide
(0.1 g), and CCl.sub.4 (10 mL was heated to reflux under
irradiation of a UV lamp for 14 h. The reaction mixture was cooled
and filtered to remove the succinimide formed in the reaction, and
the filtrate was evaporated to dryness. The resulting solid was
purified by flash chromatography to give the title lamp (400 mg,
1.5 mmol). .sup.1H-NMR (CDCl.sub.3): .delta. 7.94 (d, 1H), 7.47 (t,
1H), 7.42 (d, 1H), 4.82 (s, 2H, CH.sub.2). HPLC Rt: 7.19 min.
Step 5:
6-Chloro-9-(7-chloro-benzothiazol-2-ylmethyl)-9H-purin-2-ylamine
[0620] A mixture of 2-bromomethyl-7-chloro-benzothiazole (60 mg,
0.2286 mmol), 2-amino-6-chloropurine (32 mg, 0.19 mmol),
Cs.sub.2CO.sub.3 (67.86 mg, 0.208 mmol), and DMF (2 ml) was heated
to 40.degree. C. for 1 h. The reaction was cooled to r.t. and the
solvent was removed on a rotary evaporator. The resulting solid was
purified by preparative TLC to give the title compound (50 mg, 0.14
mmol). HPLC Rt: 5.81 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.0 (s,
1H), 7.95 (d, 1H), 7.48 (t, 1H), 7.43 (d, 1H), 5.69 (s, 2H), 5.17
(s, 2H).
Example 117
6-Chloro-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Step 1: 2,3,5-Collidine-N-oxide
[0621] See Example 1, Method 1, step 1.
Step 2: 4-Bromo-2,3,5-collidine-N-oxide
[0622] See Example 1, Method 1, step 2.
Step 3: 2,3,4,5-Tetramethyl-pyridine 1-oxide
[0623] 4-Bromo-2,3,5-trimethyl-pyridine 1-oxide (2 g, 9.2 mmole)
and catalytic tetrakis(triphenylphosphino)-palladium (80 mg, 4% by
wt) in 20 mL of dry THF before treating with trimethylaluminum (2M
in toluene, 15.2 mmole) under nitrogen. The solution was heated to
reflux for 3 h, diluted with toluene (20 mL) before quenching the
reaction with 4 mL of methanol followed by ammonium chloride (15
mmole). The mixture was refluxed for 2 h and filtered, while hot,
on Celite. See J. Med Chem. 1999, 42(12), 2064-2086. HPLC Rt: 4.183
min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.05 (s, 1H), 2.55 (s, 3H),
2.27 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H).
Step 4: Acetic acid 3,4,5-trimethyl-pyridin-2-ylmethyl ester
[0624] The compound was obtained by dissolving in acetic anhydride
before bringing the reaction to reflux for 0.5 h as described in
the general procedure 2.2. Quenching the reaction with water and
extracting with chloroform yielded the titled product. HPLC Rt:
3.843 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.20 (s, 1H), 5.22 (s,
2H), 2.26 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H).
Step 5: (3,4,5-Trimethyl-pyridin-2-yl)-methanol
[0625] The compound was obtained by hydrolysis of acetic acid
3,4,5-trimethyl-pyridin-2-ylmethyl ester in MeOH and
K.sub.2CO.sub.3 at 50.degree. C. for 0.5 h as described in the
general procedure 2.3. After removing MeOH, the residue was
dissolved in water and extracted with chloroform. HPLC Rt: 3.405
min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.18 (s, 1H), 5.00 (s, 1H),
4.67 (s, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H).
Step 6: 2-bromomethyl-3,4,5-trimethyl-pyridine
[0626] The compound was obtained from reacting
(3,4,5-trimethyl-pyridin-2-yl)-methanol with triphenyl phosphine
and carbon tetrabromide in dichloromethane as described in the
general procedure 2.5. HPLC Rt: 3.979 min. .sup.1H-NMR
(CDCl.sub.3): .delta. 8.18 (s, 1H), 4.63 (s, 2H), 2.35 (s, 3H),
2.48 (s, 3H), 2.24 (s, 3H).
Step 7:
6-Chloro-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0627] The compound was obtained by reacting
2-bromomethyl-3,4,5-trimethyl-pyridine with
6-chloro-9H-purin-2-ylamine in the presence of K.sub.2CO.sub.3 at
50.degree. C. for 0.5 h as described in the general procedure 1.1.
HPLC Rt: 3.903 min. .sup.1H-NMR (CDCl.sub.3): .delta. 8.18 (s, 1H),
7.84 (s, 1H), 5.38 (s, 2H), 5.08 (s, 2H), 2.29 (s, 3H), 2.27 (s,
3H), 2.22 (s, 3H).
Example 118
6-Bromo-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0628] The compound was obtained by reacting
2-bromomethyl-3,4,5-trimethyl-pyridine (see example 117) with
6-bromo-9H-purin-2-ylamine in the presence of K.sub.2CO.sub.3 in
DMF for 0.5 h at 50.degree. C. as described in the general
procedure 1.1. HPLC Rt: 4.045 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 8.18 (s, 1H), 7.85 (s, 1H), 5.37 (s, 2H), 5.10 (s, 2H),
2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Example 119
6-Bromo-9-(3,4,5-trimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine
[0629] The compound was obtained by the oxidation of
6-bromo-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
with m-CPBA in dichloromethane as described in the general
procedure 2.1. HPLC Rt: 5.611 min. .sup.1H-NMR (CDCl.sub.3):
.delta. 9.13 (s, 1H), 8.08 (s, 1H), 5.91 (s, 2H), 2.70 (s, 3H),
2.27 (s, 3H), 2.22 (s, 3H).
BIOLOGY EXAMPLES
Example A
rHSP90 Competitive Binding Assay
[0630] Five microgram of purified rHSP90 protein (Stressgen, BC,
Canada, #SPP-770) in phosphated buffered saline (PBS) was coated on
96 well plates by incubating overnight at 4.degree. C. Unbound
protein was removed and the coated wells were washed twice with 200
.mu.L PBS. DMSO controls (considered as untreated samples) or test
compounds were then added at 100-30-10-3-1-0.3 .mu.M dilutions (in
PBS), the plates mixed for 30 seconds on the plate shaker, and then
incubated for 60 min. at 37.degree. C. The wells were washed twice
with 200 .mu.L PBS, and 10 .mu.M biotinylated-geldanamycin
(biotin-GM) was added and incubated for 60 min. at 37.degree. C.
The wells were washed again twice with 200 .mu.L PBS, before the
addition of 20 .mu.g/mL streptavidin-phycoerythrin
(streptavidin-PE) (Molecular Probes, Eugene, Oreg.) and incubation
for 60 min. at 37.degree. C. The wells were washed again twice with
200 .mu.L PBS. Relative fluorescence units (RFU) was measured using
a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices,
Sunnyvale, Calif.) with an excitation at 485 nm and emission at 580
nm; data was acquired using SOFTmax.RTM.PRO software (Molecular
Devices Corporation, Sunnyvale, Calif.). The background was defined
as the RFU generated from wells that were not coated with HSP90 but
were treated with the biotin-GM and streptavidin-PE. The background
measurements were substrated from each sample treated with
biotin-GM and streptavidin-PE measurements before other
computation. Percent inhibition of binding for each sample was
calculated from the background subtracted values as follows: %
binding inhibition=[RFU untreated-RFU treated]/RFU
untreated].times.100.
Example B
Cell Lysate Binding Assay
[0631] MCF7 breast carcinoma cell lysates were prepared by douncing
in lysing buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl.sub.2,
100 mM KCl), and then incubated with or without test compound for
30 mins at 4.degree. C., followed by incubation with biotin-GM
linked to BioMag.TM. streptavidin magnetic beads (Qiagen) for 1 hr
at 4.degree. C. The tubes were placed on a magnetic rack, and the
unbound supernatant removed. The magnetic beads were washed three
times in lysis buffer and boiled for 5 mins at 95.degree. C. in
SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels,
and Western blots done for rHSP90. Bands in the Western Blots were
quantitated using the Bio-rad Fluor-S Multihnager, and the %
inhibition of binding of rHSP90 to the biotin-GM was
calculated.
[0632] The lysate binding ability of selected compounds of the
invention based on the above assay is summarized in Table 2. The
IC.sub.50 reported is the concentration of test compound needed to
achieve 50% inhibition of the biotin-GM binding to rHSP90 in the
MCF7 cell lysates.
Example C
HER2 Degradation Assay
[0633] MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's
modified Eagle's medium (DMEM) containing 10% fetal bovine serum
(FBS) and 10 mM HEPES, and plated in 24 well plates (50%
confluent). Twenty-four hrs later (cells are 65-70% confluent),
test compounds were added and incubated overnight for 16 h. For the
less potent compounds, the amounts added were 100 .mu.M, 30 .mu.M,
10 .mu.M and 1 .mu.M, and for more potent compounds, the amounts
added were 1 .mu.M, 0.3 .mu.M, 0.1 .mu.M, 0.03 .mu.M, 0.01 .mu.M
and 0.003 .mu.M. The wells were washed with 1 mL phosphate buffered
saline (PBS), and 200 .mu.L trypsin was added to each well. After
trypsinization was complete, 50 .mu.L of FBS was added to each
well. Then 200 .mu.L cells was transferred to 96 well plates. The
cells were pipetted up and down to obtain a single cell suspension.
The plates were centrifuged at 2,500 rpm for 1 min using a Sorvall
Legend RT.TM. tabletop centrifuge (Kendro Laboratory Products,
Asheville, N.C.). The cells were then washed once in PBS containing
0.2% BSA and 0.2% sodium azide (BA buffer). Phycoerythrin (PE)
conjugated anti HER2/Neu antibody (Becton Dickinson, #340552), or
PE conjugated anti-keyhole limpet hemacyanin [KLH] (Becton
Dickinson, #340761) control antibody was added at a dilution of
1:20 and 1:40 respectively (final concentration was 1 .mu.g/mL) and
the cells were pipetted up and down to form a single cell
suspension, and incubated for 15 mins. The cells were washed twice
with 200 .mu.L BA buffer, and resuspended in 200 .mu.L BA buffer,
and transferred to FACSCAN tubes with an additional 250 .mu.L BA
buffer. Samples were analyzed using a FACSCalibur.TM. flow
cytometer (Becton Dickinson, San Jose, Calif.) equipped with
Argon-ion laser that emits 15 mW of 488 nm light for excitation of
the PE fluorochrome. 10,000 events were collected per sample. A
fluorescence histogram was generated and the mean fluorescence
intensity (MFI) of each sample was determined using Cellquest
software. The background was defined as the MFI generated from
cells incubated with control IgG-PE, and was subtracted from each
sample stained with the HER2/Neu antibody. Cells incubated with
DMSO was always done as untreated controls since the compounds were
resuspended in DMSO. Percent degradation of HER2 was calculated as
follows: % HER2 degraded=[(MFl untreated cells-MFl treated
cells)/MFl untreated cell].times.100
[0634] The HER2 degradation ability of selected compounds of the
invention based on this assay is summarized in Table 2. IC.sub.50
is defined as the concentration at which there was 50% degradation
of the HER2/Neu protein.
Example D
MTS Assay
[0635] MTS assays measures the cytotoxicity of geldanamycin
derivatives. MTS
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulfophe-
nyl)-2H-tetrazolium is a tetrazolium dye that is converted to a
formazan product by dehydrogenase enzymes of metabolically active
cells (Corey, A. et al. "Use of an aqueous soluble
tetrazolium/formazan assay for cell growth assays in culture,"
Cancer Commun. 1991, 3, 207-212). Cells were seeded in 96 well
plates at 2000 cells/well and allowed to adhere overnight in
Dulbecco's modified Eagle's medium supplemented with 10% fetal
bovine serum. The final culture volume was 100 .mu.l. Viable cell
number was determined by using the Celltiter 96
AQ.sub.ueousNon-radioactive Cell Proliferation Assay (Promega,
Madison Wis.). The MTS/PMS (phenazine methosulfate) solution was
mixed at a ratio of 20:1, and 20 .mu.L was added per well to 100
.mu.l of culture medium. After 2-4 hours, the formation of the
formazan product was measured at 490 nm absorbance using a
multiwell plate spectrophotometer. Background was determined by
measuring the Abs 490 nm of cell culture medium and MTS-PMS in the
absence of cells and was subtracted from all values. Percent viable
cells was calculated as follows: % viable cells=(Abs at 490 nm
treated cells/Abs at 490 nm untreated cells).times.100
[0636] The effect of selected compounds of the invention on MCF7
breast carcinoma cells according to the MTS assay is summarized in
Table 2. IC.sub.50 was defined as the concentration of the compound
which gave rise to 50% viable cell number. TABLE-US-00002 TABLE 2
Biological Activities of Selected Compounds of Formula II, where
R.sup.2 = NH.sub.2, R.sub.3 = H II ##STR22## 1 51 ##STR23## Cl 0.7
0.025 0.055 0.2 2 98 ##STR24## Cl 0.7 0.03 0.025 0.1 3 102
##STR25## Br 0.9 0.022 0.055 0.1 4 77 ##STR26## Br ND ND 0.10 0.3 5
44 ##STR27## Cl ND ND 0.08 2.0 6 25 ##STR28## Cl 0.9 0.021 0.030
0.2 7 31 ##STR29## Cl 0.8 0.030 0.060 5.0 8 21 ##STR30## Br 0.7
0.030 0.045 0.3 9 41 ##STR31## Cl ND ND 0.035 0.2 10 33 ##STR32##
Cl ND ND 0.09 0.5 11 18 ##STR33## Cl ND ND 0.055 0.1 12 1 ##STR34##
Cl ND ND 0.015 0.02 13 4 ##STR35## Cl ND ND 0.020 0.13 14 24
##STR36## Br ND ND 0.060 0.4 15 19 ##STR37## Cl ND ND 0.080 0.4 16
5 ##STR38## Br ND 0.008 0.014 0.02 17 6 ##STR39## Br ND ND 0.060
0.05 18 111 ##STR40## Cl ND 0.003 0.009 0.02 19 115 ##STR41## Cl ND
ND 0.060 ND ND = not determined
[0637] The foregoing examples are not limiting and are merely
illustrative of various aspects and embodiments of the present
invention. All documents cited herein are indicative of the levels
of skill in the art to which the invention pertains and are
incorporated by reference herein in their entireties. None,
however, is admitted to be prior art.
[0638] One skilled in the art will readily appreciate that the
present invention is well adapted to carry out the objects and
obtain the ends and advantages mentioned, as well as those inherent
therein. The methods and compositions described illustrate
preferred embodiments, are exemplary, and are not intended as
limitations on the scope of the invention. Certain modifications
and other uses will occur to those skilled in the art, and are
encompassed within the spirit of the invention, as defined by the
scope of the claims.
[0639] The invention illustratively described herein suitably may
be practiced in the absence of any element or elements, limitation
or limitations which is not specifically disclosed herein. The
terms and expressions which have been employed are used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described, or portions thereof. It is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments, optional features, modifications and
variations of the concepts herein disclosed may be resorted to by
those skilled in the art, and that such modifications and
variations are considered to be within the scope of this invention
as defined by the description and the appended claims.
[0640] In addition, where features or aspects of the invention are
described in terms of Markush groups or other grouping of
alternatives, e.g., genuses, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush group
or subgenus, and exclusions of individual members as appropriate,
e.g, by proviso.
[0641] Other embodiments are within the following claims.
* * * * *