U.S. patent application number 11/567817 was filed with the patent office on 2008-01-24 for 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents.
This patent application is currently assigned to RIGEL PHARMACEUTICALS, INC.. Invention is credited to Ankush Argade, David Carroll, Susan Catalano, Hui Li, Rajinder Singh.
Application Number | 20080021020 11/567817 |
Document ID | / |
Family ID | 34138795 |
Filed Date | 2008-01-24 |
United States Patent
Application |
20080021020 |
Kind Code |
A1 |
Argade; Ankush ; et
al. |
January 24, 2008 |
2,4-Pyrimidinediamine Compounds And Uses As Anti-Proliferative
Agents
Abstract
The present invention provides 2,4-pyrimidinediamine compounds
having antiproliferative activity, compositions comprising the
compounds and methods of using the compounds to inhibit cellular
proliferation and to treat proliferative diseases such as
tumorigenic cancers.
Inventors: |
Argade; Ankush; (Foster
City, CA) ; Singh; Rajinder; (Belmont, CA) ;
Li; Hui; (Millbrae, CA) ; Carroll; David; (San
Francisco, CA) ; Catalano; Susan; (Hayward,
CA) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
RIGEL PHARMACEUTICALS, INC.
South San Francisco
CA
94080
|
Family ID: |
34138795 |
Appl. No.: |
11/567817 |
Filed: |
December 7, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10913270 |
Aug 6, 2004 |
|
|
|
11567817 |
Dec 7, 2006 |
|
|
|
60494008 |
Aug 7, 2003 |
|
|
|
60572534 |
May 18, 2004 |
|
|
|
Current U.S.
Class: |
514/224.2 ;
435/375; 514/235.8; 514/252.14; 514/275 |
Current CPC
Class: |
A61K 31/505 20130101;
C07D 413/14 20130101; A61P 35/04 20180101; A61P 35/00 20180101;
C07D 498/04 20130101; A61K 31/506 20130101; C07D 239/48 20130101;
A61P 43/00 20180101; C07D 405/12 20130101; C07D 417/14 20130101;
C07D 417/12 20130101; C07D 403/12 20130101; C07D 401/12 20130101;
A61K 31/4353 20130101; C07D 401/14 20130101; C07D 413/12
20130101 |
Class at
Publication: |
514/224.2 ;
435/375; 514/235.8; 514/252.14; 514/275 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61K 31/496 20060101 A61K031/496; A61K 31/5375
20060101 A61K031/5375; A61K 31/5415 20060101 A61K031/5415; A61P
35/00 20060101 A61P035/00; C12N 5/00 20060101 C12N005/00 |
Claims
1. A method of inhibiting proliferation of a cancer cell,
comprising contacting the cancer cell with an effective amount of a
2,4-pyrimidinediamine compound according to structural formula (I):
##STR744## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: L.sup.1 and L.sup.2 are each,
independently of one another, selected from a lower alkyldiyl
linker, a lower allylene linker and a covalent bond; R.sup.2 is
selected from the group consisting of lower alkyl optionally
substituted with an R.sup.b group, ##STR745## where Y is NH, O or
CH.sub.2; R.sup.2' is hydrogen, methyl or lower alkyl; R.sup.4' is
hydrogen, methyl or lower alkyl; R.sup.4 is selected from the group
consisting of lower alkyl optionally monosubstituted with an
R.sup.a or R.sup.b group, lower cycloalkyl optionally
monosubstituted with an R.sup.a or R.sup.b group, lower
cycloheteroalkyl optionally substituted at one or more ring carbon
and/or heteroatoms with an R.sup.a or R.sup.b group,
--(CR.sup.aR.sup.a).sub.n--R.sup.b, ##STR746## where D is
--(CR.sup.7R.sup.7).sub.m--, ##STR747## where Z.sup.1 is N or CH
and Z.sup.2 is O, S, NH, S(O) or S(O).sub.2; R.sup.5 is selected
from the group consisting of halo, fluoro and --CF.sub.3; R.sup.6
is hydrogen; each R.sup.7 is independently selected from the group
consisting of hydrogen, methyl, lower alkyl and halo; each R.sup.8
is independently selected from the group consisting of hydrogen,
lower allyl, --(CH.sub.2).sub.nOH, --OR.sup.a,
--(CH.sub.2).sub.n--NR.sup.cR.sup.c, --O(CH.sub.2).sub.n--R.sup.a,
--O(CH.sub.2).sub.n--R.sup.b, --C(O)OR.sup.a, --C(S)OR.sup.a, halo,
--CF.sub.3 and --OCF.sub.3; each R.sup.9 is independently selected
from the group consisting of hydrogen, lower alkyl, --OR.sup.a,
--(CH.sub.2).sub.n--NR.sup.cR.sup.c, O(CH.sub.2).sub.n--R.sup.a,
--O(CH.sub.2).sub.n--R.sup.b, --C(O)--NR.sup.cR.sup.c,
--C(S)--NR.sup.cR.sup.c, --S(O).sub.2NR.sup.cR.sup.c,
--NHC(O)R.sup.a, --NHC(S)R.sup.a, --C(O)--NH--(CH.sub.2),
--NR.sup.cR.sup.c, --C(S)--NH--(CH.sub.2), --NR.sup.cR.sup.c, halo,
--CF.sub.3, --OCF.sub.3, ##STR748## each R.sup.10 is independently
selected from the group consisting of hydrogen, lower alkyl,
--(CH.sub.2).sub.n--OH, --(CH.sub.2).sub.n--NR.sup.cR.sup.c,
OR.sup.a, O(CH.sub.2).sub.n--R.sup.a, --O(CH.sub.2).sub.n--R.sup.b,
e halo, --CF.sub.3, --OCF.sub.3, ##STR749## each R.sup.11 is
independently selected from the group consisting of --OR.sup.a,
--NR.sup.cR.sup.c and NR.sup.aR.sup.d; each R.sup.12 is
independently selected from the group consisting of lower alkyl,
arylalkyl, --OR.sup.a, --NR.sup.cR.sup.c, --C(O)R.sup.a,
--C(O)OR.sup.a and --C(O)NR.sup.cR.sup.c; each R.sup.13 is
independently selected from the group consisting of lower alkyl,
hydroxy, lower alkoxy, methoxy, --C(O)NR.sup.cR.sup.c and
--C(O)NH.sub.2; each R.sup.15 is independently selected from the
group consisting of hydrogen, lower alkyl, lower cycloakyl and
phenyl; each R.sup.16 is independently selected from the group
consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl,
lower branched alkyl and lower cycloalkylmethyl; each R.sup.17 is
independently selected from the group consisting of hydrogen, lower
alkyl, methyl and R.sup.d or, alternatively, R.sup.17 may be taken
together with R.sup.18 to form an oxo (.dbd.O) group; each R.sup.18
is independently selected on the group consisting of hydrogen,
lower alkyl and methyl or, alternatively, R.sup.18 may be taken
together with R.sup.17 to form all oxo (.dbd.O) group; each
R.sup.19 is independently selected form the group consisting of
hydrogen, lower alkyl, methyl and R.sup.d; each R.sup.20 is
independently selected from the group consisting of hydrogen, lower
alkyl, methyl and R.sup.d; each m is independently an integer from
1 to 3; each n is independently an integer from 1 to 3; each
R.sup.a is independently selected from the group consisting of
hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl,
phenyl and benzyl; each R.sup.b is independently selected from the
group consisting of --OR.sup.a, --CF.sub.3, --OCF.sub.3,
NR.sup.cR.sup.c, C(O)R.sup.a, --C(S)R.sup.a, --C(O)OR.sup.a,
--C(S)OR.sup.a, --C(O)NR.sup.cR.sup.c, --C(S)NR.sup.cR.sup.c,
S(O).sub.2NR.sup.cR.sup.C, --C(O)NR.sup.aR.sup.d,
--C(S)NR.sup.aR.sup.d and --S(O).sub.2NR.sup.aR.sup.d; each R.sup.c
is independently selected from the group consisting of hydrogen,
lower alkyl and lower cycloalkyl, or, alternatively, two R.sup.cs
may be taken together with the nitrogen atom to which they are
bonded to form a 5-7 membered saturated ring which optionally
includes 1-2 additional heteroatomic groups selected from O,
NR.sup.a, NR.sup.a--C(O)R.sup.a, NR.sup.a--C(O)OR.sup.a and
NR.sup.a--C(O)NR.sup.a; and each R.sup.d is independently selected
from lower mono-hydroxyalkyl and lower di-hydroxyalkyl, with the
provisos that: (i) when R.sup.2 is ##STR750## then R.sup.9 and
R.sup.10 are not both simultaneously lower alkoxy or methoxy, or
when R.sup.2 is 3,4,5-trimethoxyphenyl or
3,4,5-tri(loweralkoxy)phenyl, then R.sup.4 is ##STR751## (ii) when
R.sup.2 is lower alkyl, then R.sup.4 is ##STR752## (iii) when
R.sup.4 is ##STR753## and L.sup.2 is lower alkylene, then R.sup.2
is other than 3-(1,3-oxazolyl)phenyl; (iv) when R.sup.4 is
##STR754## where R.sup.15 is t-butyl and R.sup.2 is ##STR755## then
at least two of R.sup.8, R.sup.9 and R.sup.10 or R.sup.8, R.sup.9
and R.sup.13 are other than hydrogen; (v) when R.sup.4 is
##STR756## where R.sup.15 is t-butyl and R.sup.2 is ##STR757##
where R.sup.1 and R.sup.9 are each hydrogen, then R.sup.10 is other
than --(CH.sub.2).sub.n--OH or --O(CH.sub.2).sub.n--R.sup.b where
R.sup.b is selected from NR.sup.cR.sup.c, --C(O)R.sup.a,
--C(O)NR.sup.cR.sup.c and --C(O)NR.sup.aR.sup.d.
2. The method of claim 1 in which L.sup.1 and L.sup.2 are each a
covalent bond.
3. The method of claim 2 in which R.sup.5 is fluoro.
4. The method of claim 3 in which R.sup.2' and R.sup.4' are each
hydrogen.
5. The method of claim 3 in which R.sup.2' is hydrogen and R.sup.4'
is methyl.
6. The method of claim 3 in which R.sup.2 is ##STR758##
7. The method of claim 6 in which R.sup.4 is selected from
unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted
cyclopentyl, unsubstituted cyclohexyl ##STR759## where R.sup.e and
R.sup.f are selected from (C1-C3) alkanyl and methyl and R.sup.g is
benzyl.
8. The method of claim 7 in which R.sup.8 is hydrogen; R.sup.9 is
selected from ##STR760## and R.sup.10 is other than ##STR761##
9. The method of claim 8 in which R.sup.10 is selected from
hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and
chloro.
10. The method of claim 8 in which R.sup.12 is selected from
methyl, --C(O)CH.sub.3, --C(O)OCH.sub.3 and
--C(O)OCH.sub.2CH.sub.3.
11. The method of claim 8 in which R.sup.8 is hydrogen; R.sup.9 is
other than ##STR762## and R.sup.10 is selected from ##STR763##
12. The method of claim 11 in which R.sup.9 is selected from
hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and
chloro.
13. The method of claim 11 in which R.sup.12 is selected from
methyl, --C(O)CH.sub.3, --C(O)OCH.sub.3 and
--C(O)Cl.sub.2CH.sub.3.
14. The method of claim 8 in which R.sup.9 is other than ##STR764##
and R.sup.10) is other than ##STR765##
15. The method of claim 14 in which R.sup.8 and R.sup.9 are each
hydrogen and R.sup.10 is --OCH.sub.2NHR.sup.a.
16. The method of claim 14 in which R.sup.8, R.sup.9 and R.sup.10
are each, independently of one another, selected from hydrogen,
methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro, with
the proviso that at least two of R.sup.8, R.sup.9 and R.sup.10 are
other than hydrogen.
17. The method of claim 7 in which the 2,4-pyrimidinediamine
compound is selected from any compound in any one of TABLEs 1A-1D
having an IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor
cell line in an in vitro antiproliferation assay.
18. The method of claim 3 in which R.sup.4 is ##STR766##
19. The method of claim 18 in which R.sup.1 is hydrogen and
R.sup.15 is selected from lower branched alkyl and lower
cycloalkyl.
20. The method of claim 18 in which R.sup.15 is t-butyl or
cyclopropyl.
21. The method of claim 18 in which R.sup.2 is ##STR767##
22. The method of claim 21 in which R.sup.8 is hydrogen; R.sup.9 is
selected from ##STR768## and R.sup.10 is other than ##STR769##
23. The method of claim 22 in which R.sup.10 is selected from
methyl, trifluoromethyl and chloro.
24. The method of claim 22 in which R.sup.12 of R.sup.9 is selected
from methyl, --C(O)CH.sub.3, --C(O)OCH.sub.3 and
--C(O)CH.sub.2CH.sub.3.
25. The method of claim 21 in which R.sup.8 is hydrogen; R.sup.9 is
other than ##STR770## and R.sup.10 is selected from ##STR771##
26. The method of claim 25 in which R.sup.9 is selected from
hydrogen, methyl, trifluoromethyl and chloro.
27. The method of claim 25 in which R.sup.12 of R.sup.10 is
selected from methyl, --C(O)CH.sub.3, --C(O)OCH.sub.3 and
--C(O)CH.sub.2CH.sub.3.
28. The method of claim 18 in which the 2,4-pyrimidinediamine
compound is selected from any compound in TABLE 2 having an
IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor cell line
in an in vitro antiproliferation assay.
29. The method of claim 3 in which R.sup.4 is lower alkyl.
30. The method of claim 29 in which the lower alkyl is
branched.
31. The method of claim 30 in which R.sup.e4 is i-propyl or
t-butyl.
32. The method of claim 30 in which R.sup.2 is ##STR772##
33. The method of claim 32 in which R.sup.8 is hydrogen; R.sup.9 is
selected from ##STR773## and R.sup.10 is other than ##STR774##
34. The method of claim 33 in which R.sup.10 is selected from
hydrogen, methyl, trifluoromethyl and chloro.
35. The method of claim 33 in which R.sup.2 of R.sup.9 is
methyl.
36. The method of claim 32 in which R.sup.8 is hydrogen; R.sup.9 is
hydrogen and R.sup.10 is selected from ##STR775##
37. The method of claim 36 in which R.sup.12 is methyl.
38. The method of claim 18 in which the 2,4-pyrimidinediamine
compound is selected from any compound in TABLE 3 having an
IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor cell line
in an in vitro antiproliferation assay.
39. The method of claim 3 in which R.sup.4 is selected from
##STR776##
40. The method of claim 39 in which R.sup.19 and R.sup.20 are
different from one another such that the carbon atom to which they
are bonded is chiral.
41. The method of claim 40 in which the 2,4-pyrimidinediamine
compound is a racemate of R and S enantiomers.
42. The method of claim 40 which the 2,4-pyrimidinediamine compound
is enriched in the R enantiomer.
43. The method of claim 42 in which the 2,4-pyrimidinediamine
compound is substantially free of the S enantiomer.
44. The method of claim 40 in which the 2,4-pyrimidinediamine
compound is enriched in the S enantiomer.
45. The method of claim 44 in which the 2,4-pyrimidinediamine
compound is substantially free of the R enantiomer.
46. The method of claim 39 in which R.sup.2 is ##STR777##
47. The method of claim 46 in which R.sup.8, R.sup.9 and R.sup.10
are each, independently of one another, selected from hydrogen,
lower alkyl, methyl, lower alkoxy, methoxy, halo, chloro and
OCH.sub.2C(O)NHR.sup.a, with the proviso that at least one of
R.sup.8, R.sup.9 or R.sup.10 is other than hydrogen.
48. The method of claim 46 in which R.sup.8 is hydrogen; R.sup.9 is
selected from ##STR778## and R.sup.10 is selected from hydrogen,
methyl and chloro.
49. The method of claim 48 in which R.sup.12 is selected from
methyl, --C(O)CH.sub.3, --C(O)OCH.sub.3 and
--C(O)OCH.sub.2CH.sub.3.
50. The method of claim 46 in which R.sup.8 is hydrogen, R.sup.9 is
selected from hydrogen, methyl and chloro; and R.sup.10 is selected
from ##STR779##
51. The method of claim 50 in which R.sup.12 is selected from
methyl, --C(O)CH.sub.3, --C(O)OCH.sub.3 and
--C(O)OCH.sub.2CH.sub.3.
52. The method of claim 46 in which the substituents on the R.sup.4
and R.sup.2 groups are independently selected from any combinations
described in TABLE 4 or TABLE 6.
53. The method of claim 46 in which the 2,4-pyrimidinediamine
compound is selected from any compound in TABLE 4 or TABLE 6 having
an IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor cell
line in an in vitro antiproliferation assay.
54. The method of claim 3 in which R.sup.4 is ##STR780##
55. The method of claim 54 in which D is selected from
--CH.sub.2--CH.sub.2--, --CF.sub.2--CF.sub.2, --CH.sub.2--, and
--CF.sub.2--.
56. The method of claim 54 in which R.sup.2 is ##STR781##
57. The method of claim 56 in which R.sup.8, R.sup.9 and R.sup.10
are each, independently of one another, selected from hydrogen,
lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro,
fluoro, --OCH.sub.2C(O)NHR.sup.a, --OCH.sub.2C(O)NR.sup.cR.sup.c,
--OCH.sub.2C(O)OR.sup.a, trifluoromethyl and --O(CH.sub.2).sub.nOH,
with the proviso that at least one of R.sup.8, R.sup.9 or R.sup.10
(is other than hydrogen.
58. The method of claim 54 which is selected from any compound in
TABLE 5 having an IC.sub.50 of .ltoreq.20 .mu.M against at least
one tumor cell line in an in vitro antiproliferation assay.
59. The method of claim 3 in which R.sup.2 is ##STR782##
60. The method of claim 59 in which R.sup.11 is selected from any
R.sup.11 group listed in TABLE 7.
61. The method of claim 59 in which the 2,4-pyrimidinediamine
compound is selected from any compound in TABLE 7 having an
IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor cell line
in an in vitro antiproliferation assay.
62. The method of claim 3 in which R.sup.4 is ##STR783##
63. The method of claim 62 in which R.sup.2 is ##STR784##
64. The method of claim 63 in which each R.sup.8, R.sup.9 and
R.sup.10 is selected such that the compound is not an
N2,N4-bis(substituted phenyl)-2,4-pyrimidinediamine.
65. The method of claim 63 in which each R.sup.8, R.sup.9 and
R.sup.10 is, independently of the others, selected from hydrogen,
lower alkyl, methyl, hydroxy, trifluoromethoxy, lower linear
alkoxy, halo, --O(CH.sub.2).sub.nNR.sup.cR.sup.c,
--OCH.sub.2C(O)NR.sup.a, --OCH.sub.2C(O)NR.sup.cR.sup.c and
--OCH.sub.2C(O)OR.sup.a.
66. The method of claim 65 in which R.sup.8, R.sup.9 and R.sup.10
are each, independently of one another; selected from hydrogen,
methyl, trifluoromethyl, methoxy, trifluoromethoxy, and chloro,
with the proviso that at least one of R.sup.8, R.sup.9 and R.sup.10
on both of R.sup.2 and R.sup.4 is other than hydrogen.
67. The method of claim 66 in which at least two of R.sup.8,
R.sup.9 and R.sup.10 on both of R.sup.2 and R.sup.4 are other than
hydrogen.
68. The method of claim 63 in which R.sup.8 and R.sup.9 of R.sup.2
are each hydrogen; R.sup.10 of R.sup.2 is
--OCH.sub.2C(O)NR.sup.cR.sup.c or --OCH.sub.2C(O)NHR.sup.a; R.sup.8
and R.sup.10 of 10 are, independently of one another, selected from
hydrogen, methyl and chloro; and R.sup.9 of R.sup.4 is selected
from hydroxy, ##STR785##
69. The method of claim 63 in which the 2,4-pyrimidinediamine
compound is selected from any compound in TABLE 8 having an
IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor cell line
in an in vitro antiproliferation assay.
70. The method of claim 3 in which R.sup.2 is ##STR786##
71. The method of claim 70 in which R.sup.4 is ##STR787## where D
is --CH.sub.2CH.sub.2--.
72. The method of claim 71 in which R.sup.8, R.sup.9 and R.sup.10
are each, independently of one another, selected from hydrogen,
methyl, methoxy, fluoro and chloro.
73. The method of claim 71 which is selected from any compound in
TABLE 10 having an IC.sub.50 of .ltoreq.20 .mu.M against at least
one tumor cell line in an in vitro antiproliferation assay.
74. The method of claim 3 in which R.sup.2 is ##STR788##
75. The method of claim 74 in which R.sup.4 is ##STR789##
76. The method of claim 75 in which R.sup.16 is selected from
hydrogen, lower linear alkanyl, lower branched alkanyl, lower
cyclic alkanyl and lower cyclicalkanylmethyl.
77. The method of claim 75 in which the 2,4-pyrimidinediamine
compound is selected from any compound in TABLE 13 having an
IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor cell line
in an in vitro antiproliferation assay.
78. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is selected from any compound illustrated in TABLES 1-14
having an IC.sub.50 of .ltoreq.20 .mu.M against at least one tumor
cell line in an in vitro antiproliferation assay.
79. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is compound according to structural formula (Ia):
##STR790## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: m is as integer ranging from 1 to 3;
R.sup.21 is selected from hydrogen, lower alkyl, methyl, lower
alkoxy, methoxy, halogen and chloro; R.sup.22 is selected from
hydrogen, lower alkoxy, methoxy, halogen, chloro, ##STR791##
R.sup.23 is selected from hydrogen, methyl, lower alkyl, lower
alkoxy, methoxy, halogen, chloro, trifluomethyl,
--OCH.sub.2C(O)NHR.sup.a, ##STR792## and R.sup.24 is selected from
hydrogen and methyl, with the provisos that (i) when R.sup.22 is
##STR793## then R.sup.23 is other than ##STR794## and (ii) when
R.sup.23 is ##STR795## then R.sup.22 is other than ##STR796##
80. The method of claim 79 in which R.sup.21 and R.sup.22 are each
hydrogen and R.sup.23 is selected from --OCH.sub.2C(O)NHR.sup.a,
##STR797##
81. The method of claim 79 in which R.sup.22 is selected from
hydrogen methoxy, chloro, ##STR798##
82. The method of claim 81 in which R.sup.12 is methyl.
83. The method of claim 79 in which R.sup.21 is hydrogen and
R.sup.22 is ##STR799## where R.sup.12 is methyl.
84. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ib):
##STR800## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: R.sup.15 is selected from t-butyl and
cyclopropyl; R.sup.21, R.sup.22 and R.sup.23 are as defined in
claim 79.
85. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ic):
##STR801## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: R.sup.14 is selected from i-propyl and
t-butyl; and R.sup.21, R.sup.22 and R.sup.23 are as defined in
claim 79.
86. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Id):
##STR802## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: Z.sup.1 is selected from N and CH;
Z.sup.2 is selected from NH, O, S and S(O).sub.2; R.sup.16 is
selected from hydrogen and methyl; R.sup.19 is as defined in claim
1; R.sup.20 is as defined in claim 1; R.sup.24 is as defined in
claim 79; R.sup.41 is selected from hydrogen, lower alkyl, methyl;
hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl and
--CH.sub.2OH; R.sup.42 is selected from hydrogen, lower alkyl,
methyl, hydroxy, lower alkoxy, methoxy, halo, chloro,
trifluoromethyl, trifluoromethoxy, --OCH.sub.2C(O)NHR.sup.a,
##STR803## where R.sup.12 is as defined in claim 1; and R.sup.43 is
selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy,
methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy,
--OCH.sub.2C(O)NHR.sup.a, --OCH.sub.2C(O)OR.sup.a, ##STR804## where
R.sup.12 is as defined in claim 1, with the provisos that: (i) when
R.sup.42 is ##STR805## then R.sup.43 is other than ##STR806## and
(ii) when R.sup.43 is ##STR807## then R.sup.42 is other than
##STR808##
87. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ie):
##STR809## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein Z.sup.1, Z.sup.2, R.sup.16, R.sup.19,
R.sup.20, R.sup.24, R.sup.41, R.sup.42 and R.sup.43 are as defined
in claim 86.
88. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (If):
##STR810## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: Z.sup.3 is selected from N and CH; p is
0 or 1; R.sup.7 is selected from hydrogen and fluoro; R.sup.24 is
as defined in claim 79; R.sup.51 is selected from hydrogen, lower
alkyl, methyl, lower alkoxy, methoxy, halo, trifluoromethyl,
CH.sub.2OH and --C(O)OCH.sub.3; R.sup.52 is selected from hydrogen,
lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo,
trifluoromethyl, CH.sub.2OH and --OCH.sub.2C(O)NR.sup.aR.sup.a
where R.sup.a is as defined in claim 1; and R.sup.53 is selected
from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo,
trifluoromethyl, CH.sub.2OH, --OCH.sub.2C(O)OR.sup.a and
OCH.sub.2C(O)NHR.sup.a where R.sup.a is as defined in claim 1.
89. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ig):
##STR811## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: R.sup.28 is hydrogen or methyl; R.sup.16
is as defined in claim 86; and R.sup.21, R.sup.22, R.sup.23 and
R.sup.24 are as defined in claim 79.
90. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ih):
##STR812## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: R.sup.24 is as defined in claim 79;
R.sup.61 is selected from H and Cl; R.sup.62 is selected from
--CH.sub.2NHBoc, --CH.sub.2NH.sub.2, --C(O)NH.sub.2,
--C(O)NH--CH.sub.2--C(O)OH, --C(O)NH--CH.sub.2--C(O)OMe and
--C(O)NH--CH.sub.2CH.sub.2--N(Et).sub.2; R.sup.63 is selected from
H and Cl; R.sup.71 is H; R.sup.72 is selected from H, OMe, Cl and
--C(O)NH.sub.2; and R.sup.73 is selected from H, OMe and Cl.
91. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ii):
##STR813## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: each R.sup.24 is independently as
defined in claim 79; and R.sup.30 is selected from alkanyl and
alkenyl.
92. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ij):
##STR814## including prodrugs, salts, hydrates, solvates and
N-oxides thereof, wherein: R.sup.24 is as defined in claim 79;
R.sup.81 is selected from hydrogen, methyl and methoxy; R.sup.82 is
selected from hydrogen, methoxy and chloro; and R.sup.83 is
selected from methyl, methoxy, halo and fluoro.
93. The method of claim 1 in which the 2,4-pyrimidinediamine
compound is a compound according to structural formula (Ik), (Il),
(Im) or (In): ##STR815## including prodrugs, salts, hydrates,
solvates and N-oxides thereof, wherein: R.sup.91, if present, is
hydrogen; R.sup.92, if present, is selected from lower alkoxy,
methoxy, halo, chloro and fluoro; R.sup.93, if present, is selected
from lower alkoxy, methoxy, halo and chloro; and R.sup.96 is
selected from hydrogen, lower linear alkanyl, lower branched
alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl.
94. The method of claim 1 in which the cancer cell is a tumor
cell.
95. The method of claim 94 in which the tumor cell is a bladder,
lung, colon, breast, prostate, pancreatic, ovarian or hepatic tumor
cell.
96. The method of claim 1 which is practiced in vivo as a
therapeutic approach towards the treatment of cancer.
97. The method of claim 96 in which the cancer is a metastatic
tumor.
98. The method of claim 97 in which the cancer is selected from the
group consisting of breast, colon, pancreatic, lung, neural,
esophageal, gastric, and melanoma.
99. The method of claim 96 in which the compound is administered in
the form of a pharmaceutical composition.
100. The method of claim 99 in which the compound is administered
orally or intravenously.
101. The method of claim 100 in which the subject is a human.
Description
1. CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/913,270 filed Aug. 6, 2004, which claims
benefit to U.S. Provisional Application No. 60/494,008 filed Aug.
7, 2003 and U.S. Provisional Application No. 60/572,534 filed May
18, 2004.
2. FIELD
[0002] The present invention relates to 2,4 pyrimidinediamine
compounds that exhibit antiproliferative activity, prodrugs of the
compounds, intermediates and methods of synthesis for making the
compounds and/or prodrugs, pharmaceutical compositions comprising
the compounds acid the use of the compounds in a variety of
contexts, including for the treatment of proliferative disorders)
such as, for example, tumors and cancers.
3. BACKGROUND
[0003] Cancer is a group of varied diseases characterized by
uncontrolled growth and spread of abnormal cells. Generally, all
types of cancers involve some abnormality hi the control of cell
growth and division. The pathways regulating cell division and/or
cellular communication become altered in cancer cells such that the
effects of these regulatory mechanisms in controlling and limiting
cell growth fails or is bypassed. Through successive rounds of
mutation and natural selection, a group of abnormal cells,
generally originating from a single mutant cell, accumulates
additional mutations that provide selective growth advantage over
other cells, and thus evolves into a cell type that predominates in
the cell mass. This process of mutation and natural selection is
enhanced by genetic instability displayed by many types of cancer
cells, an instability which is gained either from somatic mutations
or by inheritance from the germ line. The enhanced mutability of
cancerous cells increases the probability of their progression
towards formation of malignant cells. As the cancer cells father
evolve, some become locally invasive and then metastasize to
colonize tissues other than the cancer cell's tissue of origin.
This property along with the heterogeneity of the tumor cell
population makes cancer a particularly difficult disease to treat
and eradicate.
[0004] Traditional cancer treatments take advantage of the higher
proliferative capacity of cancer cells and their increased
sensitivity to DNA damage Ionizing radiation, including
.gamma.-rays and x-rays, and cytotoxic agents, such as bleomycin,
cis-platin, vinblastine, cyclophosphamide, 5'-fluorouracil, and
methotrexate rely upon a generalized damage to DNA and
destabilization of chromosomal structure which eventually lead to
destruction of cancer cells. These treatments are particularly
effective for those types of cancers that have defects in cell
cycle checkpoint, which limits the ability of these cells to repair
damaged DNA before undergoing cell division. The non-selective
nature of these treatments, however, often results in severe and
debilitating side effects. The systemic use of these drugs may
result in damage to normally healthy organs and tissues, and
compromise the long term health of the patient.
[0005] Although more selective chemotherapeutic treatments have
been developed based on knowledge of how cancer cells develop, for
example, the anti-estrogen compound tamoxifen, the effectiveness of
all chemotherapeutic treatments are subject to development of
resistance to the drugs. In particular, the increased expression of
cell membrane bound transporters, such as MdrI, produces a
multidrug resistance phenotype characterized by increased efflux of
drugs from the cell. These types of adaptation by cancer cells
severely limit the effectiveness of certain classes of
chemotherapeutic agents. Consequently, identification of other
chemotherapeutic agents is critical for establishing therapies
effective for attacking the heterogeneous nature of proliferative
disease and for overcoming any resistance that may develop over the
course of therapy with other compounds. Moreover, use of
combinations of chemotherapeutic agents with differing properties
and cellular targets increases the effectiveness of chemotherapy
and limits the generation of drug resistance.
4. SUMMARY
[0006] In one aspect, the present invention provides
2,4-pyrimidinediamine compounds that exhibit antiproliferative
activity against a variety of different cell types, including a
variety of different types of tumor cells. The compounds are
generally 2,4-pyrimidinediamine compounds according to structural
formula (I): ##STR1##
[0007] including salts, hydrates, solvates and N-oxides thereof
wherein: [0008] L.sup.1 and L.sup.2 are each, independently of one
another, selected from a lower alkyldiyl linker, a lower alkylene
linker and a covalent bond; [0009] R.sup.2 is selected from the
group consisting of lower alkyl optionally substituted with an
R.sup.b group, ##STR2## where Y is NH, O or CH.sub.2; [0010]
R.sup.2' is hydrogen, methyl or lower alkyl; [0011] R.sup.4' is
hydrogen, methyl or lower alkyl; [0012] R.sup.4 is selected from
the group consisting of lower alkyl optionally monosubstituted with
an R.sup.a or R.sup.b group, lower cycloalkyl optionally
monosubstituted with an R.sup.a or R.sup.b group, lower
cycloheteroalkyl optionally substituted at one or more ring carbon
and/or heteroatoms with an R.sup.a or R.sup.b group,
--(CR.sup.aR.sup.a).sub.n--R.sup.b, ##STR3## where D is
--(CR.sup.7R.sup.7).sub.m--, ##STR4## where Z.sup.1 is N or CH and
Z.sup.2 is O, S, NH, 8(O) or 8(O).sub.2; [0013] R.sup.5 is selected
from the group consisting of halo, fluoro and --CF.sub.3; [0014]
R.sup.6 is hydrogen; [0015] each R.sup.7 is independently selected
from the group consisting of hydrogen, methyl, lower alkyl and
halo; [0016] each R.sup.8 is independently selected from the group
consisting of hydrogen, lower alkyl, --(CH.sub.2).sub.n--OH,
--OR.sup.a, --(CH.sub.2).sub.n--NR.sup.cR.sup.c,
--O(CH.sub.2).sub.n--R.sup.a, --O(CH.sub.2).sub.n--R.sup.b,
--C(O)OR.sup.a, --C(S)OR.sup.a, halo, --CF.sub.3 and --OCF.sub.3;
[0017] each R.sup.9 is independently selected from the group
consisting of hydrogen, lower alkyl, --OR.sup.a,
--(CH.sub.2).sub.n--R.sup.cR.sup.c, --O(CH.sub.2).sub.n--R.sup.a,
O(CH.sub.2).sub.n--R.sup.b, --C(O)--NR.sup.cR.sup.c,
C(S)--NR.sup.cR.sup.c, S(O).sub.2--NR.sup.cR.sup.c,
--NHC(O)R.sup.a, --NHC(S)R.sup.a,
--C(O)--NH--(CH.sub.2).sub.n--NR.sup.cR.sup.c,
--C(S)--NH--(CH.sub.2).sub.n--NR.sup.cR.sup.c, halo, --CF.sub.3,
--OCF.sub.3, ##STR5## [0018] each R.sup.10 is independently
selected from the group consisting of hydrogen, lower alkyl,
--(CH.sub.2).sub.n--OH, (CH.sub.2).sub.n, --NR.sup.cR.sup.c,
--OR.sup.a, O(CH.sub.2).sub.n--R.sup.a,
--O(CH.sub.2).sub.n--R.sup.b, halo, --CF.sub.3, --OCF.sub.3,
##STR6## [0019] each R.sup.11 is independently selected from the
group consisting of --OR.sup.a, --NR.sup.cR.sup.c and
--NR.sup.aR.sup.d; [0020] each R.sup.12 is independently selected
from the group consisting of lower alkyl, arylalkyl, --OR.sup.a,
--NR.sup.cR.sup.c, C(O)R.sup.a, --C(O)OR.sup.a and
--C(O)NR.sup.cR.sup.c; [0021] each R.sup.13 is independently
selected from the group consisting of lower alkyl, hydroxy, lower
alkoxy, methoxy, --C(O)NR.sup.cR.sup.c and --C(O)NH.sub.2; [0022]
each R.sup.15 is independently selected from the group consisting
of hydrogen, lower alkyl, lower cycloakyl and phenyl; [0023] each
R.sup.16 is independently selected from the group consisting of
hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched
alkyl and lower cycloalkylmethyl; [0024] each R.sup.17 is
independently selected from the group consisting of hydrogen, lower
alkyl, methyl and R.sup.d or, alternatively, R.sup.17 may be taken
together with R.sup.18 to form an oxo (.dbd.O) group; [0025] each
R.sup.18 is independently selected from the group consisting of
hydrogen, lower alkyl and methyl or, alternatively, R.sup.18 may be
taken together with R.sup.17 to form an oxo (.dbd.O) group; [0026]
each R.sup.19 is independently selected form the group consisting
of hydrogen, lower alkyl, methyl and R.sup.d; [0027] each R.sup.20
is independently selected from the group consisting of hydrogen,
lower alkyl, methyl and R.sup.d; [0028] each m is independently an
integer from 1 to 3; [0029] each n is independently an integer from
1 to 3; [0030] each R.sup.a is independently selected from the
group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower
cycloalkylalkyl, phenyl and benzyl; [0031] each R.sup.b is
independently selected from the group consisting of --OR.sup.a,
--CF.sub.3, --OCF.sub.3, --NR.sup.cR.sup.c, --C(O)R.sup.a,
--C(S)R.sup.a, --C(O)OR.sup.a, --C(S)OR.sup.a,
--C(O)NR.sup.cR.sup.c, --C(S)NR.sup.cR.sup.c,
S(O).sub.2NR.sup.cR.sup.c, --C(O)NR.sup.aR.sup.d,
--C(S)NR.sup.aR.sup.d and S(O).sub.2NR.sup.aR.sup.d; [0032] each
R.sup.c is independently selected from the group consisting of
hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two
R.sup.cs may be taken together with the nitrogen atom to which they
are bonded to form a 5-7 membered saturated ring which optionally
includes 1-2 additional heteroatomic groups selected from O,
NR.sup.a, NR.sup.a--C(O)R.sup.a, NR.sup.a--C(O)OR.sup.a and
NR.sup.a--C(O)NR.sup.a; and [0033] each R.sup.d is independently
selected from lower mono-hydroxyalkyl and lower
di-hydroxyalkyl.
[0034] In another aspect, the present invention provides prodrugs
of the 2,4-pyrimidinediamine compounds. Such prodrugs may be active
in their prodrug form, or may be inactive until converted under
physiological or other conditions of use to an active drug form. In
the prodrugs, one or more functional groups of the
2,4-pyrimidinediamine compounds are included in promoieties that
cleave from the molecule under the conditions of use, typically by
way of hydrolysis, enzymatic cleavage or some other cleavage
mechanism, to yield the functional groups. For example, primary or
secondary amino groups may be included in an amide promoiety that
cleaves under conditions of use to generate the primary or
secondary amino group. Thus, the prodrugs include special types of
protecting groups, termed "progroups," masking one or more
functional groups of the 2,4-pyrimidinediamine compounds that
cleave under the conditions of use to yield an active
2,4-pyrimidinediamine drug compound. Functional groups within the
2,4-pyrimidinediamine compounds that may be masked with progroups
for inclusion in a promoiety include, but are not limited to,
amines (primary and secondary), hydroxyls, sulfanyls (thiols),
carboxyls, carbonyls, phenols, catechols, diols, alkynes,
phosphates, etc. Myriad progroups suitable for masking such
functional groups to yield promoieties that are cleavable under the
desired conditions of use are known in the art. All of these
progroups, alone or in combinations, may be included in the
prodrugs. Specific examples of promoieties that yield primary or
secondary amine groups that can be included in the prodrugs
include, but are not limited to amides, carbamates, imines, ureas,
phosphenyls, phosphoryls and sulfenyls. Specific examples of
promoieties that yield sulfanyl groups that can be included in the
prodrugs include, but are not limited to, thioethers, for example
S-methyl derivatives (monothio, dithio, oxythio, aminothio
acetals), silyl thioethers, thioesters, thiocarbonates,
thiocarbamates, asymmetrical disulfides, etc. Specific examples of
promoieties that cleave to yield hydroxyl groups that can be
included in the prodrugs include, but are not limited to,
sulfonates, esters and carbonates. Specific examples of promoieties
that yield carboxyl groups that can be included in the prodrugs
include, but are not limited to, esters (including silyl esters,
oxamic acid esters and thioesters), amides and hydrazides.
[0035] In another aspect, the present invention provides
compositions comprising one or more 2,4-pyrimidinediamine compounds
and/or prodrugs and an appropriate carrier, excipient and/or
diluent. The exact nature of the carrier, excipient and/or diluent
will depend upon the desired use for the composition, and may range
from being suitable or acceptable for veterinary uses to being
suitable or acceptable for human use.
[0036] The 2,4-pyrimidinediamine compounds are potent inhibitors of
proliferation abnormal cells, such as tumor cell proliferation, in
in vitro assays. Thus, in still another aspect, the present
invention provides methods of inhibiting proliferation of abnormal
cells, in particular tumor cells. The method generally involves
contacting an abnormal cell such as a tumor cells with an amount of
a 2,4-pyrimidinediamine compound or prodrug, or an acceptable salt,
hydrate, solvate, N-oxide and/or composition thereof effective to
inhibit its proliferations The method may be practiced in in vitro
contexts or in in vivo contexts as a therapeutic approach towards
the treatment or prevention of proliferative disorders, such as
tumorigenic cancers.
[0037] In still another aspect, the present invention provides
methods of treating proliferative disorders. The methods may be
practiced in animals in veterinary contexts or in humans. The
methods generally involve administering to an animal or human
subject an amount of a 2,4-pyrimidinediamine compound or prodrug,
or an acceptable salt, hydrate, solvate, N-oxide and/or composition
thereof, effective to treat the disorder. Proliferative disorders
that can be treated according to the methods include, but are not
limited to, tumorigenic cancers.
[0038] Other aspects of the present invention include, but are not
limited to, intermediates and methods useful for synthesizing the
compound and prodrugs, as will be described in more detail herein
below.
5. DETAILED DESCRIPTION
[0039] 5.1 Definitions
[0040] As used herein, the following terms are intended to have the
following meanings:
[0041] "Alkyl" by itself or as part of another substituent refers
to a saturated or unsaturated branched, straight-chain or cyclic
monovalent hydrocarbon radical having the stated number of carbon
atoms (i.e., C1-C6 means one to six carbon atoms) that is derived
by the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene or alkyne. Typical alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl,
cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl,
cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yl-1-yl,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl,
but-3-yn-1-yl, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature "alkanyl," "alkenyl"
and/or "alkynyl" is used, as defined below, "Lower alkyl" refers to
alkyl groups having from 1 to 8 carbon atoms.
[0042] "Alkanyl" by itself or as pail of another substituent refers
to a saturated branched, straight-chain or cyclic alkyl derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane. Typical alkanyl groups include, but are not limited
to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl
(isopropyl), cyclopropan-1-yl, etch; butanyls such as butan-1-yl,
butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),
2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the
like.
[0043] "Alkenyl" by itself or as part of another substituent refers
to an unsaturated branched, straight-chain or cyclic alkyl having
at least one carbon-carbon double bond derived by the removal of
one hydrogen atom from a single carbon atom of a parent alkene. The
group may be in either the cis or trans conformation about the
double bond(s). Typical alkenyl groups include, but are not limited
to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,
prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;
cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,
2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,
buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,
cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the
like.
[0044] "Alkynyl" by itself or as part of another substituent refers
to an unsaturated branched, straight-chain or cyclic alkyl having
at least one carbon-carbon triple bond derived by the removal of
one hydrogen atom from a single carbon atom of a parent alkyne.
Typical alkynyl groups include, but are not limited to, ethynyl;
propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls
such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the
like.
[0045] "Alkyldiyl" by itself or as part of another substituent
refers to a saturated or unsaturated, branched, straight-chain or
cyclic divalent hydrocarbon group having the stated number of
carbon atoms (i.e., C1-C6 means from one to six carbon atoms)
derived by the removal of one hydrogen atom from each of two
different carbon atoms of a parent alkane, alkene or alkyne, or by
the removal of two hydrogen atoms from a single carbon atom of a
parent alkane, alkene or alkyne. The two monovalent radical centers
or each valency of the divalent radical center can form bonds with
the same or different atoms. Typical alkyldiyl groups include, but
are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl,
ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as
propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl,
cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl,
prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl,
cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,
cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such
as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,
butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,
cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,
but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,
but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,
2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,
buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl,
buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl,
cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,
cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3 dien-1,3-diyl,
but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.;
and the like. Where specific levels of saturation are intended, the
nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used.
Where it is specifically intended that the two valencies are on the
same carbon atom, the nomenclature "alkylidene" is used. A "lower
alkyldiyl" is an alkyldiyl group having from 1 to 6 carbon atoms.
In preferred embodiments the alkyldiyl groups are saturated acyclic
alkaniyldiyl groups in which the radical centers are at the
terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl
(ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and
the like (also referred to as alkylenes, defined infra).
[0046] "Alkylene" by itself or as part of another substituent
refers to a straight-chain saturated or unsaturated alkyldiyl group
having two terminal monovalent radical centers derived by the
removal of one hydrogen atom from each of the two terminal carbon
atoms of straight-chain parent alkane, alkene or alkyne. The locant
of a double bond or triple bond, if present, in a particular
alkylene is indicated in square brackets. Typical alkylene groups
include, but are not limited to, methylene (methano); ethylenes
such as ethano, etheno, ethyno; propylenes such as propano,
prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenes such as
butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno,
buta[1,3]diyno, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature alkano, alkeno and/or
alkyno is used. In preferred embodiments, the alkylene group is
(C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain
saturated alkano groups, e.g., methanol ethano, propano, butano,
and the like.
[0047] "Cycloalkyl" by itself or as part of another substituent
refers to a cyclic version of an "alkyl" group. Typical cycloalkyl
groups include, but are not limited to, cyclopropyl; cyclobutyls
such as cyclobutanyl and cyclobutenyl; cyclopentyls such as
cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl
and cyclohexenyl; and the like, "Lower cycloalkyl" refers to a
cycloalkyl group having from 3 to 8 ring carbon atoms.
[0048] "Cycloalkylalkyl" by itself or as part of another
substitutent refers to an alkyl group that comprises a linear or
branched portion and a cyclic portion. Typical cycloalkylalkyl
groups include, but are not limited to, cyclopropylmethyl,
1-cyclopropyleth-1-yl, 2-cyclopropyleth-1-yl, cyclobutylmethyl,
1-cyclobytyleth-1-yl, 2-cyclobutyleth-1-yl, cyclopentylmethyl,
1-cyclopentyleth-1-yl, 2-cyclopentyleth-1-yl, cyclohexylmethyl,
1-cyclohexyleth-1-yl, 2-cyclohexteth-1-yl, and the like. "Lower
cycloalkylalkyl" refers to a cycloalkylalkyl group in which the
linear or branched portion contains from 1 to 4 carbon atoms and
the cyclic portion contains from 3 to 8 carbon atoms.
[0049] "Heteroalkyl" by itself or as part of another substituent
refers to an alkyl group in which at least one of the carbon atoms
is replaced with a heteroatom, for example, a heteroatom selected
from O, S and N. In heteroalkyl groups including more than one
heteroatom, the heteroatoms may be the same or they may be
different Like an alkyl group, a heteroalkyl can be linear,
branched or cyclic in structure, and can be saturated or
unsaturated. Typical heteralkyl groups include, but are not limited
to, ##STR7## and the like. Where specific levels of saturation are
intended, the nomenclature "heteroalkanyl," "heteroalkenyl," and
heteroalkynyl" is used. "Lower heteroalkyl" refers to a heteroalkyl
group having from 1 to 8 carbon and heteroatoms.
[0050] "Cycloheteroalkyl" by itself or as part of another
substituent refers to a cyclic version of a heteroalkyl. Typical
examples of cycloheteroalkyl groups include, but are not limited
to, ##STR8## and the like. "Lower cycloheteroalkyl" refers to a
cycloheteroalkyl group having from 3 to 8 ring atoms.
[0051] "Parent Aromatic Ring System" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated .pi. electron
system. Specifically included within the definition of "parent
aromatic ring system" are fused ring systems in which one or more
of the rings are aromatic and one or more of the rings are
saturated or unsaturated, such as, for example, fluorene, indane,
indene, phenalene, tetrahydronaphthalene, etc. Typical parent
aromatic ring systems include, but are not limited to,
aceanthrylene, acenaphthylene, acephenanthlylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene,
hexacene, hexaphene, hexylene, indacene, s-indacene, indane,
indene, naphthalene, octacene, octaphene, octalene, ovalene,
penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,
rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and
the like, as well as the various hydro isomers thereof.
[0052] "Aryl" by itself or as part of another substituent refers to
a mionovalenit aromatic hydrocarbon group having the stated number
of carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms)
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexylene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, and the like, as well as the various hydro isomers
thereof. In preferred embodiments, the aryl group is (C5-C15) aryl,
with (C5-C10) being even more preferred, Particularly preferred
aryls are phenyl and naphthyl.
[0053] "Halogen" or "Halo" by themselves or as part of another
substituent, unless otherwise stated, refer to fluoro, chloro,
bromo and iodo.
[0054] "Haloalkyl" by itself or as part of another substituent
refers to an alkyl group in which one or more of the hydrogen atoms
is replaced with a halogen. Thus, the term "haloalkyl" is meant to
include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to
perhaloalkyls. For example, the expression "(C1-C2) haloalkyl"
includes fluoromethyl, difluoromethyl, trifluoromethyl,
1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl,
1,1,1-trifluoroethyl, perfluoroethyl, etc.
[0055] The above-defined groups may include prefixes and/or
suffixes that are commonly used in the art to create additional
well-recognized substituent groups. As non-limiting examples,
"alkyloxy" or "alkoxy" refers to a group of the formula --OR,
"alkylamine" refers to a group of the formula --NHR and
"dialkylamine" refers to a group of the formula --NRR, where each R
is independently an alkyl. As another non-limiting example,
"haloalkoxy" or "haloalkyloxy" refers to a group of the formula
--OR', where R' is a haloalkyl.
[0056] "Prodrug" refers to a derivative of an active
2,4-pyrimidinediamine compound (drug) that may require a
transformation under the conditions of use, such as within the
body, to release the active 2,4-pyrimidinediamine drug. Prodrugs
are frequently, but not necessarily, pharmacologically inactive
until converted into the active drug. Prodrugs are typically
obtained by masking a functional group in the 2,4-pyrimidinediamine
drug believed to be in part required for activity with a progroup
(defined below) to form a promoiety which undergoes a
transformation, such as cleavage, under the specified conditions of
use to release the functional group, and hence the active
2,4-pyrimidinediamine drug. The cleavage of the promoiety may
proceed spontaneously, such as by way of a hydrolysis reaction, or
it may be catalyzed or induced by another agent, such as by an
enzyme, by light, by acid or base, or by a change of or exposure to
a physical or environmental parameter, such as a change of
temperature. The agent may be endogenous to the conditions of use,
such as an enzyme present in the cells to which the prodrug is
administered or the acidic conditions of the stomach, or it may be
supplied exogenously.
[0057] A wide variety of progroups, as well as the resultant
promoieties, suitable for masking functional groups in the active
2,4-pyrimidinediamines compounds to yield prodrugs are well-known
in the art. For example, a hydroxyl functional group may be masked
as a sulfonate, ester or carbonate promoiety, which may be
hydrolyzed in vivo to provide the hydroxyl group. An amino
functional group may be masked as an amide, carbamate, imine, urea,
phosphenyl, phosphoryl or sulfenyl promoiety, which may be
hydrolyzed in viva to provide the amino group. A carboxyl group may
be masked as an ester (including silyl esters and thioesters),
amide or hydrazide promoiety, which may be hydrolyzed in vivo to
provide the carboxyl group. Other specific examples of suitable
progroups and their respective promoieties will be apparent to
those of skill in the art.
[0058] "Progroup" refers to a type of protecting group that, when
used to mask a functional group within an active
2,4-pyrimidinediamine drug to form a promoiety, converts the drug
into a prodrug. Progroups are typically attached to the functional
group of the drug via bonds that are cleavable under specified
conditions of use. Thus, a progroup is that portion of a promoiety
that cleaves to release the functional group under the specified
conditions of use. As a specific example, an amide promoiety of the
formula --NH--C(O)CH.sub.3 comprises the progroup
--C(O)CH.sub.3.
[0059] "Proliferative disorder" refers to a disease or disorder
characterized by aberrant cell proliferation, for example where
cells divide more than their counterpart normal cells. The aberrant
proliferation may be caused by any mechanism of action or
combination of mechanisms of action. For example, the cell cycle of
one or more cells may be affected such that cell(s) divide more
frequently than their counterpart normal cells, or alternatively,
one or more cells may bypass inhibitory signals which would
normally limit their number of divisions. Proliferative diseases
include, but are not limited to, slow or fast growing tumors and
cancers.
[0060] "Antiproliferative compound" refers to a compound that
inhibits the proliferation of a cell as compared to an untreated
control cell of a similar type. The inhibition can be brought about
by any mechanism or combination of mechanisms, and may operate to
inhibit proliferation cytostatically or cytotoxically. As a
specific example, inhibition as used herein includes, but is not
limited to, arrest of cell division, a reduction in the rate of
cell division, proliferation and/or growth and/or induction of cell
death.
[0061] "Pharmaceutically effective amount" or "therapeutically
effective amount" refers to an amount of a compound sufficient to
treat a specified disorder or disease or one or more of its
symptoms and/or to prevent the occurrence of the disease or
disorder. In reference to tumorigenic proliferative disorders, a
pharmaceutically or therapeutically effective amount comprises an
amount sufficient to, among other things, cause the tumor to shrink
or to decrease the growth rate of the tumor.
[0062] 5.2 Antiproliferative 2,4-Pyrimidinediamine Compounds
[0063] The antiproliferative compounds are generally
2,4-pyrimidinediamine compounds according to structural formula
(I): ##STR9##
[0064] including salts, hydrates, solvates and N-oxides thereof;
wherein: [0065] L.sup.1 and L.sup.2 are each, independently of one
another, selected from a lower alkyldiyl linker; a lower alkylene
linker and a covalent bond; [0066] R.sup.2 is selected from the
group consisting of lower alkyl optionally substituted with an
R.sup.b group, ##STR10## where Y is NH, O or CH.sub.2; [0067]
R.sup.2' is hydrogen, methyl or lower alkyl; [0068] R.sup.4' is
hydrogen, methyl or lower alkyl; [0069] R.sup.4 is selected from
the group consisting of lower alkyl optionally monosubstituted with
an R.sup.a or R.sup.b group, lower cycloalkyl optionally
monosubstituted with an R.sup.a or R.sup.b group, lower
cycloheteroalkyl optionally substituted at one or more ring carbon
and/or heteroatoms with an R.sup.a or R.sup.b group,
--(CR.sup.aR.sup.a).sub.n--R.sup.b, ##STR11## where D is
--(CR.sup.7R.sup.7).sub.m--, ##STR12## where Z.sup.1 is N or CH and
Z.sup.2 is O, S, NH, S(O) or S(O).sub.2; [0070] R.sup.5 is selected
from the group consisting of halo, fluoro and --CF.sub.3; [0071]
R.sup.6 is hydrogen; [0072] each R.sup.7 is independently selected
from the group consisting of hydrogen, methyl, lower alkyl and
halo; [0073] each R.sup.8 is independently selected from the group
consisting of hydrogen, lower alkyl, --(CH.sub.2).sub.n--OH,
--OR.sup.a, (CH.sub.2).sub.n--NR.sup.cR.sup.c,
--O(CH.sub.2).sub.n--R.sup.a, --O(CH.sub.2).sub.n--R.sup.b,
--C(O)OR.sup.a, --C(S)OR.sup.a halo, --CF.sub.3 and --OCF.sub.3;
[0074] each R.sup.9 is independently selected from the group
consisting of hydrogen, lower alkyl, --OR.sup.a,
--(CH.sub.2).sub.n--NR.sup.cR.sup.c, --O(CH.sub.2).sub.n--R.sup.a,
--O(CH.sub.2).sub.n--R.sup.b, --C(O)--NR.sup.cR.sup.c,
--C(S)--NR.sup.cR.sup.c, --S(O).sub.2--NR.sup.cR.sup.c,
--NHC(O)R.sup.a, --NHC(S)R.sup.a,
--C(O)--NH--(CH.sub.2).sub.n--NR.sup.cR.sup.c,
--C(S)--NH--(CH.sub.2).sub.n--NR.sup.cR.sup.c, halo, --CF.sub.3,
--OCF.sub.3, ##STR13## [0075] each R.sup.10 is independently
selected from the group consisting of hydrogen, lower alkyl,
--(CH.sub.2).sub.n--OH, --(CH.sub.2).sub.n--NR.sup.cR.sup.c,
--OR.sup.a, --O(CH.sub.2).sub.n--R.sup.a,
--O(CH.sub.2).sub.n--R.sup.b, halo, --CF.sub.3, --OCF.sub.3,
##STR14## [0076] each R.sup.11 is independently selected from the
group consisting of --OR.sup.a, --NR.sup.cR.sup.c and
--NR.sup.aR.sup.d; [0077] each R.sup.12 is independently selected
from the group consisting of lower alkyl, arylalkyl, --OR.sup.a,
--NR.sup.cR.sup.c, --C(O)R.sup.a, --C(O)OR.sup.a and
--C(O)NR.sup.cR.sup.c; [0078] each R.sup.13 is independently
selected from the group consisting of lower alkyl, hydroxy, lower
alkoxy, methoxy, --C(O)NR.sup.cR.sup.c and --C(O)NH.sub.2; [0079]
each R.sup.15 is independently selected from the group consisting
of hydrogen, lower alkyl, lower cyclo alkyl and phenyl; [0080] each
R.sup.16 is independently selected from the group consisting of
hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched
alkyl and lower cycloalkylmethyl; [0081] each R.sup.17 is
independently selected from the group consisting of hydrogen, lower
alkyl, methyl and R.sup.d or, alternatively, R.sup.17 may be taken
together with R.sup.18 to form an oxo (.dbd.O) group; [0082] each
R.sup.18 is independently selected from the group consisting of
hydrogen, lower alkyl and methyl or, alternatively, R.sup.18 may be
taken together with R.sup.17 to form an oxo (.dbd.O) group; [0083]
each R.sup.19 is independently selected form the group consisting
of hydrogen, lower alkyl, methyl and R.sup.d; [0084] each R.sup.20
is independently selected from the group consisting of hydrogen,
lower alkyl, methyl and R.sup.d; [0085] each m is independently an
integer from 1 to 3; [0086] each n is independently an integer from
1 to 3; [0087] each R.sup.a is independently selected from the
group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower
cycloalkylalkyl, phenyl and benzyl; [0088] each R.sup.b is
independently selected from the group consisting of --OR.sup.a,
--CF.sub.3, --OCF.sub.3, --NR.sup.cR.sup.c, --C(O)R.sup.a,
C(S)R.sup.a, --C(O)OR.sup.a, --C(S)OR.sup.a, --C(O)NR.sup.cR.sup.c,
--C(S)NR.sup.cR.sup.c, --S(O).sub.2NR.sup.cR.sup.c,
--C(O)NR.sup.aR.sup.d, --C(S)NR.sup.aR.sup.d and
--S(O).sub.2NR.sup.aR.sup.d; [0089] each R.sup.c is independently
selected from the group consisting of hydrogen, lower alkyl and
lower cycloalkyl, or, alternatively, two R.sup.cs may be taken
together with the nitrogen atom to which they are bonded to form a
5-7 membered saturated ring which optionally includes 1-2
additional heteroatomic groups selected from O, NR.sup.a,
NR.sup.a--C(O)R.sup.a, NR.sup.a--C(O)OR.sup.a and
NR.sup.a--C(O)NR.sup.a; and [0090] each R.sup.d is independently
selected from lower mono-hydroxyalkyl and lower
di-hydroxyalkyl.
[0091] An important class of compounds of structural formula (I)
includes compounds in which L.sup.1 and L.sup.2 are each a covalent
bond, such that the compound is a 2,4-pyrimidine diamine according
to structural formula (II): ##STR15## [0092] including salts,
hydrates, solvates and N-oxides thereof, wherein R.sup.2, R.sup.2,
R.sup.2', R.sup.4, R.sup.4', R.sup.5 and R.sup.6 are as previously
defined for structural formula (I).
[0093] An important class of compounds of structural formulae (I)
and/or (II) and the salts, hydrates, solvates and N-oxides thereof,
includes compounds in which R.sup.5 is fluoro.
[0094] Another important class of compounds of structural formulae
(I) and/or (II) and the salts, hydrates, solvates and N-oxides
thereof, includes compounds in which R.sup.2' is hydrogen.
[0095] Another important class of compounds of structural formulae
(J) and/or (II) and the salts, hydrates, solvates and N-oxides
thereof, includes compounds in which R.sup.2' and R.sup.4' are
each, independently of one another, selected from hydrogen and
methyl.
[0096] Another important class of compounds of structural formulae
(I) and/or (II) and the salts, hydrates, solvates and N-oxides
thereof, includes compounds in which R.sup.4' is methyl.
[0097] Other important classes of compounds of structural formulae
(I) and/or (II) include compounds according to structural formulae
(III)-(V): ##STR16## [0098] and salts, hydrates, solvates and
N-oxides thereof, wherein R.sup.2, R.sup.2', R.sup.4 and R.sup.4',
are as previously defined for structural formula (I).
[0099] When R.sup.2 and/or R.sup.4 is ##STR17## in the compounds
described herein, for example, the compounds of structural formulae
(I)-(V), in some embodiments, R.sup.9 and R.sup.10 are not both
simultaneously lower alkoxy or methoxy. In other embodiments,
R.sup.8, R.sup.9 and R.sup.10 are not each simultaneously lower
alkoxy or methoxy. In still other embodiments R.sup.8, R.sup.9 and
R.sup.10 are each methoxy or lower alkoxy. In yet other
embodiments, R.sup.9 is selected from hydrogen, lower alkyl, lower
alkoxy, --OR.sup.a, halo, --CF.sub.3 and --OCF.sub.3 and one of
R.sup.9 or R.sup.10 is selected from ##STR18## In a specific
embodiment, the other one of R.sup.9 or R.sup.10 is other than
##STR19## In yet other embodiments, R.sup.8 is selected from
hydrogen, lower alkyl, --OR.sup.a, halo, --CF.sub.3 and --OCF.sub.3
and one of R.sup.9 or R.sup.10 is selected from
--OCH.sub.2C(O)R.sup.a, --OCH.sub.2C(O)OR.sup.a,
--OCH.sub.2C(O)NHR.sup.d, --OCH.sub.2C(O)NHR.sup.d and
--OCH.sub.2C(O)NR.sup.cR.sup.c. In a specific embodiment, the other
one of R.sup.9 or R.sup.10 is other than --OCH.sub.2C(O)R.sup.a,
OCH.sub.2C(O)OR.sup.a, --OCH.sub.2C(O)NHR.sup.a,
--OCH.sub.2C(O)NHR.sup.d or --OCH.sub.2C(O)NR.sup.cR.sup.c.
[0100] In yet other embodiments, R.sup.8 and R.sup.9 are each,
independently of one another, selected from hydrogen, lower alkyl,
--OR.sup.a, halo, --CF.sub.3 and OR.sup.a and R.sup.10 is ##STR20##
In yet other embodiments R.sup.9 is hydrogen and R.sup.8 and
R.sup.10 are each, independently of one another, selected from the
group consisting of lower alkyl, methyl, lower alkoxy, methoxy,
--CF.sub.3 and --OCF.sub.3. Specific combinations of R.sup.8 and
R.sup.10 when R.sup.9 is hydrogen are as follows: [0101] R.sup.8
and R.sup.10 are each the same lower alkyl or methyl; [0102]
R.sup.8 and R.sup.10 are each the same lower alkoxy or methoxy;
[0103] R.sup.8 is lower alkyl or methyl and R.sup.10 is --CF.sub.3;
[0104] R.sup.8 is lower alkoxy or methoxy and R.sup.10 is
--CF.sub.3; and [0105] R.sup.8 is lower alkyl or methyl and
R.sup.10 is --OCF.sub.3.
[0106] In still other embodiments, R.sup.9 is hydroxy, methoxy or
chloro and R.sup.8 and R.sup.10 are each, independently of one
another, selected from the group consisting of lower alkyl, methyl,
lower alkoxy, methoxy and chloro. Specific combinations of R.sup.8,
R.sup.9 and R.sup.10 according to this embodiment are as follows:
[0107] R.sup.8 and R.sup.10 are each methyl and R.sup.9 is hydroxy,
methoxy or chloro; [0108] R.sup.8 and R.sup.10 are each chloro and
R.sup.9 is hydroxy or methoxy; and [0109] R.sup.8 is chloro,
R.sup.10 is methyl and R.sup.9 is hydroxy or methoxy.
[0110] When R.sup.2 and R.sup.4 are each ##STR21## in the compounds
described herein, such as, for example, the compounds of structural
formulae (I)-(V), in some embodiments no more than one of R.sup.8,
R.sup.9 and R.sup.10 of the R.sup.4 phenyl is hydrogen unless at
least one of R.sup.8, R.sup.9 or R.sup.10 of the R.sup.2 phenyl is
--O(CH.sub.2).sub.n--NR.sup.cR.sup.c, ##STR22## In other
embodiments, the substitution patterns of the R.sup.2 and R.sup.4
phenyl rings are different from each other such that the compound
is not a N2,N4-bis(3,4,5-substituted phenyl)pyrimidinediamine.
[0111] In still other embodiments, the compound is a compound
according to structural formula (VI): ##STR23## including the
salts, hydrates, solvates and N-oxides thereof wherein R.sup.4',
R.sup.8, R.sup.9 and R.sup.10 are as previously defined for
structural formula (I).
[0112] In still other embodiments when R.sup.2 and R.sup.4 are each
##STR24## R.sup.8, R.sup.9 and R.sup.10 are selected such that each
R.sup.2 and R.sup.4 phenyl ring is mono-substituted.
[0113] In yet other embodiments when R.sup.2 and R.sup.4 are each
##STR25## R.sup.8, R.sup.9 and R.sup.10 are selected such that each
R.sup.2 and R.sup.4 phenyl ring is di-substituted. In one specific
embodiment, each R.sup.2 and R.sup.4 phenyl ring is substituted
with an ethylenedioxy acetal group.
[0114] In still other embodiments when R.sup.2 and R.sup.4 are each
##STR26## R.sup.10 of the R.sup.2 or R.sup.4 ring is other than
1,3-oxazolyl or 1,3-oxazol-5-yl when the R.sup.8 and R.sup.9 of the
same ring are each hydrogen. In one specific embodiment, R.sup.8,
R.sup.9 and R.sup.10 are as defined in the preceeding sentence when
R.sup.5 is fluoro and L.sup.2 is a lower alkylene. In another
specific embodiment, R.sup.2 is other than 3-(1,3-oxazolyl)phenyl
or 3-(1,3-oxazol-5-yl)phenyl when R.sup.4 is
2-(trifluoromethyl)benzyl. In another specific embodiment, the
compound is other than
N2-[3-(1,3-oxazolyl)phenyl]-N4-[2-trifluoromethy)lbenzyl]-5-fluoro-2,4-py-
rimidinediamine. In compounds where R.sup.10 is an oxazolyl, the
oxazolyl is not connected at the 5 position. In a specific
embodiment, the oxazole is connected at the 2 position. In still
another specific embodiment, the compound is not any compound
described in WO 03/040141, the disclosure of which is incorporated
herein by reference.
[0115] When R.sup.2 is ##STR27## in the compounds described herein,
such as, for example, the compounds of structural formulae
(I)-(VI), in some embodiments one of R.sup.9 or R.sup.10 is
selected from ##STR28## where R.sup.12 is as previously defined for
structural formula (I) and the other one of R.sup.9 or R.sup.10 is
other than ##STR29## In still other embodiments, R.sup.8 is
selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy
and halo and one of R.sup.9 or R.sup.10 is --OCH.sub.2--R.sup.b,
where R.sup.b is selected from --C(O)NR.sup.a and --C(O)NHR.sup.a,
and the other one of R.sup.9 or R.sup.10 is selected from hydrogen,
lower alkyl, methyl, lower alkoxy, methoxy and halo. In still other
embodiments R.sup.2 is ##STR30## where R.sup.8 is hydrogen, fluoro
or CF.sub.3. In a specific embodiment, R.sup.2 is ##STR31##
[0116] When 12 is ##STR32## in the compounds described herein, such
as, for example, the compounds according to structural formulae
(I)-(V), in some embodiments, R.sup.8 and R.sup.9 are each
independently selected from hydrogen, lower alkyl, methyl, lower
alkoxy, methoxy, halo and chloro. One specific embodiment, R.sup.8,
R.sup.9 and R.sup.13 are each independently selected from halo,
lower alkyl, methyl, lower alkoxy, and methoxy. In another specific
embodiment, R.sup.2 is selected from ##STR33##
[0117] In some embodiments of compounds in which R.sup.2 is
##STR34## including any of the above-described specific
embodiments, R.sup.4 is selected from ##STR35## where D is as
previously defined for structural formula (I).
[0118] When R.sup.2 is 3,4,5-trimethoxyphenyl or
3,4,5-tri(loweralkoxy)phenyl in the compounds described herein,
such as, for example the compounds of structural formulae (I)-(V),
in some embodiments, R.sup.4 is ##STR36## where Z.sup.1, Z.sup.2
and R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20 are as
previously described for structural formula (I).
[0119] When R.sup.9 or R.sup.10 is ##STR37## in the compounds
described herein, such as, for example, the compounds of structural
formulae (I)-(VI), in some embodiments R.sup.12 is methyl. In other
embodiments, R.sup.12 is --C(O)R.sup.a or --C(O)OR.sup.a, where
R.sup.a is lower alkyl, ethyl or methyl.
[0120] When R.sup.2 is ##STR38## in the compounds described herein,
such as, for example, the compounds of structural formulae (I)-(V),
in some embodiments (i) each R.sup.13 is, independently or the
other, selected from lower alkyl, methyl, hydroxy, lower alkoxy and
methoxy; and/or (ii) R.sup.4 is selected from ##STR39## where
Z.sup.1, Z.sup.2 and R.sup.16, R.sup.17, R.sup.18, R.sup.19 and
R.sup.20 are as previously described for structural formula (I). In
a specific embodiment, R.sup.4 is ##STR40## where Z.sup.1 is CH,
R.sup.16 is hydrogen R.sup.17 and R.sup.18 are taken together to
form an oxo (.dbd.O) group and R.sup.19 and R.sup.20 are each
hydrogen or methyl; and R.sup.2 is ##STR41## where each R.sup.13
is, independently of the other, selected from lower alkyl, methyl,
hydroxy, lower alkoxy and methoxy.
[0121] When R.sup.2 is lower alkyl in the compounds described
herein, such as, for example, the compounds of structural formulae
(I)-(V), in some embodiments, R.sup.4 is ##STR42## where D is as
previously defined for structural formula (I)
[0122] When R.sup.2 is ##STR43## in the compounds described herein,
such as, for example, the compounds of structural formulae (I)-(V),
in some embodiments, R.sup.11 is selected from the group consisting
of hydroxy, methoxy, ethoxy, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--NHCH.sub.2CH(OH)CH.sub.2OH, --NHCH.sub.2CH(OH)(CH.sub.3).sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2OH and
--N(CH.sub.3)C(CH.sub.3).sub.2CH.sub.2OH and Y is as previously
defined.
[0123] When R.sup.2 is ##STR44## in the compounds described herein,
such as the compounds of structural formulae (I)-(V), in some
embodiments the ring is connected to the remainder of the molecule
at the 5-position ##STR45## In other embodiments, it is connected
to the remainder of the molecule at the 6-position ##STR46## In
some embodiments, R.sup.16 is selected from lower n-alkanyl, lower
branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl.
In some embodiments, R.sup.4 is selected from ##STR47##
[0124] When R.sup.2 is ##STR48## in the compounds described herein,
such as, for example, the compound of structural formulae (I)-(V),
in some embodiments, R.sup.4 is selected from lower cycloalkyl and
lower cycloheteroalkyl optionally substituted at one or more ring
carbon or heteroatoms with an R.sup.a or an R.sup.b group. In a
specific embodiment, R.sup.4 is selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, ##STR49## where R.sup.e and
R.sup.f are selected from (C1-C3) alkanyl and methyl and R.sup.g is
benzyl. In some embodiments, each R.sup.e is methyl. In some
embodiments, R.sup.f is ethyl.
[0125] When R.sup.4 is selected from lower alkyl, isopropyl,
t-butyl, lower cycloalkyl, ##STR50## in the compounds described
herein, such as, for example, the compounds of structural formulae
(I)-(V), in some embodiments R.sup.2 is selected from ##STR51##
where R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are as previously
defined for structural formula (I). In a specific embodiment,
R.sup.2 is selected from any of the above-described embodiments of
these substituted phenyls. In other embodiments, R.sup.2 is
##STR52## where R.sup.8 and R.sup.9 are a previously defined for
structural formula (I).
[0126] When R.sup.4 is ##STR53## where R.sup.15 is lower branched
alkyl or t-butyl, and R.sup.2 is ##STR54## in the compounds
described herein, such as, for example, the compounds of structural
formulae (I)-(V), in some embodiments at least one of R.sup.8 or
R.sup.10 is other than hydrogen. In other embodiments, at least two
of R.sup.8, R.sup.9 and R.sup.10 are other than hydrogen. In still
other embodiments, at least two of R.sup.8, R.sup.9 and R.sup.13
are other than hydrogen.
[0127] In still other embodiments, either: (i) R.sup.9 is ##STR55##
and R.sup.10 is other than ##STR56## or (ii) R.sup.10 is ##STR57##
and R.sup.9 is other than ##STR58##
[0128] In a specific embodiment of alternative (i), R.sup.10 is
hydrogen. In a specific embodiment of alternative (ii), R.sup.9 is
hydrogen.
[0129] In still other embodiments, when R.sup.2 is ##STR59## where
R.sup.8 and R.sup.9 are each hydrogen, then R.sup.10 is other than
lower branched alkyl, t-butyl or --O(CH.sub.2).sub.nR.sup.b, where
n is as previously defined for structural formula (I) and R.sup.b
is selected from NRCRA, --C(O)OR.sup.a, --C(O)NR.sup.cR.sup.c and
--C(O)NR.sup.aR.sup.d.
[0130] In still other embodiments, when R.sup.2 is ##STR60## where
R.sup.9 is hydrogen and R.sup.13 is selected from hydrogen, lower
alkyl and methyl, then R.sup.8 is other than
--O(CH.sub.2).sub.nR.sup.b, where it is as previously defined for
structural formula (I) and R.sup.b is --NR.sup.cR.sup.c. In still
other embodiments, the compound is not any compound described in WO
01/64656, WO 03/026665 or WO 03/026666, the disclosures of which
are incorporated herein by reference.
[0131] When R.sup.4 is --(CH.sub.2).sub.n--R.sup.b in the compounds
described herein, such as, for example, the compounds of structural
formulae (II)-(V), in some embodiments R.sup.b is selected from the
group consisting of --OR.sup.a, --NR.sup.cR.sup.c, --C(O)R.sup.a
and --C(O)NR.sup.cR.sup.c, where each R.sup.c is independently
selected from hydrogen and lower alkyl.
[0132] When R.sup.4 is ##STR61## in the compounds described herein,
such as, for example, the compounds of structural formulae (I)-(V)
in some embodiments R.sup.2 is ##STR62## where R.sup.9 is selected
from the group consisting of --OR.sup.a, methoxy, isopropoxy,
OCH.sub.2C(O)OR.sup.a, --OCH.sub.2C(O)NHR.sup.a,
--OCH.sub.2C(O)NR.sup.aR.sup.a and
--OCH.sub.2CH.sub.2NR.sup.aR.sup.a; and R.sup.8 and R.sup.10 are as
previously defined for structural formula (I). In a specific
embodiment, R.sup.8 and R.sup.10 are selected from one of the
following combinations: [0133] R.sup.8 and R.sup.10 are each the
same lower alkyl or methyl; [0134] R.sup.8 is lower alkyl or methyl
and R.sup.10 is halo, fluoro or chloro; and [0135] R.sup.9 and
R.sup.10 are each the same halo, fluoro or chloro.
[0136] When R.sup.4 is selected from lower alkyl optionally
monosubstituted with an R.sup.b group, a lower cycloalkyl
optionally monosubstituted with an R.sup.b group and
C(R.sup.aR.sup.a).sub.n--R.sup.b, where, R.sup.a and R.sup.b are as
previously defined for structural formula (I), and/or L.sup.2 is a
lower alkylene linker in the compounds described herein, in some
embodiments, R.sup.2 is other than mono-substituted phenyl,
3-hydroxyphenyl, 3-halophenyl, 3-chlorophenyl, 3-bromophenyl,
4-halophenyl, 4-chlorophenyl, 4-bromophenyl, 3,4-dihalophenyl,
3,4-dichlorophenyl or 3,4-dichlorophenyl. In a specific embodiment,
R.sup.2 is other than these defined groups in compounds in which
R.sup.5 is --CF.sub.3. In another specific embodiment, the compound
is not any compound described in US 2003/0171359 and/or WO
03/032997, the disclosures of which are incorporated herein by
reference.
[0137] When R.sup.4 is ##STR63## and R.sup.2 is ##STR64## in the
compounds described herein, such as, for example, the compounds of
structural formulae (I)-(V), in some embodiments, R.sup.9 and
R.sup.9 are non-bulky substitutents. In a specific embodiment,
R.sup.9 is other than ##STR65## and R.sup.10 is other than
##STR66## In another specific embodiment, R.sup.8, R.sup.9 and
R.sup.10 are each, independently of one another, selected from
hydrogen lower alkyl, methyl hydroxy, lower alkoxy, methoxy, halo,
fluoro and chloro. In another specific embodiment, R.sup.8 is
selected from hydrogen, lower alkyl, methyl, lower alkoxy and
methoxy, R.sup.9 is selected from hydrogen, lower alkoxy and
methoxy and R.sup.10 is selected from lower alkyl, methyl, lower
alkoxy, methoxy, halo, fluoro and ##STR67##
[0138] In all of the compounds described herein in which R.sup.4 is
##STR68## in some embodiments D is selected from the group
consisting of --CH.sub.2--, --CF.sub.2--, --CH.sub.2CH.sub.2--,
--CF.sub.2--CF.sub.2-- and --CH.sub.2--CH.sub.2--CH.sub.2--.
[0139] In all of the compounds described herein having lower alkyl
substitutents or substituents including lower alkyl groups (e.g.,
lower alkoxy groups, etc.), in some embodiments the lower alkyl
substituent or group is a saturated straight-chained, branched or
cyclic alkyl (i.e., an alkanyl).
[0140] Additional exemplary embodiments of the compounds described
herein are illustrated in the following TABLES 1-14, below
TABLE-US-00001 TABLE IA Type A Type B ##STR69## ##STR70## No. Type
n R.sup.21 R.sup.22 R.sup.23 R.sup.4' A549 H1299 101 A 1 H
##STR71## H H + 102 A 1 H H ##STR72## H + + 103 A 1 H H ##STR73## H
+ + 104 A 1 H ##STR74## H H + + 105 A 1 H ##STR75## H H + + 106 A 1
H H ##STR76## H + + 107 A 2 H ##STR77## H H + + 108 A 2 H ##STR78##
H H + + 109 A 2 H H ##STR79## H + + 110 A 2 H H ##STR80## H + + 111
A 2 H Cl Cl H + + 112 A 2 H OMe Cl H + + 113 A 2 H H ##STR81## H +
+ 114 A 2 Cl OMe Cl H + + 115 A 2 H H ##STR82## H + + 116 A 2 Me H
Me H + + 117 A 2 OMe H OMe H + + 118 A 2 OMe H CF.sub.3 H - + 119 A
2 H H ##STR83## H + + 120 A 2 H H ##STR84## H + + 121 A 2 H
##STR85## H H + + 122 A 2 H ##STR86## H H + + 123 A 2 H ##STR87## H
Me + + 124 A 2 H ##STR88## H Me + + 125 A 2 H ##STR89## H Me + +
126 (HCl salt) A 2 H ##STR90## H Me + + 127 A 2 H H ##STR91## Me +
+ 128 A 2 H H ##STR92## Me + + 129 A 2 H H ##STR93## Me + + 130 A 2
H H ##STR94## Me + + 131 A 2 H ##STR95## H H + + 132 A 2 H
##STR96## H H + + 133 A 3 H ##STR97## H H + + 134 A 3 H ##STR98## H
H + + 135 A 3 H H ##STR99## H + + 136 A 3 H H ##STR100## H + + 137
A 3 H H ##STR101## H + + 138 A 3 H H ##STR102## H + + 139 A 4 H
##STR103## H H + + 140 A 4 H ##STR104## H H + + 141 A 4 H
##STR105## H H + + 142 A 4 H ##STR106## H H + + 143 A 4 H H
##STR107## H + + 144 A 4 H H ##STR108## H + + 145 A 4 H H
##STR109## H + + 146 A 4 H H ##STR110## H + + 147 A 3 H ##STR111##
H H + + 148 A 3 H ##STR112## H H + + 149 A 4 H ##STR113## H H + +
150 A 4 H ##STR114## H H + + 151 A 2 H H ##STR115## Me + + 152 A 2
H ##STR116## Cl H + + 153 A 4 H ##STR117## Cl H + + 154 (HCl salt)
A 2 H ##STR118## H H + + 155 (TsOH salt) A 4 H ##STR119## H H + +
156 (HCl salt) A 4 H ##STR120## H H + + 157 A 3 H ##STR121## Cl H +
+ 158 A 2 H ##STR122## Cl H + + 159 A 4 H ##STR123## Cl H + + 160 A
2 H ##STR124## Me H + + 161 A 3 H ##STR125## Me H + + 162 A 4 H
##STR126## Me H + + 163 A 2 H ##STR127## CF.sub.3 H + + 164 A 2 H
##STR128## CF.sub.3 H + + 165 A 4 H ##STR129## CF.sub.3 H + + 166 A
2 H ##STR130## Me H + + 167 B 2 H ##STR131## -- H + + 168 B 3 H
##STR132## -- H + + 169 B 4 H ##STR133## -- H + + 170 A 2 H
##STR134## CH.sub.2OH H 171 B 2 Me ##STR135## -- H + + 172 B 3 Me
##STR136## -- H + + 173 B 4 Me ##STR137## -- H + + 174 A 2 H
##STR138## CH.sub.2OH H + + 175 A 3 H ##STR139## H H + - 176 A 3 H
##STR140## H H + + 177 A 3 H ##STR141## H H + + TABLE 1B Type A
Type B ##STR142## ##STR143## No. Type R.sup.21 R.sup.22 R.sup.23
R.sup.4' A549 H1299 178 A H ##STR144## H H + + 179 A H H ##STR145##
H + + 180 A H ##STR146## Cl H + + 181 A H ##STR147## Me H + + 182 A
H ##STR148## CF.sub.3 H + + 183 B H ##STR149## -- H + + 184 B Me
##STR150## -- H + + TABLE 1C Type A Type B ##STR151## ##STR152##
No. Type R.sup.21 R.sup.22 R.sup.23 R.sup.4' A549 H1299 185 A H
##STR153## H H + + 186 A H H ##STR154## H + + 187 A H ##STR155## Cl
H + + 188 A H ##STR156## Me H + + 189 A H ##STR157## CF.sub.3 H + +
190 B H ##STR158## -- H + + TABLE 1D Type A Type B ##STR159##
##STR160## No. Type R.sup.21 R.sup.22 R.sup.23 R.sup.4' A549 H1299
191 A H ##STR161## H H 192 A H ##STR162## H H 193 A H ##STR163## H
H 194 A H ##STR164## H H 195 A H H ##STR165## H 196 A H H
##STR166## H 197 A H H ##STR167## H 198 A H H ##STR168## H
[0141] TABLE-US-00002 TABLE 2 ##STR169## No. R.sup.15 R.sup.21
R.sup.22 R.sup.23 A549 H1299 199 t-butyl H H ##STR170## + 200
t-butyl H H ##STR171## + + 201 t-butyl H H ##STR172## + + 202
t-butyl H ##STR173## H + + 203 t-butyl H ##STR174## H + + 204
t-butyl H ##STR175## H + + 205 cyclopropyl H H ##STR176## + + 206
cyclopropyl H ##STR177## H + + 207 cyclopropyl H H ##STR178## + +
208 cyclopropyl H H ##STR179## 209 cyclopropyl H ##STR180## H + +
210 cyclopropyl H ##STR181## H + - 211 cyclopropyl H H ##STR182## +
+ 212 cyclopropyl H ##STR183## Cl + + 213 cyclopropyl H ##STR184##
Me + + 214 cyclopropyl H ##STR185## CF.sub.3 + +
[0142] TABLE-US-00003 TABLE 3 Type A Type B ##STR186## ##STR187##
No. Type R.sup.4 R.sup.21 R.sup.22 R.sup.23 A549 H1299 215 A
i-propyl H ##STR188## H + + 216 A i-propyl H ##STR189## Cl + + 217
A i-propyl H ##STR190## Me + + 218 A i-propyl H ##STR191## CF.sub.3
+ + 219 A i-propyl H H ##STR192## + + 220 A t-butyl H ##STR193## H
+ + 221 A t-butyl H H ##STR194## + + 222 A t-butyl H ##STR195## Cl
+ + 223 A t-butyl H ##STR196## Me + + 224 A t-butyl H ##STR197##
CF.sub.3 + + 225 B i-propyl H ##STR198## -- + + 226 B t-butyl H
##STR199## -- + + 227 B i-propyl Me ##STR200## -- + +
[0143] TABLE-US-00004 TABLE 4 ##STR201## No. Z.sup.1 Z.sup.2
R.sup.16 R.sup.19 R.sup.20 R.sup.21 R.sup.22 R.sup.23 R.sup.4' A549
H1299 228 CH O H Me (R) H H OMe Cl H 229 CH O H Me (S) H Me H Me H
+ + 230 CH O H Me (R) H Me H Me H - + 231 CH O H Me (R) H Cl OMe H
H - - 232 CH O H Me (R) H Cl OMe H H + - 233 CH O H Me (R) H Cl OMe
H H 234 CH O H Me (R) H Cl OMe H H 235 CH O H Me (R) H Cl OMe H H
236 CH O H H H H H ##STR202## H + + 237 CH O H CH.sub.2CH.sub.2OH H
H H ##STR203## H + + 238 CH O H CH.sub.2CH.sub.2OH H H H ##STR204##
H + + 239 CH O H H H H H ##STR205## H - + 240 CH O H Me (S) H H H
##STR206## H + - 241 CH O H Me (R) H H H ##STR207## H 242 CH O H Me
(S) H H H ##STR208## H 243 CH S H H H H H ##STR209## H 244 CH S H H
H OMe H OMe H 245 CH S H H H H OMe Cl H 246 CH S Me H H H H
##STR210## H 247 CH S Me H H OMe H OMe H 248 CH O H H H H H
C(S)NH.sub.2 H 249 CH O H CH.sub.2CH.sub.2OH H H H C(S)NH.sub.2 H
250 CH S(O).sub.2 H Me H OMe H OMe H + + 251 CH S(O).sub.2 H Me H
Me H Me H + + 252 CH S(O).sub.2 H Me H OMe OMe OMe H 253 CH O H H H
H H ##STR211## H 254 CH O H H H H H OH H + 255 CH O Me H H H H OH H
256 CH O H Me H H H ##STR212## H + 257 CH O H Me (S) H Cl OMe Cl H
258 CH O H Me (R) H Cl OMe Cl H 259 CH O H CH.sub.2CH.sub.2OH H OMe
H OMe H 260 CH O H CH.sub.2CH.sub.2OH H Cl OMe H H 261 CH O H Me
(S) H OMe H OMe H 262 CH O H Me (R) H OMe H OMe H 263 CH S(O).sub.2
H Me Me OMe H OMe H - - 264 CH S(O).sub.2 H Me Me Me H Me H - + 265
CH S(O).sub.2 H Me Me OMe OMe OMe H + + 266 CH S H Me H OMe H OMe
267 CH S H Me H Me H Me H 268 CH S H Me H OMe OMe OMe H 269 CH
S(O).sub.2 H Me Me H H ##STR213## H 270 CH S(O).sub.2 H Me Me H OMe
Cl H 271 CH S H Me H H H ##STR214## H 272 CH S H Me H H OMe Cl H
273 CH S H H H H H OH H 274 CH S H Me H H H OH H 275 CH S(O).sub.2
H Me Me H H OH H 276 CH S(O).sub.2 H Me H H H OH H 277 CH
S(O).sub.2 H Me H H H ##STR215## H 278 CH S(O).sub.2 H Me H H OMe
Cl H 279 CH S H H H OMe OMe OMe H 280 CH S H Me Me H OMe Cl H 281
CH S H Me Me OMe H OMe H 282 CH S H Me Me Me H Me H 283 CH S H Me
Me OMe OMe OMe H 284 CH S H Me Me H H CH H 285 CH S H Me Me H H
##STR216## H 286 CH S(O).sub.2 H Me H H OMe F H 287 CH S(O).sub.2 H
Me Me H OMe F H + + 288 CH S H Me H H OMe F H + + 289 CH S H Me Me
H OMe F H + + 290 CH S H H H H OMe F H + + 291 CH S H H H Me O Me H
- + 292 CH S(O).sub.2 H H H Me O Me H 293 CH S(O).sub.2 H H H OMe H
OMe H 294 CH S(O).sub.2 H H H H OMe Cl H 295 CH S(O).sub.2 H H H H
H ##STR217## H 296 CH S(O).sub.2 H H H OMe OMe OMe H 297 CH
S(O).sub.2 H H H H H OH H 298 CH S(O).sub.2 H H H H OMe F H 299 CH
O Me H H H H ##STR218## H + - 300 CH O H Me (S) H H H ##STR219## H
+ 301 CH O H Me (R) H H H ##STR220## H 302 CH O H Me (S) H Cl OMe H
H 303 CH O H Me (R) H Cl OMe H H 304 CH O H Me Me OMe Me Me H 305
CH O H Me Me OMe H OMe H + 306 CH O H Me Me Cl Me Cl H + + 307 CH O
H Me Me Cl OMe Cl H + 308 CH O H Me Me Cl H Cl H 309 CH O H Me Me
OMe H CF.sub.3 H + 310 CH O H Me Me Me H Me H + 311 CH O H Me Me
OMe H OMe H + 312 CH O H Me Me OMe H OMe H + 313 CH O H Me Me OMe H
OMe H + 314 CH O H Me Me OMe H OMe H + 315 CH O H Me Me OMe H OMe H
316 CH O H Me Me Me H Me H 317 CH O H Me Me Me H Me H 318 CH O H Me
Me H OMe Cl H 319 CH O H Me Me Me Cl Me H 320 CH O H Me Me
CH.sub.2OH H CH.sub.2OH H + + 321 CH O H Me Me Cl H OMe H + + 322
CH O H Me Me H OMe Cl H 323 CH O H Me Me OMe H OMe Me + + 324 CH O
Me Me Me Me H Me Me + - 325 CH O Me Me Me H OMe Cl Me + + 326 CH O
Me Me Me OMe H OMe Me + + 327 CH O H Me Me H OMe Cl Me + + 328 CH O
Me Me Me Me H Me H 329 CH O Me Me Me OMe H OMe H 330 CH O H Me Me H
C(O)NHMe Cl H 331 CH O H Me Me H S(O).sub.2NHMe OMe H 332 CH O H Me
Me H H ##STR221## H 333 CH O H Me Me C(O)OMe H ##STR222## H - - 334
CH O H Me Me CF.sub.3 H ##STR223## H + - 335 N O H Me Me Me OMe Me
H 336 N O H Me Me Me OMe Me H 337 N O H Me Me Me OMe Me H 338 CH O
H Me Me OMe OMe OMe H + + 339 CH O H Me Me Me ##STR224## Me H + +
340 N O H Me Me OMe OMe OMe H 341 N O H Me Me OMe OMe OMe H 342 N O
H Me Me OMe OMe OMe H 343 N O H Me Me OMe OMe OMe H 344 N O H Me Me
OMe OMe OMe H 345 N O H Me Me OMe OMe OMe H 346 N O H Me Me OMe OMe
OMe H 347 N O H Me Me OMe OMe OMe H 348 N O H Me Me OMe OMe OMe H
349 N O H Me Me OMe OMe OMe H 350 N O H Me Me Me Cl Me H 351 N O H
Me Me OMe OMe OMe H 352 N O H Me Me Cl OH Cl H + + 353 N O Me Me Me
OMe OMe OMe H 354 N O H Me Me OMe ##STR225## OMe H + + 355 CH O H
Me Me H H ##STR226## H + + 356 CH O H Me Me H H OH H + - 357 N O H
Me Me H H ##STR227## H 358 CH O H Me Me Me OH Cl H + 359 CH O H Me
Me Me OMe Cl H + + 360 N O H Me Me H H ##STR228## H 361 N O H Me Me
H H ##STR229## H 362 N O H Me Me H OMe Cl H 363 N O H Me Me OMe H
OMe H 364 N O H Me Me H Cl Cl H 365 (HCl salt) N O H Me Me H H
##STR230## H 366 (bis HCl salt) N O H Me Me H H ##STR231## H 367
(nitrate salt) N O H Me Me H H ##STR232## H 368 (bis nitrate salt)
N O H Me Me H H ##STR233## H 369 (mesylate salt) N O H Me Me H H
##STR234## H 370 N O H Me Me H H ##STR235## H 371 N O H Me Me H H
t-butyl H + + 372 N O H Me Me H H OH H 373 N O H Me Me H H
##STR236## H 374 N O H Me Me H OMe F H - - 375 N O H Me Me H H Cl H
- - 376 N O H Me Me Cl H Cl H + + 377 CH O H Me Me Me OMe Cl H 378
N O H Me Me H OCF.sub.3 Cl H - - 379 N O H Me Me Me OMe Cl H 380 N
O H Me Me H H ##STR237## H 381 N O H Me Me Me OH Cl H 382 N O H Me
Me Me OMe Me H - - 383 N O H Me Me H H i-propyl H 384 N O H Me Me
OMe OMe OMe H + + 385 CH O H Me Me Cl OEt Me H + - 386 N O Me Me Me
Me OMe Cl H 387 N O H Me Me Cl OEt Me H - - 388 N O Me Me Me H H
##STR238## H + + 389 CH O H Me Me Me ##STR239## Cl H 390 N O Me Me
Me H H ##STR240## H 391 CH O H Me Me H H ##STR241## H + + 392 N O
Me Me Me H H ##STR242## H 393 CH O H Me Me Me ##STR243## Cl H 394
CH O Me Me Me H H ##STR244## H + - 395 CH O H Me Me H H ##STR245##
Me - + 396 CH O H Me Me H H ##STR246## H 397 CH O Me Me Me H H
##STR247## Me + + 398 N O H Me Me Me ##STR248## Cl H - - 399 N O H
Me Me H H ##STR249## H 400 N O H Me Me H H ##STR250## H 401 CH O Me
Me Me H H ##STR251## Me + +
402 CH O Me Me Me Me OMe Me Me + - 403 CH O Me Me Me Me ##STR252##
Cl Me + - 404 N O Me Me Me Me OMe Me H 405 N O Me Me Me Me
##STR253## Cl H + + 406 N O H Me Me H H ##STR254## H 407 CH O H Me
Me H H ##STR255## H + + 408 N O H Me Me Me ##STR256## Cl H 409 N O
H Me Me Me ##STR257## Me H 410 CH O H Me Me Me i-propoxy Cl H 411 N
O H Me Me Me i-propoxy Cl H 412 N O H Me Me Me ##STR258## Me H 413
N O H Me Me Me ##STR259## Cl H 414 N O H Me Me Me ##STR260## Cl H -
- 415 N O H Me Me Me ##STR261## Me H 416 CH O H Me Me H H
##STR262## H 417 N O H Me Me H C(O)NHMe Cl H 418 N O H H H H H
##STR263## H 419 N O H H H H ##STR264## H H 420 N O H H H H
##STR265## H H 421 N O H H H H Cl Cl H 422 N O H H H H OMe Cl H 423
N O H H H Cl OMe Cl H 424 N O H H H OMe H OMe H 425 N O H H H H OMe
F H 426 N O H H H H OMe H H 427 N O H H H H OCF.sub.3 H H 428 N O H
H H H OEt H H 429 N O H H H H OBu H 430 N O H H H H ##STR266## H H
431 N O H H H H O-iPr H H 432 N O H Me Me H ##STR267## H H 433 N O
H H H H OMe OMe H 434 N O H Me Me H ##STR268## H H 435 N O H H H H
##STR269## H H + + 436 N O H Me Me H ##STR270## H H + 437 N O H H H
Me H Me M 436 N O H Me Me Me H Me H 439 N O H H H H H i-propyl H -
- 440 N O H H H H Me Cl H - - 441 N O H H H CF.sub.3 H OMe H - -
442 N O H H H Cl H Cl H - - 443 N O H H H H H Br H - - 444 N O H H
H H H t-butyl H - - 445 N O H H H OMe OMe OMe H 446 N O H H H H F F
H - - 447 N O H H H Me OMe Me H 448 N O H H H Me OH Me H + + 449 N
O H H H H H ##STR271## H + + 450 N O H H H H H ##STR272## H + + 451
N O H H H H ##STR273## H H - - 452 N O H H H H H ##STR274## H 453 N
O H H H H H ##STR275## H + + 454 N O H Me Me H H ##STR276## H - -
455 N O H Me Me H H ##STR277## H + + 456 N O H Me Me H ##STR278## H
H + + 457 N O H Me Me H H ##STR279## H 458 N O H Me Me H ##STR280##
H + + 459 N O H Me (S) H H OMe Cl H 460 N O H Me (S) H OMe OMe OMe
H 461 N O H Me (S) H Me H Me H 462 CH O H Me (R) H H C(O)NH.sub.2 H
H -- + 463 CH O H Me (S) H CH.sub.2NHBOC H H H 464 CH O H Me (R) H
CH.sub.2NHBOC H H H 465 CH O H Me (S) H CH.sub.2NH.sub.2 H H H 466
CH O H Me (R) H CH.sub.2NH.sub.2 H H H 467 CH O H Me Me H H
##STR281## H 468 CH O H Me (S) H H H ##STR282## H 469 CH O H Me (R)
H H H ##STR283## H 470 CH O H Me Me H ##STR284## H H - - 471 CH O H
Me (S) H H ##STR285## H H + - 472 N O H Me Me H C(O)NH.sub.2 H H +
+ 473 N .fwdarw. O O H Me Me OMe OMe OMe H + +
.sup..dagger..dagger.In TABLE 4, compounds having chirality at the
carbon labeled with an asterisk (*) that, through substituent
R.sup.19, designate a specified stereochemistry were synthesized
and tested as the substantially pure enantiomer; compounds that do
not designate a specified stereochemistry at this carbon atom were
synthesized and, if tested, were tested as the racemate.
[0144] TABLE-US-00005 TABLE 5 ##STR286## No. m R.sup.7 R.sup.21
R.sup.22 R.sup.23 R.sup.4' A549 H1299 474 1 H H ##STR287## H H -
475 1 H H ##STR288## H H - 476 0 F H H ##STR289## H 477 1 H H
hexoxy H H - 478 1 H H OEt H H + 479 1 H H butoxy H H - 480 1 H H
##STR290## H H - 481 1 H H H ##STR291## H - 482 1 H H H OH H - 483
1 H H OEt H H - 484 1 H H OMe OMe H 485 1 H H F Cl H - 486 1 H H
t-butyl H H 487 1 H H F H H - 488 1 H H H F H 489 1 H H Et H H -
490 1 H H ##STR292## H H - 491 1 H H H ##STR293## H - + 492 1 H H H
##STR294## H - 493 1 H H H ##STR295## H -/+ + 494 1 H H H
##STR296## H + + 495 1 H H H ##STR297## H -/+ + 496 1 H H H
##STR298## H + 497 1 H H H ##STR299## H + 498 1 H H H ##STR300## H
- 499 1 H H H ##STR301## H 500 1 H H H ##STR302## H + 501 1 H H
##STR303## H H - 502 1 H H ##STR304## H H - 503 1 F H H ##STR305##
H -/+ 504 1 H H H ##STR306## H + 505 1 H H Me ##STR307## H 506 1 H
OMe OMe OMe H + 507 1 H CF OH Cl H + 508 1 H H H ##STR308## H - 509
1 H H H ##STR309## H - 510 1 H H H ##STR310## H - 511 1 H H
i-propyl H H - 512 1 H OMe H OMe H + + 513 0 F H H Cl H + + 514 1 H
H H CF.sub.3 H - 515 1 H H H ##STR311## H + + 516 1 H H H
##STR312## H + 517 1 H H H ##STR313## H 518 1 H H OMe ##STR314## H
519 1 H H H ##STR315## H 520 1 H H H ##STR316## H + 521 1 H Me H OH
H + - 522 1 H F H CF.sub.3 H - - 523 1 H Me H CF.sub.3 H - + 524 1
H F H F H - - 525 1 H H OMe Cl H 526 1 H H OCF.sub.2 Cl H + - 527 1
H Me H Me H + 528 1 H Me Cl Me H + 529 1 H CH.sub.2OH H CH.sub.2OH
H + + 530 1 H Cl H Cl H + + 531 1 H OMe H CF.sub.3 H - + 532 1 F
OMe H OMe H + + 533 1 F Me Cl Me H - + 534 1 F CH.sub.2OH H
CH.sub.2OH H + 535 1 F Cl H Cl H + + 536 1 F OMe H CF.sub.3 H + +
537 1 F Me H Me H + + 538 1 F Me H CF.sub.3 H + - 539 1 H Cl H OMe
H + + 540 0 H OMe H OMe H 541 0 H OMe H CF.sub.3 H + + 542 0 H Me H
CF.sub.3 H - - 543 0 H Cl H Cl H + + 544 0 H Me H Me H - - 545 0 H
H H ##STR317## Me 546 1 H OMe H OMe Me + - 547 1 H Me H Me Me + +
548 1 H H H ##STR318## Me 549 1 H H H ##STR319## Me + + 550 1 H H H
##STR320## H + + 551 1 H H H H + + 552 1 F H H ##STR321## H + + 553
1 F H ##STR322## H H + + 554 1 H H C(O)NHMe Cl H + + 555 1 H H
C(O)NHMe Cl Me 556 1 H H S(O).sub.2NHMe OMe H 557 1 H H H
##STR323## H 558 1 H C(O)OMe H ##STR324## H + + 559 1 H CF.sub.3 H
##STR325## H + 560 0 F OMe OMe OMe H + + 561 0 F OMe H OMe H + +
562 0 F Me H Me H + + 563 0 F Cl OH Cl H + + 564 0 F Cl H Cl H + +
565 0 F Me Cl Me H - - 566 0 F Me OH Cl H + + 567 0 F OMe H
CF.sub.3 H + + 568 0 F Me H CF.sub.3 H - + 569 1 H Me ##STR326## Me
H + + 570 0 H Me ##STR327## Me H + + 571 1 F H H ##STR328## H + +
572 1 F H H ##STR329## Me + + 573 1 H Me ##STR330## Me Me + + 574 1
F Me ##STR331## Me Me + + 575 1 F Me ##STR332## Me H + + 576 1 H H
H ##STR333## H + 577 2 H H ##STR334## H H 578 2 H H ##STR335## H H
579 2 H H ##STR336## H H 580 2 H H H ##STR337## H - 581 2 H H H
##STR338## H + 582 2 H H H ##STR339## H 583 1 H Me OH Cl H 584 1 H
Me OMe Me H 585 1 H Me OMe Cl H 586 1 H H H ##STR340## H - 587 1 H
H ##STR341## H H +
[0145] TABLE-US-00006 TABLE 6 ##STR342## No. Y.sup.1 Y.sup.2
Z.sup.3 R.sup.17 R.sup.18 R.sup.19 R.sup.20 R.sup.21 R.sup.22
R.sup.23 R.sup.4' A549 H1299 588 N O CH Me Me H H OMe H OMe H + +
589 N O CH H H H H H H ##STR343## H + + 590 N O CH Me Me H H H H
##STR344## H + + 591 N O CH H H H H H H ##STR345## H + + 592 N O CH
Me Me H H H H ##STR346## H -- -- 593 N O CH H H H
CH.sub.2CH.sub.2OH OMe H OMe H 594 N O CH H H H CH.sub.2CH.sub.2OH
Me H Me H 595 N S CH H H H H H H ##STR347## H 596 N O CH H H Me Me
H H ##STR348## H 597 N O CH H H Me Me Me OMe Cl H + + 598 N O CH H
H Me Me OMe H OMe H 599 N O N H H Me Me H H ##STR349## H 600 N O N
H H H H H H ##STR350## H 601 N O N H H H H H ##STR351## H H 602 N O
N H H H H H H ##STR352## H 603 N O N H H H H H ##STR353## H H + +
604 N O N H H H H H ##STR354## H H - + 605 N O N H H H H H H
##STR355## H + + 606 N O N H H H H H H ##STR356## H + + 607 N O N H
H H H H H ##STR357## H + + 608 N O N H H H H H ##STR358## H H + +
609 N O N H H H H H H ##STR359## H + + 610 N O N H H H H H H
##STR360## H + + 611 N O N H H H H OMe OMe OMe H + + 612 N O N H H
H H H OMe Cl H - - 613 N O N H H H H H H ##STR361## H + + 614 N O N
H H H H H H ##STR362## H + + 615 N O N H H H H H ##STR363## Cl H +
+ 616 N O N H H H H H ##STR364## Me H + +
[0146] TABLE-US-00007 TABLE 7 Type A Type B ##STR365## ##STR366##
No. Type R.sup.4' R.sup.4 Y R.sup.11 A549 HTC116 H1299 617 A H
##STR367## NH OEt - 618 A H ##STR368## NH OEt + 619 A H ##STR369##
O OMe - 620 A H ##STR370## O OMe 621 A H ##STR371## NH OH - 622 A H
##STR372## O OH - 623 A H ##STR373## O OMe - 624 A H ##STR374## O
##STR375## - 625 A H ##STR376## O ##STR377## + + 626 A H ##STR378##
O ##STR379## -/+ + 627 A H ##STR380## O NHMe - 628 A H ##STR381## O
NHMe - 629 A H ##STR382## O NHMe + + 630 A H ##STR383## O
NH(CH.sub.2).sub.2OH - 631 A H ##STR384## O NH(CH.sub.2).sub.2OH +
+ 632 A H ##STR385## O ##STR386## + + 633 A H ##STR387## O
##STR388## + + 634 A H ##STR389## O ##STR390## + - 635 A H
##STR391## O ##STR392## + 636 A H ##STR393## O OMe + - 637 A H
##STR394## NH OEt 638 A H ##STR395## O OMe - 639 A H ##STR396## O
OH - 640 A H ##STR397## O ##STR398## - 641 A H ##STR399## O OMe -
642 A H ##STR400## O NHMe + 643 A H ##STR401## O N(Me).sub.2 - 644
A H ##STR402## O ##STR403## + + 645 A H ##STR404## O ##STR405## + +
646 B H ##STR406## NH OEt + + + 647 B H ##STR407## NH OEt + + 648 B
H ##STR408## NH OEt + + 649 B H ##STR409## NH NHMe + + 650 A H
##STR410## O OMe 651 A H ##STR411## O OMe - 652 A H ##STR412## O
OMe - 653 B H ##STR413## NH NHMe + + 654 B H ##STR414## NH NHMe + +
655 B H ##STR415## NH NHMe + + 656 A H ##STR416## O OMe - - 657 A H
##STR417## O OH - - 658 A H ##STR418## NH Me - + 659 B H ##STR419##
NH N(Me)CH.sub.2CH.sub.2OH + + + 660 B H ##STR420## NH
NHC(Me).sub.2CH.sub.2OH + + + 661 B Me ##STR421## O OMe - - 662 A
Me ##STR422## O OMe - + 663 B Me ##STR423## NH NHMe + + 664 B H
##STR424## NH OEt + + 665 B H ##STR425## NH NHMe + + 666 B Me
##STR426## NH OEt + + 667 B H CH.sub.2CH.sub.2OH NH OEt - - - 668 B
H ##STR427## NH NHMe - + 669 B H ##STR428## NH NHMe + + 670 B H
##STR429## NH NHMe - - 671 A Me ##STR430## O OMe - - 672 A Me
##STR431## O OMe - - 673 A H ##STR432## O OMe 674 A H ##STR433## O
OMe 675 A H ##STR434## O NHMe - 676 A H ##STR435## O OMe + 677 A H
##STR436## O OMe + - 678 B H ##STR437## NH OEt - -
[0147] TABLE-US-00008 TABLE 8 ##STR438## No. R.sup.4' R.sup.21
R.sup.22 R.sup.23 679 H Cl H H 680 H Me Me H 681 H H H Br 682 H Cl
H H 683 H Me Me H 684 H H Cl H 685 H H OEt H 686 H H OMe H 687 H H
H H 688 H Me H H 689 H H Br H 690 H H H H 691 H H H Br 692 H Me H H
693 H H H ##STR439## 694 H H ##STR440## 695 H H H ##STR441## 696 H
H H ##STR442## 697 H H H ##STR443## 698 H H H ##STR444## 699 H H H
##STR445## 700 H H H Me 701 H H CF.sub.3 H 702 H H OMe H 703 H H
CF.sub.3 F 704 H H OEt H 705 H H H OCF.sub.3 706 H H Cl CF.sub.3
707 H H H OEt 708 H H H OMe 709 H H OMe OMe 710 H H OMe OMe 711 H H
H OH 712 H H OMe OMe 713 H H OEt H 714 H H H OH 715 H H H OH 716 H
H Cl H 717 H H H Cl 718 H H t-butyl H 719 H H F Cl 720 H H F H 721
H H Me H 722 H H Et H 723 H H ##STR446## H 724 H H H ##STR447## 725
H H OMe OH 726 H H Me OH 727 H H ##STR448## H 728 H H ##STR449## H
729 H H ##STR450## H 730 H H OH H 731 H H OH Me 732 H H H
##STR451## 733 H H ##STR452## H 734 H H ##STR453## H 735 H H
##STR454## H 736 H H ##STR455## H 737 H H ##STR456## H 738 H H
##STR457## H 739 H H ##STR458## H 740 H H OH Cl 741 H H ##STR459##
Cl 742 H H OH F 743 H OMe OMe OMe 744 H H ##STR460## H 745 H H
i-propoxy H 746 H H H OH 747 H H ##STR461## H 748 H H H ##STR462##
749 H H H ##STR463## 750 H H H ##STR464## 751 H H H ##STR465## 752
H H H ##STR466## 753 H H H ##STR467## 754 H H H ##STR468## 755 H H
H ##STR469## 756 H H H ##STR470## 757 H H Me ##STR471## 758 H H Me
##STR472## 759 H H Me ##STR473## 760 H OMe OMe OMe 761 H H H
##STR474## 762 H H H ##STR475## 763 H H H OH 764 H H i-pr H 765 H
OMe H OMe 766 H H H ##STR476## 767 H H H ##STR477## 768 H H H OH
769 H OMe H OMe 770 H H H ##STR478## 771 H OMe H OMe 772 H H H
##STR479## 773 H H OMe 774 H H H ##STR480## 775 H H H ##STR481##
776 H H H ##STR482## 777 H H H ##STR483## 778 H H H ##STR484## 779
H H H ##STR485## 780 H H H ##STR486## 781 H H OCF.sub.3 Cl 782 H Br
H CF.sub.3 783 H H H ##STR487## 784 H H H ##STR488## 785 H H H
##STR489## 786 H H H OH 787 H Cl OH Me 788 H H H ##STR490## 789 H H
H ##STR491## 790 H H H ##STR492## 791 H H H ##STR493## 792 H H H
##STR494## 793 H H H ##STR495## 794 H H H ##STR496## 795 H
##STR497## H ##STR498## 796 H OH H ##STR499## 797 H OH H ##STR500##
798 H ##STR501## H ##STR502## 799 H H H OH 800 H H OMe Cl 801 H Me
OH Cl 802 H Me OMe Cl 803 H H H ##STR503## 804 H H H ##STR504## 805
H OMe H OMe 806 H CF.sub.3 H OMe 807 H H H ##STR505## 808 H Cl H Cl
809 H Me H Me 810 H CF.sub.3 H OMe 811 H Me Me Me 812 H OMe H OMe
813 H Me H Me 814 H OMe H OMe 815 H OMe H CF.sub.3 816 H Me H
CF.sub.3 817 H Me H Me 818 H OMe H OMe 819 H CF.sub.3 H OMe 820 H
Me H CF.sub.3 821 H OMe OMe OMe 822 H Me OH Cl 823 H Cl H Cl 824 H
CH.sub.2OH H CH.sub.2OH 825 H Me Cl Me 826 H H H ##STR506## 827 H H
H ##STR507## 828 H Cl OH Cl 829 H Cl OH Cl 830 H H H ##STR508## 831
H Cl OMe Cl 832 H Cl OMe Cl 833 H H H ##STR509## 834 H Cl OMe
Cl
835 H OMe H OMe 836 H OMe H OMe 837 H OMe H OMe 838 H Me H Me 839 H
OMe H OMe 840 H OMe H OMe 841 H Me H Me 842 H CH.sub.2OH H
CH.sub.2OH 843 H CH.sub.2OH H CH.sub.2OH 844 H CH.sub.2OH H
CH.sub.2OH 845 H Me Me Me 846 H Me H Me 847 H Cl H Cl 848 H Me H
CF.sub.3 849 H OMe H CF.sub.3 850 Me H H ##STR510## 851 Me Me H Me
852 Me OMe H OMe 853 Me H OMe Cl 854 Me H Cl OMe 855 H Me H Me 856
H OMe H OMe 857 H H H ##STR511## 858 H H H ##STR512## 859 H H H
##STR513## 860 H H OMe Cl 861 H H H ##STR514## 862 H H H ##STR515##
863 H H ##STR516## H 864 Me Me H Me 865 Me OMe H OMe 866 H H
##STR517## H 867 Me H H ##STR518## 868 Me H H ##STR519## 869 Me H
##STR520## H 870 Me H H ##STR521## 871 H H C(O)NHMe Cl 872 H H
C(O)NHMe Cl 873 H H C(O)NHMe Cl 874 H H C(O)NHMe Cl 875 Me H
C(O)NHMe Cl 876 H OMe H OMe 877 H Me H Me 878 H H H ##STR522## 879
H H S(O).sub.2NHMe OMe 880 H H S(O).sub.2NHMe OMe 881 H H
S(O).sub.2NHMe OMe 882 H H S(O).sub.2NHMe OMe 883 H H
S(O).sub.2NHMe OMe 884 H OMe H OMe 885 H H H ##STR523## 886 H H H
##STR524## 887 H C(O)OMe H ##STR525## 888 H C(O)Me H ##STR526## 889
H CF.sub.3 H ##STR527## 890 H H H ##STR528## 891 H ##STR529## H
##STR530## 892 H CF.sub.3 H ##STR531## 893 H Cl OH Cl 894 H H
##STR532## Me 895 H OMe OMe OMe 896 H Me Cl Cl 897 H CH.sub.2OH H
CH.sub.2OH 898 H Cl H Cl 899 H Cl Cl Cl 900 H Me Cl Me 901 H Me
##STR533## Me 902 H Me ##STR534## Me 903 Me OMe H OMe 904 Me Me OMe
Cl 905 Me Me ##STR535## Me 906 Me H H ##STR536## 907 Me H Me H 908
Me OMe H OMe 909 Me Me H Me 910 Me H H ##STR537## 911 Me OMe H OMe
912 Me Me H Me 913 Me H H ##STR538## 914 Me H H ##STR539## 915 H Me
H Me 916 H OMe H OMe 917 H H OMe Cl 918 H Me Cl Me 919 H H C(O)NHMe
Cl 920 H H C(O)NHMe Cl 921 Me H C(O)NHMe Cl 922 H Me H Me 923 H OMe
H OMe 924 H H OMe Cl 925 H Me Cl Me 926 H Me H Me 927 H OMe H OMe
928 H OMe Cl H 929 H Me Cl Me 930 H H Cl OMe 931 H Me ##STR540## Me
932 H H H ##STR541## 933 H H H ##STR542## 934 H H ##STR543## H 935
H H H ##STR544## 936 H H ##STR545## H 937 H H ##STR546## H 938 H H
F Cl 939 H H H OH 940 H H H ##STR547## 941 H Cl OH Cl 942 H Me OH
Cl 943 H Cl OH Me 944 H H H OH 945 H H OMe OMe 946 H Me OH Cl 947 H
H H ##STR548## 948 H H H ##STR549## 949 H H H ##STR550## 950 H H H
##STR551## 951 H H H t-Bu 952 H H H ##STR552## 953 H H H t-Bu 954 H
H H ##STR553## 955 H H H t-Bu 956 H H H t-Bu 957 H H H ##STR554##
958 H H H ##STR555## 959 H Me OH Cl 960 H H H ##STR556## 961 H H H
##STR557## 962 H H H ##STR558## 963 H H H ##STR559## 964 H H H OEt
965 H H H ##STR560## 966 H H H ##STR561## 967 H H H ##STR562## 968
H H H i-pr 969 H H OMe OMe 970 H H H ##STR563## 971 H H ##STR564##
H 972 H H ##STR565## H 973 H H ##STR566## H 974 H H H OH 975 H H
##STR567## H 976 H H H ##STR568## 977 H H H ##STR569## 978 H H H
##STR570## 979 H H H ##STR571## 980 H H H ##STR572## 981 H H H
##STR573## 982 H H H ##STR574## 983 H H H ##STR575## 984 H H H
##STR576## 985 H H H ##STR577## 986 H H H ##STR578## 987 H H H
##STR579## 988 H H H ##STR580## 989 H H H ##STR581## 990 H H H
##STR582## 991 H H H ##STR583##
992 H H H ##STR584## 993 H H H ##STR585## 994 H H H ##STR586## 995
H H H ##STR587## 996 H H OH CF.sub.3 997 H H H Me 998 H H Me H 999
H H H ##STR588## 1000 H H H ##STR589## 1001 H H H ##STR590## 1002 H
H H ##STR591## 1003 H H H ##STR592## 1004 H H H ##STR593## 1005 H H
H ##STR594## 1006 H H H ##STR595## 1007 Me Me H Me 1008 Me H OMe Cl
1009 Me OMe H OMe 1010 Me Cl OMe Cl 1011 Me H OCF.sub.3 Cl 1012 H H
CH.sub.2NHBoc H 1013 H H CH.sub.2NH.sub.2 H 1014 H H ##STR596## H
1015 H H H CH.sub.2NHBoc 1016 H H H CH.sub.2NHBoc 1017 H H H
CH.sub.2NHBoc 1018 H H H CH.sub.2NHBoc 1019 H H ##STR597## H 1020
Me H ##STR598## H 1021 H H ##STR599## H 1022 H H C(O)NH.sub.2 H
1023 H H CH.sub.2NHBoc H 1024 H H CH.sub.2NHBoc H 1025 H H
##STR600## H 1026 H H H OH 1027 H Cl OH Cl 1028 H H OMe Cl 1029 H H
C(O)NH.sub.2 H 1030 Me H C(O)NH.sub.2 H 1031 Me H ##STR601## H 1032
H H C(O)NH.sub.2 H 1033 H H C(O)NH.sub.2 Cl 1034 H H C(O)NH.sub.2
Cl 1035 H H ##STR602## H 1036 H H C(O)NH.sub.2 H No. R.sup.31
R.sup.32 R.sup.33 A549 H1299 679 Cl H H 680 Me Me H 681 H H Br 682
Cl H H 683 Me Me H 684 H Cl H 685 H OEt H 686 H OMe H 687 H H H 688
Me H H 689 H Br H 690 H H H 691 H H Br 692 Me H H 693 H H OH + 694
H H ##STR603## + + 695 H F F 696 H Cl H 697 H Cl Cl + + 698 H H
OCF.sub.3 699 H OCF.sub.3 Cl + 700 H OCF.sub.3 Cl 701 H CF.sub.3 H
- - 702 H OMe H + + 703 H CF.sub.3 F - 704 H OEt H + + 705 H H
OCF.sub.3 - 706 H Cl CF.sub.3 - 707 H H OEt + 708 H H OMe + 709 H
OEt H - 710 H OMe OMe + 711 H H H + 712 H H H - 713 H OMe OMe + +
714 H OEt H - 715 H OMe OMe + 716 H Cl H - 717 H H Cl + 718 H
t-butyl H - - 719 H F Cl - - 720 H F H + - 721 H Me H - - 722 H Et
H - 723 H ##STR604## H + 724 H H ##STR605## - + 725 H OMe OH + 726
H Me OH 727 H ##STR606## H 728 H H OH 729 H H OH - 730 H OH H + 731
H OH Me - 732 H H OH + 733 H ##STR607## H - 734 H ##STR608## H -
735 H ##STR609## H 736 H H Cl - 737 H ##STR610## H - 738 H
##STR611## H - 739 H ##STR612## H - 740 H OH Cl 741 H Cl 742 H OH F
743 OMe OMe OMe - 744 H H OH + 745 H i-propoxy H - 746 H ##STR613##
H - 747 H t-Bu H - 748 H t-Bu H - 749 H t-Bu H - 750 H t-Bu H - 751
H i-propoxy H -/+ 752 H i-propoxy H - 753 H OMe OMe - 754 H OMe OMe
- 755 H H OMe + 756 H Me OH 757 H H OH 758 H Me OH 759 H Me
##STR614## + + 760 H H OH - 761 H H OH 762 H H OH - 763 H H
##STR615## - + 764 H H OH - 765 H H OH + 766 OMe H OMe - + 767 OMe
H OMe - 768 OMe H OMe + + 769 H H ##STR616## - - 770 H H CF.sub.3 +
771 H H ##STR617## + 772 H OEt H + + 773 H H OH 774 H H OH 775 H H
Cl 776 CF.sub.3 H OMe 777 H OMe OH 778 H OMe CF.sub.3 779 H F
CF.sub.3 780 H Me Cl 781 H H OH + + 782 H H OH 783 H OCF.sub.3 H
784 H CF.sub.3 H 785 H Cl CF.sub.3 786 H H OCF.sub.3 787 H H OH 788
H OMe Cl + 789 H OMe F 790 H Me OMe + 791 H H ##STR618## + + 792 H
H + + 793 H Me CF.sub.3 794 H F Me 795 H H OH 796 H H OH 797 H H OH
+ - 798 H H OH - - 799 H OMe Cl 800 H OMe Cl + - 801 H OMe Cl 802 H
OMe Cl - - 803 H O-iPr Cl 804 H OMe Cl 805 H ##STR619## Cl 806 H
##STR620## Cl + + 807 H OMe Cl 808 H OMe Cl + + 809 H OMe Cl 810 H
OMe Cl + - 811 H OMe Cl + - 812 H H OCF.sub.3 + + 813 H H OCF.sub.3
- - 814 Me H Me + + 815 Me H Me + + 816 Me H Me + +/- 817 CF.sub.3
H OMe + + 818 CF.sub.3 H OMe + + 819 CF.sub.3 H OMe + + 820
CF.sub.3 H OMe +/- + 821 CF.sub.3 H OMe + + 822 CF.sub.3 H OMe + +
823 CF.sub.3 H OMe + + 824 CF.sub.3 H OMe + -/+ 825 CF.sub.3 H OMe
+ + 826 H Cl OMe
827 H ##STR621## Cl 828 H OMe Cl + + 829 H OCF.sub.3 Cl + + 830 H
##STR622## Cl 831 H OMe Cl - - 832 H OCF.sub.3 Cl + - 833 Cl OMe Cl
834 H Cl Cl + + 835 H Cl Cl + + 836 H OMe Cl 837 H OCF.sub.3 Cl 838
H Cl Cl + - 839 OMe H OMe + 840 OMe H OMe + + 841 Me H Me + + 842
OMe H OMe + + 843 H OMe Cl + + 844 H Cl Cl + + 845 OMe H OMe + +
846 OMe H OMe + + 847 OMe H OMe + 848 OMe H OMe + 849 OMe H OMe + +
850 OMe H OMe - - 851 OMe H OMe + + 852 OMe H OMe + + 853 OMe H OMe
- - 854 OMe H OMe - - 855 OMe H OMe + + 856 H OMe OMe + + 857 H OMe
OMe 858 H OMe OMe + + 859 H OMe OMe + + 860 H OMe OMe 861 OMe H OMe
+ + 862 H OMe OMe + + 863 H OMe OMe + + 864 H OMe OMe + + 865 H OMe
OMe + + 866 OMe H OMe + + 867 H OMe OMe - + 868 H OMe OMe + + 869 H
OMe OMe + + 870 H OMe OMe - - 871 H OMe OMe + + 872 OMe H OMe + +
873 H OMe Cl 874 H H OH 875 H OMe OMe + + 876 H C(O)NHMe Cl 877 H
C(O)NHMe Cl 878 H C(O)NHMe Cl 879 H OMe OMe + + 880 OMe H OMe + +
881 H Cl CF.sub.3 882 H OCF.sub.3 Cl 883 H H Cl 884 H
S(O).sub.2NHMe OMe + + 885 H H OH + + 886 H OMe OMe + + 887 H OMe
OMe + + 888 H H OH + + 889 H OMe OMe + + 890 H H OH + + 891
##STR623## H ##STR624## - - 892 CF.sub.3 H ##STR625## + + 893 Cl
OMe Cl 894 H ##STR626## Me + + 895 Me H Me + + 896 Me H Me + + 897
Me H Me + + 898 Me H Me - - 899 Me H Me + + 900 Me H Me - - 901 H
OMe Cl 902 OMe H OMe + + 903 H OMe Cl + + 904 H OMe Cl - - 905 H
OMe Cl + + 906 H OMe Cl + + 907 H OMe Cl - + 908 H Cl OMe 909 H Cl
OMe + + 910 H Cl OMe + - 911 Me Cl Me 912 Me Cl Me - - 913 Me Cl Me
+ + 914 Me Cl Me - - 915 H ##STR627## Cl 916 H ##STR628## Cl 917 H
##STR629## Cl + + 918 H ##STR630## Cl 919 H Cl OMe 920 H Cl
CF.sub.3 921 Me Cl Me + + 922 H ##STR631## Cl 923 H ##STR632## Cl
924 H ##STR633## Cl 925 H ##STR634## Cl 926 H ##STR635## Cl 927 H
##STR636## Cl 928 H ##STR637## Cl 929 H ##STR638## Cl 930 H
##STR639## Cl 931 OMe H OMe + + 932 OMe OMe OMe + + 933 OH OH
##STR640## + + 934 H H OH + 935 H i-pr H - 936 H i-pr H - 937 H
i-pr H + 938 H F Cl - 939 H H ##STR641## - 940 OMe H OMe + + 941 Cl
OH Cl - 942 Me OH Cl + + 943 H H OH + 944 Cl OH Me 945 H ##STR642##
Me + + 946 H ##STR643## H 947 Me OH Me - + 948 Me OH Me - 949 Me OH
Me + + 950 Me OH Me + + 951 H H OH - 952 Cl OH Me - + 953 H OMe OMe
- 954 Cl OH Me - 955 H H ##STR644## - - 956 H H ##STR645## - 957 Cl
OH Me + 958 H H t-Bu - - 959 H H t-Bu - 960 H H t-Bu - 961 H H t-Bu
-/+ 962 H H t-Bu - - 963 H H t-Bu - 964 H H i-pr - 965 H H i-pr -
966 H H i-pr + 967 H CH.sub.2OH CH.sub.2OH - 968 H H i-pr - + 969 H
H OH + + 970 H H CH.sub.2NH.sub.2 + + 971 H ##STR646## H - 972 H
##STR647## H 973 H ##STR648## H - 974 H ##STR649## H + + 975 H H OH
976 H H OH - 977 H i-propoxy H - 978 H H OH - 979 Me OH Me - + 980
Me OH Me + 981 Me OH Me + 982 Me OH Me - 983 Cl OH Me + 984 Cl OH
Me + 985 Me OMe Me - 986 Me OMe Me - 987 Me OMe Me - 988 H
##STR650## H + + 989 H ##STR651## H + + 990 H ##STR652## H + + 991
Me OH Cl + 992 H ##STR653## H - - 993 H ##STR654## H + + 994 H H
##STR655## 995 H H ##STR656## + + 996 H OH CF.sub.3 -/+ 997 H H Me
+ 998 H Me H - 999 Cl OH Cl - - 1000 Cl OH Cl 1001 Cl OH Cl - -
1002 H ##STR657## H - 1003 H ##STR658## H - 1004 H OH H - 1005 H
OMe CH.sub.2OH 1006 H Cl Cl + + 1007 H Cl Cl - - 1008 H Cl Cl 1009
H Cl Cl - - 1010 H Cl Cl 1011 H Cl Cl 1012 H CH.sub.2NHBoc H + +
1013 H CH.sub.2NH.sub.2 H + + 1014 H Cl Cl 1015 H H CH.sub.2NHBoc +
+ 1016 H H CH.sub.2NHBoc + + 1017 H Cl Cl 1018 H Cl Cl 1019 H Cl Cl
1020 H Cl Cl 1021 H OMe Cl + + 1022 H OMe Cl + + 1023 H OMe Cl + +
1024 H OMe Cl + + 1025 H OMe Cl - + 1026 H C(O)NH.sub.2 H - +
1027 H C(O)NH.sub.2 H + + 1028 H C(O)NH.sub.2 H + + 1029 H
C(O)NH.sub.2 H - - 1030 H Cl C + + 1031 H Cl Cl + + 1032 H Cl OMe -
- 1033 H OMe Cl + + 1034 H Cl OMe - + 1035 H Cl OMe + + 1036 H H H
+ +
[0148] TABLE-US-00009 TABLE 9 ##STR659## No. R.sup.4' R.sup.2'
R.sup.2 A549 H1299 1037 H H CH.sub.2CH.dbd.CH.sub.2 - 1038 Me H Me
+ + 1039 Me Me Me + + 1040 Me H CH.sub.2CH.sub.2OH + + 1041 Me H
i-propyl + + 1042 Me CH.sub.2CH.sub.2OH CH.sub.2CH.sub.2OH - + 1043
Me H CH.sub.2CH.dbd.CH.sub.2 + + 1044 H H Me - -
[0149] TABLE-US-00010 TABLE 10 ##STR660## No. R.sup.4' R.sup.40
R.sup.41 R.sup.42 A549 H1299 1045 H H OMe OMe - 1046 H H OMe Me + +
1047 H OMe H Me + + 1048 H Me H F + + 1049 H OMe Cl OMe + +
[0150] TABLE-US-00011 TABLE 11 ##STR661## No. R.sup.21 R.sup.22
R.sup.23 A549 H1299 1050 Me OMe Me + + 1051 H OMe F + + 1052 Me H
Me + + 1053 OMe H OMe + + 1054 H H ##STR662## + + 1055 H H
##STR663## - - 1056 H ##STR664## H - - 1057 H ##STR665## H - - 1058
H ##STR666## H - - 1059 H H ##STR667## - -
[0151] TABLE-US-00012 TABLE 12 ##STR668## No. R.sup.13a R.sup.13b
R.sup.19 R.sup.20 A549 H1299 1060 Me OH Me Me + + 1061 Me OMe Me Me
+ + 1062 Me OMe H H + + 1063 Me OH H H + + 1064 Me OH Me Me + +
1065 Me OMe Me Me + -
[0152] TABLE-US-00013 TABLE 13 Type A ##STR669## Type B ##STR670##
Type C ##STR671## Type D ##STR672## No. Type R.sup.16 R.sup.31
R.sup.32 R.sup.33 A549 H1299 1066 B ethyl H OMe Cl 1067 B ethyl H
Cl Cl 1068 B ethyl -- -- -- 1069 B ethyl H F OMe 1070 A ethyl H OMe
Cl 1071 A ethyl H Cl Cl 1072 C ethyl -- -- -- 1073 A ethyl H F OMe
1074 B n-propyl H OMe Cl + + 1075 B n-propyl H Cl Cl - - 1076 D
n-propyl -- -- -- + + 1077 A n-propyl H F OMe + + 1078 B n-propyl H
OMe Cl + + 1079 B n-propyl H Cl Cl + + 1080 C n-propyl -- -- -- + +
1081 A n-propyl H F OMe + + 1082 B n-butyl H OMe Cl + - 1083 B
n-butyi H Cl Cl + + 1084 D n-butyl -- -- -- + + 1085 B n-butyl H F
OMe + + 1086 A n-butyl H OMe Cl + + 1087 A n-butyl H Cl Cl + + 1088
C n-butyl -- -- -- + + 1089 A n-butyl H F OMe + + 1090 B ##STR673##
H OMe Cl + + 1091 B ##STR674## H Cl Cl - - 1092 D ##STR675## -- --
-- + + 1093 B ##STR676## H F OMe + + 1094 A ##STR677## H OMe Cl + +
1095 A ##STR678## H Cl Cl + + 1096 C ##STR679## -- -- -- + + 1097 A
##STR680## H F OMe - + 1098 B ##STR681## H OMe Cl - + 1099 B
##STR682## H Cl Cl + + 1100 D ##STR683## -- -- -- + + 1101 B
##STR684## H F OMe + + 1102 A ##STR685## H OMe Cl + + 1103 A
##STR686## H Cl Cl .degree. - 1104 C ##STR687## -- -- -- + + 1105 A
##STR688## H F OMe + + 1106 B ##STR689## H OMe Cl + + 1107 B
##STR690## H Cl Cl - - 1108 D ##STR691## -- -- -- + + 1109 B
##STR692## H F OMe + + 1110 A ##STR693## H OMe Cl + + 1111 A
##STR694## H Cl Cl + + 1112 C ##STR695## -- -- -- + + 1113 A
##STR696## H F OMe + + 1114 B ##STR697## H OMe Cl 1115 B ##STR698##
H Cl Cl + + 1116 D ##STR699## -- -- -- 1117 8 ##STR700## H F OMe +
+ 1118 A ##STR701## H OMe Cl + + 1119 A ##STR702## H Cl Cl + + 1120
C ##STR703## -- -- -- 1121 A ##STR704## H F OMe + + 1122 C methyl
-- -- -- 1123 C methyl -- -- -- 1124 C methyl -- -- -- 1125 C
methyl -- -- -- 1126 C methyl -- -- -- 1127 B i-propyl H OMe Cl
1128 B i-propyl H Cl Cl 1129 D i-propyl -- -- -- 1130 B i-propyl H
F OMe 1131 A i-propyl H OMe Cl 1132 A i-propyl H Cl Cl 1133 C
i-propyl -- -- -- 1134 C methyl -- -- -- 1135 C H -- -- -- 1136 C H
-- -- -- 1137 C ethyl -- -- -- 1138 C i-propyl -- -- --
[0153] TABLE-US-00014 TABLE 14 No. Structure A549 H1299 1139
##STR705## + - 1140 ##STR706## - - 1141 ##STR707## - - 1142
##STR708## + - 1143 ##STR709## 1144 ##STR710## 1145 ##STR711## + +
1146 ##STR712## + - 1147 ##STR713## + + 1148 ##STR714## 1149
##STR715## 1150 ##STR716## 1151 ##STR717## 1152 ##STR718## 1153
##STR719## 1154 ##STR720## 1155 ##STR721## 1156 ##STR722## 1157
##STR723## 1158 ##STR724## + + 1159 ##STR725## + + 1160 ##STR726##
+ + 1161 ##STR727## + 1162 ##STR728## + + 1163 ##STR729## + + 1164
##STR730## + +
[0154] Those of skill in the art will appreciate that the
2,4-pyrimidinediamine compounds described herein may include
functional groups that can be masked with progroups to create
prodrugs. Such prodrugs are usually, but need not be,
pharmacologically inactive until converted into their active drug
form. For example, ester groups commonly undergo acid-catalyzed
hydrolysis to yield the parent carboxylic acid when exposed to the
acidic conditions of the stomach, or base-catalyzed hydrolysis when
exposed to the basic conditions of the intestine or blood. Thus,
when administered to a subject orally, 2,4-pyimidinediamines that
include ester moieties may be considered prodrugs of their
corresponding carboxylic acid, regardless of whether the ester form
is pharmacologically active.
[0155] In the prodrugs of the invention, any available functional
moiety may be masked with a progroup to yield a prodrug. Functional
groups within the 2,4-pyrimidinediamine compounds that may be
masked with progroups for inclusion in a promoiety include, but are
not limited to, amines (primary and secondary), hydroxyls,
sulfanyls (thiols), carboxyls, etc. Myriad progroups suitable for
masking such functional groups to yield promoieties that are
cleavable under the desired conditions of use are known in the art.
All of these progroups, alone or in combinations, may be included
in the prodrugs of the invention.
[0156] In one illustrative embodiment, the prodrugs are compounds
according to structural formulae (I)-(VI) in which R.sup.aR.sup.b
and R.sup.c may be, in addition to their previously-defined
alternatives, a progroup.
[0157] In another illustrative embodiment, the prodrugs are
compounds according to structural formulae (I)-(VI) in which
R.sup.2' and R.sup.4' are each, independently of one another, a
progroup. Specific examples of progroups according to this
embodiment of the invention include, but are not limited to,
--C(O)CH.sub.3, --C(O)NHR.sup.h and --S(O).sub.2R.sup.h, where
R.sup.h is selected from the group consisting of lower alyl,
(C5-C15) aryl and (C3-C8) cycloalkyl.
[0158] Those of skill in the art will appreciate that many of the
compounds and prodrugs described herein, as well as the various
compound species specifically described and/or illustrated herein,
may exhibit the phenomena of tautomerism, conformational isomerism,
geometric isomerism and/or optical isomerism. For example, the
compounds and prodrugs may include one or more chiral centers
and/or double bonds and as a consequence may exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers and diasteromers and mixtures thereof, such
as racemic mixtures. As another example, the compounds and prodrugs
may exist in several tautomeric forms, including the enol form, the
keto form and mixtures thereof. As the various compound names,
formulae and compound drawings within the specification and claims
can represent only one of the possible tautomeric, conformational
isomeric, optical isomeric or geometric isomeric forms, it should
be understood that the invention encompasses any tautomeric,
conformational isomeric, optical isomeric and/or geometric isomeric
forms of the compounds or prodrugs having one or more of the
utilities described herein, as well as mixtures of these various
different isomeric forms. In cases of limited rotation around the
2,4-pyrimidinediamine core structure, atrop isomers are also
possible and are also specifically included in the compounds and/or
prodrugs of the invention.
[0159] Depending upon the nature of the various substituents, the
2,4-pyrimidinediamine compounds and prodrugs may be in the form of
salts. Such salts include salts suitable for pharmaceutical uses
("pharmaceutically-acceptable salts"), salts suitable for
veterinary uses, etc. Such salts may be derived from acids or
bases, as is well-known in the art.
[0160] In some embodiments, the salt is a pharmaceutically
acceptable salt. Generally, pharmaceutically acceptable salts are
those salts that retain substantially one or more of the desired
pharmacological activities of the parent compound and which are
suitable for administration to humans. Pharmaceutically acceptable
salts include acid addition salts formed with inorganic acids or
organic acids. Inorganic acids suitable for forming
pharmaceutically acceptable acid addition salts include, by way of
example and not limitation, hydrohalide acids (e.g., hydrochloric
acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric
acid, phosphoric acid, and the like. Organic acids suitable for
forming pharmaceutically acceptable acid addition salts include, by
way of example and not limitation, acetic acid, trifluoroacetic
acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,
glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic
acid, succinic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, palmitic acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic
acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,
etc.), arylsulfonic acids (e.g., benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid, etc.),
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like.
[0161] Pharmaceutically acceptable salts also include salts formed
when an acidic proton present in the parent compound is either
replaced by a metal ion (egg, an alkali metal ion, an alkaline
earth metal ion or an aluminum ion) or coordinates with an organic
base (e.g., ethanolamine, diethanolamine, triethanolamine,
N-methylglucamine, morpholine, piperidine, dimethylamine,
diethylamine, etc.).
[0162] The 2,4-pyrimidinediamine compounds and prodrugs, as well as
the salts thereof, may also be in the form of hydrates, solvates
and N-oxides, as are well-known in the art.
[0163] 5.3 Methods of Synthesis
[0164] The 2,4-pyrimidinediamine compounds and prodrugs may be
synthesized via a variety of different synthetic routes using
commercially available starting materials and/or starting materials
prepared by conventional synthetic methods. Suitable exemplary
methods that may be routinely adapted to synthesize the
2,4-pyrimidinediamine compounds and prodrugs are found in U.S. Pat.
No. 5,958,935, the disclosure of which is incorporated herein by
reference. Specific examples describing the synthesis of numerous
2,4-pyrimidinediamine compounds and prodrugs, as well as
intermediates therefor, are described in copending U.S. application
Ser. No. 10/355,543, filed Jan. 31, 2003 (US 2004-0029902 published
Feb. 12, 2004), WO 03/63794, copending U.S. application Ser. No.
10/631,029, filed Jul. 29, 2003, WO 2004/014312, copending
application Ser. No. ______, filed Jul. 30, 2004 (identified by
attorney docket no, 28575/US/US/US) and international application
no. ______, filed Jul. 30, 2004 (identified by attorney docket no.
28575/US/US/PCT), the contents of which are incorporated herein by
reference, All of the compounds described herein (including
prodrugs) can be prepared according to, or by routine adaptation
of, these various methods.
[0165] A variety of exemplary synthetic routes that can be used to
synthesize the 2,4-pyrimidinediamine compounds and prodrugs are
described in Schemes (I)-(XI), below. In Schemes (I)-(XI),
like-numbered compounds have similar structures. These methods may
be routinely adapted to synthesize the corresponding N2- and/or
N4-alkylated compounds and prodrugs, as illustrated in Scheme
(XII).
[0166] In one exemplary embodiment, the compounds can be
synthesized from substituted or unsubstituted uracils or
thiouracils as illustrated in Scheme (I), below: ##STR731##
[0167] In Scheme (I), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1
and L.sup.2 are as previously defined for structural formulae (I),
X is a halogen (e.g., F, Cl, Br or I) and G and G' are each,
independently of one another, selected from the group consisting of
O and S. Referring to Scheme (I), uracil or thiouracil 2 is
dihalogenated at the 2- and 4-positions using standard halogenating
agent POX.sub.3 (or other standard halogenating agent) under
standard conditions to yield 2,4-bishalo pyrimidine 4, Depending
upon the R.sup.5 substituent, in pyrimidine 4, the halide at the C4
position is more reactive towards nucleophiles than the halide at
the C2 position. This differential reactivity can be exploited to
synthesize 2,4-pyrimidinediamines according structural formulae (I
by first reacting 2,4-bishalopyrimidine 4 with one equivalent of
amine 10, yielding 4N-substituted-2-halo-4-pyiimidineamine 8,
followed by amine 6 to yield a 2,4-pyrimidinediamine according
structural formulae (U)
2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be
obtained by reacting 2,4-bishalopyrimidine 4 with excess 6 or 10,
respectivel.
[0168] In most situations, the C4 halide is more reactive towards
nucleophiles, as illustrated in the Scheme, However, as will be
recognized by skilled artisans, the identity of the R.sup.5
substituent may alter this reactivity. For example, when R.sup.5 is
trifluoromethyl, a 50:50 mixture of
4N-substituted-4-pyrimidineamine 8 and the corresponding
2N-substituted-2-pyrimidineamine is obtained Regardless of the
identity of the R.sup.5 substituent, the regioselectivity of the
reaction can be controlled by adjusting the solvent and other
synthetic conditions (such as temperature), as is well-known in the
art.
[0169] The reactions depicted in Scheme (1) may proceed more
quickly when the reaction mixtures are heated via microwave. When
heating in this fashion, the following conditions may be used: heat
to 175.degree. C. in ethanol for 5-20 min, in a Smith Reactor
(Personal Chemistry) in a sealed tube (at 20 bar pressure).
[0170] The uracil or thiouracil 2 starting materials may be
purchased from commercial sources or prepared using standard
techniques of organic chemistry, Commercially available uracils and
thiouracils that can be used as starting materials in Scheme (I)
include, by way of example and not limitation, uracil (Aldrich
#13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4;
CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS
Registry 2001-93-6); 5-bromouracil (Aldrich #85,247-3; CAS Registry
51-20-7; 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8);
5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1);
5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5);
5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry
54-20-6). Additional 5-substituted uracils and/or thiouracils are
available from General Intermediates of Canada, Inc., Edmonton,
Calif. (www.generalintermediates.com) and/or Interchim, Cedex,
France (www.interchim.com), or may be prepared using standard
techniques. Myriad textbook references teaching suitable synthetic
methods are provided infra.
[0171] Amines 6 and 10 may be purchased from commercial sources or,
alternatively, may be synthesized utilizing standard techniques.
For example, suitable amines may be synthesized from nitro
precursors using standard chemistry. Specific exemplary reactions
are provided in the Examples section. See also Vogel, 1989,
Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John
Wiley & Sons, Inc.
[0172] Skilled artisans will recognize that in some instances,
amines 6 and 10 and/or substituents R.sup.5 and/or R.sup.6 on
uracil or thiouracil 2 may include functional groups that require
protection during synthesis. The exact identity of any protecting
group(s) used will depend upon the identity of the functional group
being protected, and will be apparent to these of skill in the art.
Guidance for selecting appropriate protecting groups, as well as
synthetic strategies for their attachment and removal, may be
found, for example, in Greene & Wuts, Protective Groups in
Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New
York (1999) and the references cited therein (hereinafter "Greene
& Wuts").
[0173] A specific embodiment of Scheme (1) utilizing 5-fluorouracil
(Aldrich #32,937-1) as a starting material is illustrated in Scheme
(II), below. ##STR732##
[0174] In Scheme (II), R.sup.2, R.sup.4, L.sup.1 and L.sup.2 are as
previously defined for Scheme (I). According to Scheme (II),
5-fluorouracil 3 is halogenated with POCl.sub.3 to yield
2,4-dichloro-5-fluoropyrimidine 5, which is then reacted with
excess amine 6 or 10 to yield N2,N4-bis substituted
5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively.
Alternatively,
non-bis-2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be
obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one
equivalent of amine 10 (to yield
2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by
one or more equivalents of amine 6.
[0175] In another exemplary embodiment, the 2,4-pyrimidinediamine
compounds of the invention may be synthesized from substituted or
unstibstituted cytosines as illustrated in Schemes (IIa) and (IIb),
below: ##STR733## ##STR734##
[0176] In Schemes (IIa) and (IIb), R.sup.2, R.sup.4, R.sup.5,
R.sup.6, L.sup.1, L.sup.2 and X are as previously defined for
Scheme (I) and PG represents a protecting group. Referring to
Scheme (IIa), the C4 exocyclic amine of cytosine 20 is first
protected with a suitable protecting group PG to yield N4-protected
cytosine 22. For specific guidance regarding protecting groups
useful in this context, see Vorbruggen and Ruh-Pohlenz, 2001,
Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp,
1-631 ("Vorbruggen"). Protected cytosine 22 is halogenated at the
C2 position using a standard halogenation reagent under standard
conditions to yield 2-chloro-4N-protected-4-pyrimidineamine 24
Reaction with amine 6 followed by deprotection of the C4 exocyclic
amine and reaction with amine 10 yields a 2,4-pyrimidinediamine
according to structural formulae (I).
[0177] Alternatively, referring to Scheme (IIb), cytosine 20 may be
reacted with amine 10 or protected amine 21 to yield N4-substituted
cytosine 23 or 27, respectively. These substituted cytosines may
then be halogenated as previously described, deprotected (in the
case of N4-substituted cytosine 27) and reacted with amine 6 to
yield a 2,4-pyrimidinediamine according to structural formulae
(I).
[0178] Commercially-available cytosines that may be used as
starting materials in Schemes (IIa) and (IIb) include, but are not
limited to, cytosine (Aldrich #14,201-8; CAS Registry 71-30-7);
N.sup.4-acetylcytosine (Aldrich #37,791-0; CAS Registry
14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry
2022-85-7); and 5-(trifluoromethyl)-cytosine. Other suitable
cytosines useful as starting materials in Schemes (IIa) are
available from General Intermediates of Canada, Inc., Edmonton,
Calif. (www.generalintermediates.com) and/or Interchim, Cedex,
France (www.interchim.com), or may be prepared using standard
techniques, Myriad textbook references teaching suitable synthetic
methods are provided infra.
[0179] In still another exemplary embodiment, the
2,4-pyrimidinediamine compounds may be synthesized from substituted
or unsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme
(III), below: ##STR735##
[0180] In Scheme (III), R.sup.2, R.sup.4, R.sup.5, R.sup.6,
L.sup.1, L.sup.2 and X are as previously defined for Scheme (1) and
Z is a leaving group as discussed in more detail in connection with
Scheme IV, infra, Referring to Scheme (III), 2-amino-4-pyrimidinol
30 is reacted with amine 6 (or optionally protected amine 21) to
yield N2-substituted-4-pyrimidinol 32, which is then halogenated as
previously described to yield
N2-substituted-4-halo-2-pyrimidineamine 34, Optional deprotection
(for example if protected amine 21 was used in the first step)
followed by reaction with amine 10 affords a 2,4-pyrimidinediamine
according to structural formulae (I). Alternatively, pyrimidinol 30
can be reacted with acylating agent 31.
[0181] Suitable commercially-available 2-amino-4-pyrimidinols 30
that can be used as starting materials in Scheme (III) are
available from General Intermediates of Canada, Inc, Edmonton,
Calif. (www.generalintermediates.com) and/or Interchim, Cedex,
France (www.interchim.com), or may be prepared using standard
techniques. Myriad textbook references teaching suitable synthetic
methods are provided infra.
[0182] Alternatively, the 2,4-pyrimidinediamine compounds may be
prepared from substituted or unsubstituted 4-amino-2-pyrimidinols
as illustrated in Scheme (IV), below: ##STR736##
[0183] In Scheme (IV), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1
and L.sup.2 awe as previously defined for Scheme (I) and Z
represents a leaving group. Referring to Scheme (IV), the
C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards
nucleophiles than the C4-amino such that reaction with amine 6
yields N2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction
with compound 44, which includes a good leaving group Z, or amine
10 yields a 2,4-pyrimidinediamine according to structural formulae
(I) Compound 44 may include virtually any leaving group that can be
displaced by the C4-amino of N2-substituted-2,4-pyrimidinediamine
42, Suitable leaving groups Z include, but are not limited to,
halogens, methanesulfonyloxy (mesyloxy; "OMs"),
trifluoromethanesulfonyloxy ("OTf") and p-toluenesulfonyloxy
(tosyloxy; "OTs"), benzene sulfonyloxy ("besylate") and metanitro
benzene sulfonyloxy ("nosylate"). Other suitable leaving groups
will be apparent to those of skill in the art.
[0184] Substituted 4-amino-2-pyrimidinol starting materials may be
obtained commercially or synthesized using standard techniques.
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0185] In still another exemplary embodiment, the
2,4-pyrimidinediamine compounds can be prepared from
2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as
illustrated in Scheme (V), below: ##STR737##
[0186] In Scheme (V), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1,
L.sup.2 and X are as defined for Scheme (I) and Z is as defined for
Scheme (IV). Referring to Scheme (V), 2-amino-4-chloropyrimidine 50
is reacted with amino 10 to yield 4N-substituted-2-pyrimidineamine
52 which, following reaction with compound 31 or amine 6, yields a
2,4-pyrimidinediamine according to structural formulae (I).
Alternatively, 2-chloro-4-amino-pyrimidine 54 may be reacted with
compound 44 followed by amine 6 to yield a compound according to
structural formulae (I).
[0187] A variety of pyrimidines 50 and 54 suitable for use as
starting materials in Scheme (V) are commercially available from
General Intermediates of Canada, Inc., Edmonton, Calif.
(www.generalintermediates.com) and/or Interchim, Cedex, France
(www.interchim.com), or may be prepared using standard techniques
Myriad textbook references teaching suitable synthetic methods are
provided infra.
[0188] Alternatively, 4-chloro-2-pyrimidineamines 50 may be
prepared as illustrated in Scheme (Va): ##STR738##
[0189] In Scheme (Va), R.sup.5 and R.sup.6 are as previously
defined for structural formulae (I). In Scheme (Va), dicarbonyl 53
is reacted with guanidine to yield 2-pyrimidineamine 51, Reaction
with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid
or urea hydrogen peroxide complex yields N-oxide 55, which is then
halogenated to give 4-chloro-2-pyrimidineamine 50. The
corresponding 4-halo-2-pyrimidineamines may be obtained by using
suitable halogenation reagents.
[0190] In yet another exemplary embodiment, the
2,4-pyrimidinediamine compounds can be prepared from substituted or
unsubstituted uridines as illustrated in Scheme (VI) below:
##STR739##
[0191] In Scheme (VI), R.sup.2, R.sup.4, R.sup.5, R.sup.6, L.sup.1,
L.sup.2 and X are as previously defined for Scheme (I) and the
superscript PG represents a protecting group, as discussed in
connection with Scheme (IIb). According to Scheme (VI), uridine 60
has a C4 reactive center such that reaction with amine 10 or
protected amine 21 yields N4-substituted cytidine 62 or 64,
respectively, Acid-catalyzed deprotection of N4-substituted 62 or
64 (when "PG" represents an acid-labile protecting group) yields
N4-substituted cytosine 28, which may be subsequently halogenated
at the C2-position and reacted with amine 6 to yield a
2,4-pyrimidinediamine according to structural formulae (I).
[0192] Cytidines may also be used as starting materials in an
analogous manner, as illustrated in Scheme (VII), below:
##STR740##
[0193] In Scheme (VII), R.sup.2, R.sup.4, R.sup.5, R.sup.6,
L.sup.1, L.sup.2 and X are as previously defined in Scheme (I) and
the superscript PG represents a protecting group as discussed
above. Referring to Scheme (VII, like uridine 60, cytidine 70 has a
C4 reactive center such that reaction with anine 10 or protected
amine 21 yields N4-substituted cytidine 62 or 64, respectively.
These cytidines 62 and 64 are then treated as previously described
for Scheme (VI) to yield a 2,4-pyrimidinediamine according to
structural formulae (I).
[0194] Although Schemes (VI) and (VII) are exemplified with
ribosylnucleosides, skilled artisans will appreciate that the
corresponding 2'-deoxyribo and 2',3'-dideoxyribo nucleosides, as
well as nucleosides including sugars or sugar analogs other than
ribose, would also work.
[0195] Numerous uridines and cytidines useful as starting materials
in Schemes (VI) and (VII) are known in the art, and include, by way
of example and not limitation, 5-trifluoromethyl-2'-deoxycytidine
(Chem, Sources #ABCR F07669; CAS Registry 66,384-66-5);
5-bromouridine (Chem. Sources Int'l 2000; CAS Registry 957-75-5);
5-iodo-2'-deoxyuridine (Aldrich #1-775-6; CAS Registry 54-42-2);
5-fluorouridine (Aldrich #32,937-1; CAS Registry 316-46-1);
5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);
5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry
70-00-8); 5-trifluoromethyl-2'-deoxyuridine (Chem. Sources Int'l
2000; CAS Registry 70-00-8). Additional uridines and cytidines that
can be used as starting materials in Schemes (VI) and (VII) are
available from General Intermediates of Canada, Inc., Edmonton,
Calif. (www.generalintermediates.com) and/or Interchim, Cedex,
France (www.interchim.com), or may be prepared using standard
techniques. Myriad textbook references teaching suitable synthetic
methods are provided infra.
[0196] As will be recognized by skilled artisans, certain
2,4-pyrimidinediamines compounds synthesized via the exemplary
methods described above, or by other well-known means, may also be
utilized as starting materials and/or intermediates to synthesize
additional 2,4-pyrimidinediamine compounds. A specific example is
illustrated in Scheme (VIII), below: ##STR741##
[0197] In Scheme (VIII), R.sup.4, R.sup.5, R.sup.6, L.sup.1,
L.sup.2, Y, R.sup.a and R.sup.c are as previously defined for
structural formulae (I). Each R.sup.a' is independently an R.sup.5,
and may be the same or different from the illustrated R.sup.a.
Referring to Scheme (VIII), carboxylic acid or ester 100 may be
converted to amide 104 by reaction with amine 102. In amine 102,
R.sup.a' may be the same or different than R.sup.a of acid or ester
100. Similarly, carbonate ester 106 may be converted to carbamate
108.
[0198] A second specific example is illustrated in Scheme (IX),
below: ##STR742##
[0199] In Scheme (IX) R.sup.4, R.sup.5, R.sup.6, L.sup.2, Y and
R.sup.c are as previously defined for structural formulae (I).
Referring to Scheme (IX), amide 110 or 116 may be converted to
amine 114 or 118, respectively, by borane reduction with borane
methylsulfide complex 112. Other suitable reactions for
synthesizing 2,4-pyrimidinediamine compounds from
2,4-pyrimidinediamine starting materials will be apparent to those
of skill in the art.
[0200] Compounds including alkyl groups at the amine groups at the
2- and/or 4-position of the 2,4-pyrimidinediamine ring can be
prepared using routine alkylation procedures. An exemplary scheme
for selectively methylating the amine group at the 4-position of
the 2,4-pyrimidinediamine is illustrated in Scheme (XII):
##STR743##
[0201] In Scheme (XII), L.sup.1, L.sup.2, R.sup.2, R.sup.4, R.sup.5
and R.sup.6 are as previously defined for structural formula (I).
The above Scheme can be routinely adapted to synthesize other
N-alkylated compounds.
[0202] Compounds that are entiomerically or diasteriomerically pure
can be synthesized via chiral-specific syntheses utilizing
enantiomerically or diasteriomerically pure starting reagents as is
known in the art. Alternatively, specified enantiomers,
diastereomers and/or mixtures thereof can be isolated utilizing
conventional chiral separation techniques.
[0203] Although many of the synthetic schemes discussed above do
not illustrate the use of protecting groups, skilled artisans will
recognize that in some instances certain substituents, such as, for
example, R.sup.2 and/or R.sup.4, may include functional groups
requiring protection. The exact identity of the protecting group
used will depend upon, among other things, the identity of the
functional group being protected and the reaction conditions used
in the particular synthetic scheme, and will be apparent to those
of skill in the art Guidance for selecting protecting groups and
chemistries for their attachment and removal suitable for a
particular application can be found, for example, in Greene &
Wuts, supra.
[0204] Prodrugs as described herein may be prepared by routine
modification of the above-described methods, Alternatively, such
prodrugs may be prepared by reacting a suitably protected
2,4-pyrimidinediamine of structural formula (I), (II), (III), (IV)
and/or (V) with a suitable progroup. Conditions for carrying out
such reactions and for deprotecting the product to yield a prodrugs
as described herein are well-known.
[0205] Myriad references teaching methods useful for synthesizing
pyrimidines generally, as well as starting materials described in
Schemes (I)-(IX), are known in the art. For specific guidance, the
reader is referred to Brown, D. J., "The Pyrimidines", in The
Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A.,
Ed.), 1962, Interscience Publishers, (A Division of John Wiley
& Sons), New York ("Brown I"); Brown, D. J., "The Pyrimidines",
in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I
(Weissberger, A. and Taylor, E. C., Ed.), 1970, Wiley-Interscience,
(A Division of John Wiley & Sons), New York (Brown II"); Brown,
D. J., "The Pyrimidines", in The Chemistry of Heterocyclic
Compounds, Volume 16, Supplement II (Weissberger, A, and Taylor, E.
C., Ed.), 1985, An Interscience Publication (John Wiley &
Sons), New York ("Brown III"); Brown, D. J., "The Pyrimidines" in
The Chemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A.
and Taylor; E. C., Ed.), 1994, John Wiley & Sons, Inc., New
York, pp. 1-1509 (Brown IV"); Kenner, G. W. and Todd, A., in
Heterocyclic Compounds, Volume 6, (Elderfield, R. C., Ed.), 1957,
John Wiley, New York, Chapter 7 (pyrimidines); Paquette, L, A.,
Principles of Modern Heterocyclic Chemistry, 1968, W. A. Benjamin,
Inc., New York, pp. 1-401 (uracil synthesis pp. 313, 315;
pyrimidine synthesis pp. 313-316; amino pyrimidine synthesis pp.
315); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic
Chemistry, 3.sup.rd Edition, 1995, Chapman and Hall, London, U-K,
pp. 1-516; Vorbruggen, H. and Ruh-Pohlenz, C., Handbook of
Nucleoside Synthesis, John Wiley & Sons, New York, 2001, pp.
1-631 (protection of pyrimidines by acylation pp. 90-91; silylation
of pyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G.
F., Heterocyclic Chemistry, 4.sup.th Edition, 2000, Blackwell
Science, Ltd, Oxford, UK., pp. 1-589; and Comprehensive Organic
Synthesis, Volumes 1-9 (Trost, B. M. and Fleming, I., Ed.), 1991,
Pergamon Press, Oxford, UK.
[0206] 5.4 Activity of the Antiproliferative Compounds
[0207] Active 2,4-pyrimidinediamine compounds typically inhibit
proliferation of desired cells, such as tumor cells, with an
IC.sub.50 in the range of about 1 mM or less, as measured in a
standard in vitro cellular proliferation assay. Of course, skilled
artisans will appreciate that compounds which exhibit lower
IC.sub.50s, for example on the order of 100 P, 20 .mu.M, 10 .mu.M,
1 .mu.M, 100 nM, 10 mM, 1 nM, or even lower, may be particularly
useful in therapeutic applications. The antiproliferative activity
may be cytostatic or it may be cytotoxic. In instances where
antiproliferative activity specific to a particular cell type is
desired, the compound may be assayed for activity with the desired
cell type and counter-screened for a lack of activity against other
cell types. The desired degree of "inactivity" in such counter
screens, or the desired ratio of activity vs. inactivity may vary
for different situations, and may be selected by the user.
[0208] 5.5 Uses of the Antiproliferative Compounds
[0209] The antiproliferative 2,4-pyrimidinediamine compounds,
including the various salts, prodrugs, hydrates and N-oxide forms
thereof, may be used to inhibit cell proliferation in a variety of
contexts. According to some embodiments of the method, a cell or
population of cells is contacted with an amount of such a compound
effective to inhibit proliferation of the cell or cell population.
The compound may act cytotoxically to kill the cell, or
cytostatically to inhibit proliferation without killing the
cell.
[0210] In some embodiments, the methods may be practiced as a
therapeutic approach towards the treatment of proliferative
disorders. Thus, in a specific embodiment, the
2,4-pyrimidinediamine compounds (and the various forms described
herein) may be used to treat proliferative disorders in animal
subjects, including humans. The method generally comprises
administering to the subject an amount of a compound of the
invention, or a salt, prodrug, hydrate or N-oxide thereof,
effective to treat the disorder. In one embodiment, the subject is
a mammal, including, but not limited to, bovine, horse, feline,
canine, rodent, or primate. In another embodiment, the subject is a
human.
[0211] A variety of cellular proliferative disorders may be treated
with the compounds of the present invention. In one embodiment, the
compounds are used to treat various cancers in afflicted subjects.
Cancers are traditionally classified based on the tissue and cell
type from which the cancer cells originate. Carcinomas are
considered cancers arising from epithelial cells while sarcomas are
considered cancers arising from connective tissues or muscle. Other
cancer types include leukemias, which arise from hematopoietic
cells, and cancers of nervous system cells, which arise from neural
tissue. For non-invasive tumors, adenomas are considered benign
epithelial tumors with glandular organization while chondomas are
benign tumor arising from cartilage. In the present invention, the
described compounds may be used to treat proliferative disorders
encompassed by carcinomas, sarcomas, leukemias, neural cell tumors,
and non-invasive tumors.
[0212] In a specific embodiment, the compounds are used to treat
solid tumors arising from various tissue types, including, but not
limited to, cancers of the bone, breast, respiratory tract (e.g.,
bladder), brain reproductive organs, digestive tract, urinary
tract, eye, liver, skin, head, neck, thyroid, parathyroid, and
mestastatic forms thereof.
[0213] Specific proliferative disorders include the following: a)
proliferative disorders of the breast include, but are not limited
to, invasive ductal carcinoma, invasive lobular carcinoma, ductal
carcinoma, lobular carcinoma in situ, and metastatic breast cancer;
b) proliferative disorders of the skin include, but are not limited
to, basal cell carcinoma, squamous cell carcinoma, malignant
melanoma, and Karposi's sarcoma; c) proliferative disorders of the
respiratory tract include, but are not limited to, small cell and
non-small cell lung carcinoma, bronchial adema, pleuropulmonary
blastoma, and malignant mesothelioma; d) proliferative disorders of
the brain include, but are not limited to, brain stem and
hyptothalamic glioma, cerebellar and cerebral astrocytoma,
medullablastoma, ependymal tumors, oligodendroglial, meningiomas,
and neuroectodermal and pineal tumors; e) proliferative disorders
of the male reproductive organs include, but are not limited to,
prostate cancer, testicular cancer, and penile cancer f)
proliferative disorders of the female reproductive organs include,
but are not limited to, uterine cancer (endometrial), cervical,
ovarian, vaginal, vulval cancers, uterine sarcoma, ovarian germ
cell tumor; g) proliferative disorders of the digestive tract
include, but are not limited to, anal, colon, colorectal,
esophageal, gallbladder, stomach (gastric), pancreatic cancer,
pancreatic cancer-Islet cell, rectal, small-intestine, and salivary
gland cancers; h) proliferative disorders of the liver include, but
are not limited to, hepatocellular carcinoma, cholangiocarcinioma,
mixed hepatocellular cholangiocarcinoma, and primary liver cancer;
i) proliferative disorders of the eye include, but are not limited
to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma; j)
proliferative disorders of the head and cancers include, but are
not limited to, laryngeal, hypopharyngeal, nasopharyngeal,
oropharyngeal cancers, and lip and oral cancer, squamous neck
cancer, metastatic paranasal sinus cancer; k) proliferative
disorders of the lymphomas include, but are not limited to, various
T cell and B cell lymphomas, non-Hodgkins lymphoma, cutaneous T
cell lymphoma, Hodgkins disease, and lymphoma of the central
nervous system; 1) leukemias include, but are not limited to, acute
myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic
leukemia, chronic myelogenous leukemia, and hair cell leukemia, m)
proliferative disorders of the thyroid include thyroid cancer,
thymoma, and malignant thymoma; n) proliferative disorders of the
urinary tract include, but are not limited to, bladder cancer; o)
sarcomas include, but are not limited to, sarcoma of the soft
tissue, osteosarcoma, malignant fibrous histiocytoma,
lymphosarcoma, and rhabdomyosarcoma.
[0214] It is to be understood that the descriptions of
proliferative disorders is not limited to the conditions described
above, but encompasses other disorders characterized by
uncontrolled growth and malignancy. It is further understood that
proliferative disorders include various metastatic forms of the
tumor and cancer types described herein. The compounds of the
present invention may be tested for effectiveness against the
disorders described herein, and a therapeutically effective regimen
established Effectiveness, as further described below, includes
reduction or remission of the tumor, decreases in the rate of cell
proliferation, or cytostatic or cytotoxic effect on cell
growth.
[0215] 5.6 Combination Therapies
[0216] The compounds of the present invention may be used alone, in
combination with one another, or as an adjunct to, or in
conjunction with, other established antiproliferative therapies.
Thus, the compounds of the present invention may be used with
traditional cancer therapies, such as ionization radiation in the
form of .gamma.-rays and x-rays, delivered externally or internally
by implantation of radioactive compounds, and as a follow-up to
surgical removal of tumors.
[0217] In another aspect, the compounds of the present invention
may be used with other chemotherapeutic agents useful for the
disorder or condition being treated. These compounds may be
administered simultaneously, sequentially, by the same route of
administration, or by a different route.
[0218] In one embodiment, the present compounds may be used with
other anti-cancer or cytotoxic agents. Various classes of
anti-cancer and anti-neoplastic compounds include, but are not
limited to, alkylating agents, antimetabolites, vinca alkyloids,
taxanes, antibiotics, enzymes, cytokines, platinum coordination
complexes, substituted ureas, tyrosine kinase inhibitors, hormones
and hormone antagonists. Exemplary alkylating agents include, by
way of example and not limitation, mechlorothamine,
cyclophosphamide, ifosfamide, melphalan, chlorambucil,
ethyleneimines, methylmelamines, alkyl sulfonates (egg, busulfan),
and carmustine. Exemplary antimetabolites include, by way of
example and not limitation, folic acid analog methotrexate;
pyrimidine analog fluorouracil, cytosine arbinoside; purine analogs
mercaptopurine, thioguanine, and azathioprine. Exemplary vinca
alkyloids include, by way of example and not limitation,
vinblastine, vincristine, paclitaxel, and colchicine. Exemplary
antibiotics include, by way of example and not limitation,
actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme
effective as anti-neoplastic agents include L-asparaginase.
Exemplary coordination compounds include, by way of example and not
limitation, cisplatin and carboplatin. Exemplary hormones and
hormone related compounds include, by way of example and not
limitation, adrenocorticosteroids prednisone and dexamethasone;
aromatase inhibitors amino glutethlimide, formestane, and
anastrozole; progestin compounds hydroxyprogesteron caproate,
medroxyprogesterone; and anti-estrogen compound tamoxifen.
[0219] These and other useful anti-cancer compounds are described
in Merck Index, 13th Ed, (O'Neil M. J, et al., ed) Merck Publishing
Group (2001) and Goodman and Gilmans The Pharmacological Basis of
Therapeutics, 10th Edition, Hardman, J. G. and Limbird, L. E. eds.,
pg. 1381-1287, McGraw Hill, (1996), both of which are incorporated
by reference herein.
[0220] Additional anti-proliferative compounds useful in
combination with the compounds of the present invention include, by
way of example and not limitation, antibodies directed against
growth factor receptors (erg, anti-Her2); antibodies for activating
T cells (e.g., anti-CTLA-4 antibodies); and cytokines such as
interferon-.alpha. and interferon-.gamma., interleukin-2, and
GM-CSF.
[0221] 5.7 Formulations and Administration
[0222] When used to treat or prevent such diseases, the active
compounds may be administered singly, as mixtures of one or more
active compounds or in mixture or combination with other agents
useful for treating such diseases and/or the symptoms associated
with such diseases. The active compounds may also be administered
in mixture or in combination with agents useful to treat other
disorders or maladies, such as steroids, membrane stabilizers. The
active compounds or prodrugs may be administered per se, or as
pharmaceutical compositions, comprising an active compound or
prodrug.
[0223] Pharmaceutical compositions comprising the active compounds
of the invention (or prodrugs thereof) may be manufactured by means
of conventional mixing, dissolving, granulating, dragee-making
levigating, emulsifying, encapsulating, entrapping or
lyophilization processes. The compositions may be formulated in
conventional manner using one or more physiologically acceptable
carriers, diluents, excipients or auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically (see Remington's Pharmaceutical Sciences,
15.sup.th Ed, Hoover, J. E. ed., Mack Publishing Co. (2003)
[0224] The active compound or prodrug may be formulated in the
pharmaceutical compositions per se, or in the form of a hydrate,
solvate, N-oxide or pharmaceutically acceptable salt, as previously
described Typically, such salts are more soluble in aqueous
solutions than the corresponding free acids and bases, but salts
having lower solubility than the corresponding free acids and bases
may also be formed.
[0225] Pharmaceutical compositions of the invention may take a form
suitable for virtually any mode of administration, including, for
example, topical, ocular, oral, buccal, systemic, nasal, injection,
transdermal, rectal, vaginal, etc., or a form suitable for
administration by inhalation or insufflation.
[0226] For topical administration, the active compound(s) or
prodrug(s) may be formulated as solutions, gels, ointments, creams,
suspensions, etc, as are well-known in the art.
[0227] Systemic formulations include those designed for
administration by injection, e.g., subcutaneous, intravenous,
intramuscular, intrathecal or intraperitoneal injection, as well as
those designed for transdermal, transmucosal oral or pulmonary
administration.
[0228] Useful injectable preparations include sterile suspensions,
solutions or emulsions of the active compound(s) in aqueous or oily
vehicles. The compositions may also contain formulating agents,
such as suspending, stabilizing and/or dispersing agent. The
formulations for injection may be presented in unit dosage form,
e.g., in ampules or in multidose containers, and may contain added
preservatives.
[0229] Alternatively, the injectable formulation may be provided in
powder form for reconstitution with a suitable vehicle, including
but not limited to sterile pyrogen free water, buffer, dextrose
solution, etc., before use. To this end, the active compound(s) may
be dried by any art-known technique, such as lyophilization, and
reconstituted prior to use.
[0230] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are known in the art.
[0231] For oral administration, the pharmaceutical compositions may
take the form of, for example, lozenges, tablets or capsules
prepared by conventional means with pharmaceutically acceptable
excipients such as binding agents (e.g., pregelatinised maize
starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose);
fillers (e.g., lactose, microcrystalline cellulose or calcium
hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or
silica); disintegrants (e.g., potato starch or sodium starch
glycolate); or wetting agents (e.g., sodium lauryl sulfate,
lecithin). The tablets may be coated by methods well known in the
art with, for example, sugars, films or enteric coatings.
[0232] Liquid preparations for oral administration may take the
form of, for example, elixirs, solutions, syrups or suspensions, or
they may be presented as a dry product for constitution with water
or other suitable vehicle before use. Such liquid preparations may
be prepared by conventional means with pharmaceutically acceptable
additives such as suspending agents (e.g., sorbitol syrup,
cellulose derivatives or hydrogenated edible fats); emulsifying
agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g.,
almond oil, oily esters, ethyl alcohol, cremophore.TM. or
fractionated vegetable oils); and preservatives (e.g., methyl or
propyl-p-hydroxybenzoates or sorbic acid). The preparations may
also contain buffer salts, preservatives, flavoring, coloring and
sweetening agents as appropriate.
[0233] Preparations for oral administration may be suitably
formulated to give controlled release of the active compound or
prodrug, as is well known.
[0234] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0235] For rectal and vaginal routes of administration, the active
compound(s) may be formulated as solutions (for retention enemas)
suppositories or ointments containing conventional suppository
bases such as cocoa butter or other glycerides.
[0236] For nasal administration or administration by inhalation or
insufflation, the active compound(s) or prodrug(s) can be
conveniently delivered in the form of an aerosol spray from
pressurized packs or a nebulizer with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other
suitable gas. In the case of a pressurized aerosol, the dosage unit
may be determined by providing a valve to deliver a metered amount.
Capsules and cartridges for use in an inhaler or insufflator (for
example capsules and cartridges comprised of gelatin) may be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch.
[0237] For ocular administration, the active compound(s) or
prodrug(s) may be formulated as a solution, emulsion, suspension,
etc, suitable for administration to the eye. A variety of vehicles
suitable for administering compounds to the eye are known in the
art. Specific none limiting examples are described in U.S. Pat. No.
6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S.
Pat. No. 5,800,807; U.S. Pat. No. 5,776,445; U.S. Pat. No.
5,698,219; U.S. Pat. No. 5,521,222; U.S. Pat. No. 5,403,841; U.S.
Pat. No. 5,077,033; U.S. Pat. No. 4,882,150; and U.S. Pat. No.
4,738,851.
[0238] For prolonged delivery, the active compound(s) or prodrug(s)
can be formulated as a depot preparation for administration by
implantation or intramuscular injection. The active ingredient may
be formulated with suitable polymeric or hydrophobic materials
(e.g., as an emulsion in an acceptable oil) or ion exchange resins,
or as sparingly soluble derivatives, e.g., as a sparingly soluble
salt. Alternatively, transdermal delivery systems manufactured as
an adhesive disc or patch which slowly releases the active
compound(s) for percutaneous absorption may be used. To this end,
permeation enhancers may be used to facilitate transdermal
penetration of the active compound(s), Suitable transdermal patches
are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.
No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168;
U.S. Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No.
5,164,189; U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S.
Pat. No. 5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No.
4,921,475.
[0239] Alternatively, other pharmaceutical delivery systems may be
employed. Liposomes and emulsions are well-known examples of
delivery vehicles that may be used to deliver active compound(s) or
prodrug(s). Certain organic solvents such as dimethylsulfoxide
(DMSO) may also be employed, although usually at the cost of
greater toxicity.
[0240] The pharmaceutical compositions may, if desired, be
presented in a pack or dispenser device which may contain one or
more unit dosage forms containing the active compound(s). The pack
may, for example, comprise metal or plastic foil, such as a blister
pack. The pack or dispenser device may be accompanied by
instructions for administration.
[0241] 5.8 Effective Dosages
[0242] The active compound(s) or prodrug(s) of the invention, or
compositions thereof will generally be used in an amount effective
to achieve the intended result, for example in an amount effective
to treat or prevent the particular disease being treated. The
compound(s) may be administered therapeutically to achieve
therapeutic benefit. By therapeutic benefit is meant eradication or
amelioration of the underlying disorder being treated and/or
eradication or amelioration of one or more of the symptoms
associated with the underlying disorder such that the patient
reports an improvement in feeling or condition, notwithstanding
that the patient may still be afflicted with the underlying
disorder. Therapeutic benefit also includes halting or slowing the
progression of the disease, regardless of whether improvement is
realized.
[0243] The amount of compound administered will depend upon a
variety of factors, including, for example, the particular
indication being treated, the mode of administration, the severity
of the indication being treated and the age and weight of the
patient, the bioavailability of the particular active compound,
etc. Determination of an effective dosage is well within the
capabilities of those skilled in the art.
[0244] Effective dosages may be estimated initially from in vitro
assays. For example, an initial dosage for use in animals may be
formulated to achieve a circulating blood or serum concentration of
active compound that is at or above an IC.sub.50 of the particular
compound as measured in an in vitro assay, such as the in vitro
assays described in the Examples section. Calculating dosages to
achieve such circulating blood or serum concentrations talking into
account the bioavailability of the particular compound is well
within the capabilities of skilled artisans. For guidance, the
reader is referred to Fingl & Woodbury, "General Principles,"
In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics,
Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the
references cited therein.
[0245] Initial dosages may also be estimated from in vivo data,
such as animal models. Animal models useful for testing the
efficacy of compounds to treat or prevent the various diseases
described above are well-known in the art. Dosage amounts will
typically be in the range of from about 0.0001 or 0.001 or 0.01
mg/kg/day to about 100 mg/kg/day, but may be higher or lower,
depending upon, among other factors, the activity of the compound,
its bioavailability, the mode of administration and various factors
discussed above. Dosage amount and interval may be adjusted
individually to provide plasma levels of the compound(s) which are
sufficient to maintain therapeutic or prophylactic effect. For
example, the compounds may be administered once per week, several
times per week (e.g., every other day), once per day or multiple
times per day, depending upon, among other things, the mode of
administration, the specific indication being treated and the
judgment of the prescribing physician. In cases of local
administration or selective uptake, such as local topical
administration, the effective local concentration of active
compound(s) may not be related to plasma concentration Skilled
artisans will be able to optimize effective local dosages without
undue experimentation.
[0246] Preferably, the compound(s) will provide therapeutic or
prophylactic benefit without causing substantial toxicity. Toxicity
of the compound(s) may be determined using standard pharmaceutical
procedures. The dose ratio between toxic and therapeutic (or
prophylactic) LD.sub.50/ED.sub.50 effect is the therapeutic index
(LD.sub.50 is the dose lethal to 50% of the population and
ED.sub.50 is the dose therapeutically effective in 50% of the
population). Compounds(s) that exhibit high therapeutic indices are
preferred.
[0247] 5.9 Kits
[0248] The compounds and/or prodrugs described herein may be
assembled in the form of kits. In some embodiments, the kit
provides the compound(s) and reagents to prepare a composition for
administration. The composition may be in a dry or lyophilized
form, or in a solution, particularly a sterile solution. When the
composition is in a dry form, the reagent may comprise a
pharmaceutically acceptable diluent for preparing a liquid
formulation. The kit may contain a device for administration or for
dispensing the compositions, including, but not limited to syringe,
pipette, transdermal patch, or inhalant.
[0249] The kits may include other therapeutic compounds for use in
conjunction with the compounds described herein. In some
embodiments, the therapeutic agents are other anti-cancer and
anti-neoplastic compounds. These compounds may be provided in a
separate form, or mixed with the compounds of the present
invention.
[0250] The kits will include appropriate instructions for
preparation and administration of the composition, side effects of
the compositions, and any other relevant information. The
instructions may be in any suitable format, including, but not
limited to, printed matter, videotape, computer readable disk, or
optical disc.
6. EXAMPLES
6.1 In vitro Cellular Experiments
[0251] The compounds illustrated in TABLES 1-14, supra, were
synthesized using the methods described herein. Salts of the
compounds were prepared using standard techniques.
[0252] The IC.sub.50 values of various compounds against a various
different tumor cell lines were determined using standard in vitro
antiproliferation assays. The tumor cell lines tested were as
follows: A549 (lung); H1299 (lung), ACHN (kidney/p53 wt), CAKI
(renal cell carcinoma), NCI-H460 (lung); HCT116 (colon/p53 wt);
HELA (cervix/p53 wt), HUH7 (liver/p53 wt), HUVEC (primary
endothelial), LNCAP (prostate), HT-29 (colon); MCF-7 (breast);
MCF-7 (breast/ER positive), MDA MB435S (breast); MDA MB231
(breast/ER negative), DU145 (prostate); BxPC-3 (pancreatic); SKOV-3
(ovarian); HepG2 (hepatic), NDHF primary normal human dermal
fibroblast), SKMEL28 (breast/p53mut), SKMEL5 (breast/p53 wt), U2OS
(bone) and PCS3 (prostate). The activity of the compounds against
A549 cells and H1299 cells is reported in TABLES 1-14, supra. In
the tables, a "+" indicates an IC.sub.50 of 20 .mu.M or less, a "-"
indicates an IC.sub.50 of >20 .mu.M. A value of "-/+" indicates
that the specific compound exhibited an IC.sub.50 of .gtoreq.20
.mu.M in a 3-point assay, but exhibited an IC.sub.50 of .ltoreq.20
.mu.M in a higher-point (e.g., 6-point) assay. A value of "+/-"
indicates that the specific compound exhibited an IC.sub.50 of
.ltoreq.20 .mu.M in a 3-point assay, but exhibited an IC.sub.50 of
>20 .mu.M in a higher-point (e.g., 6-point) assay. A blank
indicates the specified compound was not tested against the
specified cell line. Many of the compounds tested exhibited IC50s
against A549 and/or H1299 cells in the nanomolar range.
[0253] Many of the compounds were tested against other cell lines.
Their activity is reported in TABLE 15, below, where +", "-", "-/+"
or "+/-" values are as described for TABLES 1-14. Where the cell
line includes a value in a parenthetical, the value indicates the
seeding density at which the assay was performed TABLE-US-00015
TABLE 15 No ACHN CAKI HCT116 HELA HUH7 HUVEC LNCAP MCF7(2K)
MCF7(4K) 254 256 300 + 697 + 699 710 + 717 - 493 -/+ 494 + 534 +
626 + 495 + 629 + 631 + 632 + 633 + 634 - 496 - 497 - 732 + 500 +
636 - 742 501 502 746 747 642 748 643 749 750 751 752 503 + 753 754
755 + 504 + 506 - 507 - 508 509 644 + 645 + 510 761 762 763 764 765
511 512 + - + + + + 766 767 646 + + - + + + + 647 + 649 - + + + +
516 + 523 + - + + + + 790 651 - 652 - 305 + 306 - 307 + 835 + + 309
+ 310 + 311 + 312 + 313 -/+ 314 -/+ 838 - 527 + 528 + 839 + 841 +
529 + 845 + 846 + + + + 847 + 848 + 654 + + 851 + + 858 + + + + +
868 + + + 869 + 933 + 938 940 + 580 581 + 942 + + + + + + + 947 948
949 + 950 + 954 955 956 957 958 959 960 961 962 355 - + 356 - 676
677 - 358 -/+ 359 +/- + 978 979 + 980 + 981 982 983 984 985 986 987
418 101 + + + 102 + + + 103 + + + 991 + 104 - 105 + 106 + + + 107 +
+ - + + + + + + 419 + 420 - 110 + 111 + 112 + 113 + 114 + 432 + 435
+ 436 + 211 + + + + 125 + + + + 141 + + + + 1006 + 1007 - 1009 + No
MDA-MB-231(2K) MDA-MB-231(4K) NDHF PC3 SKMEL28 SKMEL5 U20S 254 +
256 + 300 697 699 - 710 717 493 494 534 626 495 629 631 632 633 634
496 497 732 500 - 636 742 + 501 - 502 - 746 - 747 + 642 + 748 - 643
- 749 - 750 + 751 - 752 - 503 - 753 - 754 - 755 504 506 507 508 -
509 - 644 - 645 - 510 - 761 - 762 + 763 - 764 - 765 + 511 + 512 + -
+ + + 766 - 767 - 646 + + + + 647 649 + + 516 + 523 + + + + 790 +
651 652 305 306 307 835 + 309 310 311 312 313 314 838 527 528 839
841 529 845 846 + + 847 848 654 + + 851 + 858 + + + + + 868 + + +
869 + +
933 938 - 940 + 580 - 581 942 + + + + 947 + 948 + 949 + + 950 + 954
- 955 - 956 - 957 + 958 - 959 - 960 - 961 - 962 - 355 + 356 676 +
677 358 359 978 - 979 - 980 - 981 + 982 - 983 - 984 + 985 - 986 -
987 + 418 + 101 + + 102 + + 103 + + 991 104 105 106 + + 107 + + + +
+ + 419 420 110 111 112 113 114 432 435 436 211 + + 125 + + 141 + +
1006 1007 1009
6.2 In Vivo Xenograft Experiments
[0254] Compounds 107, 858, 164, 211 and 156 were tested for their
ability to shrink tumors generated from A549 cells in standard
xenograft experiments. Compounds 141 and 211 were tested against
H1299 tumors. When palpable tumors appeared and were of a
preselected volume (approximately 40-150 mm.sup.3), the mice were
administered test compounds as specified in TABLE 16, below.
Preliminary results are reported in TABLE 16, TABLE-US-00016 TABLE
16 Test Preliminary Compound Cell Type Dose Dose Schedule
Formulation Comments Results 107 A549 40 mg/kg 3x a day for 4
Liposome No No significant days followed by Vehicle (DMPC)
precipitation reduction in 5 days rest. was noted tumor size 107
A549 25 mg/kg and Bid, daily 16% Cremophor/ Compound No significant
50 mg/kg And 16% EtOH/ crashed out of reduction in Bid 4 days w/8
68% Saline solution when tumor size seen days rest saline was with
either added dose 858 A549 25 mg/kg Bid, daily 5% EtOH/ No No
significant 15% Cremophor/ precipitation reduction in 80% Saline
was noted tumor size seen 164, 211 A549 25 mg/kg R563-5 days bid
100% DMSO No 23.2% with 2 days of precipitation reduction in rest
was noted tumor size in R565 - bid, daily mice treated with 211.
Compound 164 showed no significant reduction in tumor size. 141,
211 H1299 25 mg/kg Bid, daily 100% DMSO Compound 141 No significant
precipitated out reduction in on day 2. tumor size was Compound was
seen with prepared fresh either for days 3, 4, compound. and 5. No
precipitation was noted for Compound 211 156 A549 25 mg/kg and Bid,
daily 0.9% Saline No 60.4% 50 mg/kg precipitation reduction in was
noted tumor size was observed in mice treated with 50 mg/kg. No
significant reduction was seen at the lower dose.
[0255] Although the foregoing inventions have been described in
some detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
[0256] It is to be understood that when ranges of integers are
described herein, the description is intended to include the
endpoints and each intervening integer as though each integer were
explicitly delineated. As a specific example, the description "an
integer from 1 to 6," is intended to explicitly describe 1, 2, 3,
4, 5 and 6.
[0257] All literature and patent references cited throughout the
application are incorporated by reference into the application for
all purposes.
* * * * *