Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-14
2004-10-05
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S204000
Reexamination Certificate
active
06800653
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the fields of organic synthesis, medicinal chemistry, cancer chemotherapeutic agents and cancer chemotherapy. Specifically, the invention relates to microtubule-stabilizing antitumor compounds of the epothilone class.
BACKGROUND OF THE INVENTION
Epothilones are macrolide compounds which find utility in the pharmaceutical field. For example, Epothilones A and B having the structures:
have been found to exert microtubule-stabilizing effects similar to TAXOL™ and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease; see Hofle et al.,
Angew. Chem. Int. Ed. Engl.,
1996, 35:1567-1569.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula I and formula II:
Q is selected from the group consisting of
G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo,
L is O, S, SO, SO
2
or NR
13
or CR
14
R
15
;
W is O or NR
16
;
X is O, S, CHR
17
or H, R
18
;
Z is O; S; H, R
19
or R
20
, R
21
;
Y is selected from the group consisting of O; H, H; H, OR
22
; OR
23
, OR
23
; NOR
24
; H, NOR
25
; H, NR
26
R
27
; NHNR
28
R
29
; H, NHNR
30
R
31
; or CHR
32
; where OR
23
, OR
23
can be a cyclic ketal;
B
1
and B
2
are selected from the group consisting of H, OR
33
, OCOR
34
, OCONR
35
R
36
, NR
37
R
38
or NR
39
CONR
40
R
41
;
D is selected from the group consisting of NR
42
R
43
or heterocyclo;
M is selected from the group consisting of S, C═O, S═O, SO
2
, NR
44
, or CR
45
R
46
;
J, E, U, and V are selected from carbon, oxygen, nitrogen or sulfur; or V may be absent;
R
1
, R
2
, R
3
, and R
4
, are selected from H, lower alkyl;
R
5
, R
8
, R
9
, R
10
and R
11
are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo;
R
6
and R
7
are selected from the group consisting of H, alkyl, substituted alkyl, halogen, nitro, cyano, OR
47
, NR
48
R
49
, R
50
C═O;
R
17
, R
18
, R
22
and R
23
are selected from the group consisting of H, alkyl, and substituted alkyl;
R
20
, R
21
, R
24
, R
25
, R
26
, R
28
, R
30
, R
32
, R
33
, R
34
, R
35
, R
36
, R
37
, R
39
, R
40
, R
41
, R
42
, R
47
, R
48
, R
50
, R
52
, R
53
, R
54
, R
56
, R
57
, R
58
, R
59
, R
61
, R
62
, R
64
, and R
65
are selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl; heterocyclo or substituted heterocyclo;
R
63
is H, alkyl having 2 to 20 carbon atoms, substituted alkyl, aryl, substituted aryl; heterocyclo or substituted heterocyclo;
or R
62
and R
63
, together with the nitrogen atom to which they are attached, form a heterocycle or substituted heterocycle;
R
51
is heterocyclo or substituted heterocyclo;
R
12
, R
13
, R
16
, R
27
, R
29
, R
31
, R
38
, R
43
, R
49
, R
55
and R
60
are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R
51
C═O, R
52
OC═O, R
53
SO
2
, hydroxy, O-alkyl or O-substituted alkyl; when X is O then R
16
is not R
51
C═O, R
52
OC═O, and R
53
SO
2
; and wherein R
44
is further amino and R
61
R
64
NC═O;
R
44
is R
51
C═O, R
62
R
63
NSO
2
, or (C═O)—(C═O)—R
65
;
R
14
and R
15
are selected from the group consisting of H, halogen, alkyl, or substituted alkyl;
R
19
is selected from the group consisting of H, alkyl, substituted alkyl, O-alkyl, O-substituted alkyl, NR
54
R
55
, R
56
C═O; when L is O, S, or NR
13
then R
19
is not O-alkyl, O-substituted alkyl, NR
54
R
55
.
R
45
and R
46
are selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R
56
C═O, R
57
OC═O, R
58
NHC═O, hydroxy, O-alkyl or O-substituted alkyl, NR
59
R
60
;
and any salts, solvates or hydrates thereof, with the proviso that
when Q is
M is CR
45
R
46
then W is only NR
16
.
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Borzilleri Robert M.
Kim Soong-Hoon
Regueiro-Ren Alicia
Vite Gregory D.
Bristol-Myers Squibb Compnay
Lambkin Deborah C.
Winslow Anastasia P.
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