Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-26
2003-02-18
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S469000, C548S507000
Reexamination Certificate
active
06521658
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compounds useful for treating pathological states which arise from or are exacerbated by cell proliferation, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting cell proliferation in a mammal.
BACKGROUND OF THE INVENTION
Neoplastic diseases, characterized by the proliferation of cells which are not subject to normal cell proliferating controls, are a major cause of death in humans and other mammals. Cancer chemotherapy has provided new and more effective drugs to treat these diseases and has also demonstrated that drugs which disrupt microtubule synthesis are effective in inhibiting the proliferation of neoplastic cells.
Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The microtubule system of eucaryotic cells comprises a dynamic assembly and disassembly matrix in which heterodimers of tubulin polymerize to form microtubules in both normal and neoplastic cells. Within noeplastic cells, tubulin is polymerized into microtubules which form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Agents which disrupt the polymerization or depolymerization of microtubules in neoplastic cells, thereby inhibiting the proliferation of these cells, comprise some of the most effective cancer chemotherapeutic agents in use.
Because of the pivotal role played by cell proliferation, agents which inhibit microtubule polymerization have been the subject of active current research for their clinical potential. See, for example, U.S. Pat. Nos. 5,767,283, 5,721,246, 5,610,320, FR 2,729,421-A1, and WO96/27295. But there is still a need for tubulin polymerization-inhibiting compounds with modified or improved profiles of activity.
SUMMARY OF THE INVENTION
In one embodiment of the present invention are disclosed microtubule polymerization-inhibiting compounds represented by formula (I)
or pharmaceutically acceptable salts or prodrugs thereof, wherein
L
1
is selected from the group consisting of
(1) —S(O)
2
O—,
(2) —OS(O)
2
—,
(3) —NR
7
SO
2
—, wherein R
7
is selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amidinyl,
(d) a nitrogen-protecting group,
(e) alkanoyl,
(f) alkyl,
(g) alkenyl,
(h) alkynyl,
(i) cycloalkyl,
(j) cycloalkylalkyl,
(k) cycloalkenyl,
(l) cycloalkenylalkyl,
(m) aryloyl,
(n) alkoxy,
wherein (e)-(n) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(i) hydroxyl,
(ii) halo,
(iii) cyano,
(iv) azido,
(v) carboxy,
(vi) amidinyl,
(vii) alkyl,
(viii) aryl,
(ix) oxo,
(x) heteroaryl,
(xi) heterocycloalkyl,
(xii) —NR
c
R
d
, wherein R
c
and R
d
are independently selected from the group consisting of
(1′) hydrogen,
(2′) alkyl,
(3′) aryl, and
(4′) alkoxyalkyl, and
(xiii) -(alkylene)-NR
c
R
d
,
wherein for (x) and (xi), the heteroaryl and the heterocycloalkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(1′) alkyl, and
(2′) a nitrogen protecting group,
(o) heterocycloalkyloyl, wherein the heterocycloalkyloyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl, and
(ii) a nitrogen protecting group, and
(p) —(CH
2
)
x
NR
A
R
B
, wherein x is 0-6, and R
A
and R
B
are independently selected from the group consisting of
(i) hydrogen,
(ii) alkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
(vii) cycloalkenyl, and
(viii) cycloalkenylalkyl,
(4) —SO
2
NR
7
—, wherein R
7
is defined above,
(5) —S(O)CR
12
R
13
—, wherein R
12
and R
13
are independently selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) alkenyl, and
(d) alkynyl,
(6) —SO
2
CR
12
R
13
—,
(7) —SCR
12
R
13
—,
(8) —CR
12
R
13
S(O)—,
(9) —CR
12
R
13
SO
2
—, and
(10) —CR
12
R
13
S—,
wherein (1)-(10) are shown with their left ends attached to R
1
and their right ends attached to the phenyl ring;
R
1
is aryl or heteroaryl, wherein the aryl or the heteroaryl can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
(a) oxo,
(b) azido,
(c) carboxy,
(d) carboxaldehyde,
(e) cyano,
(f) halo,
(g) hydroxy,
(h) nitro,
(i) perfluoroalkyl,
(j) perfluoroalkoxy,
(k) alkyl,
(l) alkenyl,
(m) alkynyl,
(n) alkanoyloxy,
(o) alkoxycarbonyl,
(p) cycloalkyl,
(q) cycloalkylalkyl,
(r) cycloalkenyl,
(s) cycloalkenylalkyl,
(t) alkanoyl,
(u) alkoxy,
(v) cycloalkoxy,
(w) aryloxy,
(x) heteroaryloxy,
(y) thioalkoxy
(z) alkylsulfinyl,
(aa) alkylsulfonyl,
(bb) —NR
8
R
9
, wherein R
8
and R
9
are independently selected from the group consisting of
(i) hydrogen
(ii) alkyl,
(iii) arylalkyl, and
(iv) alkanoyl, wherein the alkanoyl can be optionally substituted with 1 or 2 substituents independently selected from the group consisting of
(1′) halo
(2′) hydroxy, and
(3′) —NR
10
R
11
wherein R
10
and R
11
are independently hydrogen or alkyl, and
(cc) —SO
2
NR
8
R
9
, wherein R
8
and R
9
are defined above;
R
2
and R
6
are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) alkoxy,
(4) thioalkoxy; and
(5) hydroxy, and
R
3
, R
4
, and R
5
are independently selected from the group consisting of
(1) alkyl,
(2) alkoxy,
(3) thioalkoxy, and
(4) hydroxy;
all of the foregoing with the proviso that combinations wherein L
1
is —NR
7
SO
2
— and R
1
is
(1) unsubstituted or substituted 1H-indoly-7-yl,
(2) phenyl which is 2-monosubstituted with —NR
8
R
9
,
(3) pyrid-3-yl which is 2-monosubstituted with —NR
8
R
9
, or
(4) pyrimidin-5-yl which is 4-monosubstituted with —NR
8
R
9
, are excluded therefrom.
In a preferred embodiment of the invention are compounds wherein L
1
is —SO
2
NR
7
—, and R
7
is defined above.
In another preferred embodiment of the invention are compounds wherein R
1
is aryl.
In another preferred embodiment of the invention are compounds wherein R
1
optionally substituted heteroaryl, particularly N-methyl substituted 1H-indolyl.
In another preferred embodiment of the invention are compounds wherein R
7
is substituted alkanoyl, substituted aryloyl, or optionally substituted heterocycloalkyloyl.
In another preferred embodiment of the invention are compounds wherein L
1
is —NR
7
SO
2
—, and R
7
is defined above.
In another preferred embodiemtn of the invention are compounds wherein L
1
is —SO
2
CR
12
R
13
—.
In another preferred embodiemtn of the invention are compounds wherein L
1
is —SCR
12
R
13
—.
In another preferred embodiemtn of the invention are compounds wherein L
1
is —CR
12
R
13
S(O)—.
In another preferred embodiemtn of the invention are compounds wherein L
1
is —CR
12
R
13
SO
2
—.
In another preferred embodiemtn of the invention are compounds wherein L
1
is —CR
12
R
13
S—.
In yet another preferred embodiment of the invention are compounds wherein L
1
is —OSO
2
—.
In still yet another preferred embodiment of the invention are compounds wherein L
1
is —SO
2
O—.
In another embodiment of the invention are disclosed methods of inhibiting polymerization of tubulin in a mammal in recognized need of such treatment comprising administering an effective amount of a compound having formula (I).
In yet another embodiment of the invention are disclosed methods of treating cancer in a mammal in recognized need of such treatment comprising administering an effective amount of a compound having formula (I).
In still yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds having formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
The term “alkanoyl,” as used herein, refers to an alkyl group attached to the parent molecular group through a carbonyl group. The alkanoyl groups of this invention can be optionally substituted.
The term “alkanoyloxy,” as used herein, refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
The term “alkenyl,” as used herein, refers to a mono
Barr Kenneth J.
Gwaltney, II Stephen L.
Imade Hovis M.
Li Qun
Rosenberg Saul
Abbott Laboratories
Donner B. Gregory
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