Oxazoline antiproliferative agents

Details Oxazoline antiproliferative agents Oxazoline antiproliferative agents

1999-07-23

2001-05-08

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S314000, C514S340000, C514S374000, C546S121000, C546S166000, C546S167000, C546S209000, C548S237000, C548S239000

Reexamination Certificate

active

06228868

ABSTRACT:

TECHNICAL FIELD
The present invention relates to substituted oxadiazolines which are 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 are characterized by the proliferation of cells which are not subject to normal cell growth and are a major cause of death in humans and other mammals. Cancer chemotherapy has not only provided new and more effective drugs to treat these diseases but has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton are effective in inhibiting the proliferation of neoplastic cells.
The microtubule system of eucaryotic cells is a major component of the cytoskeleton and is a dynamic assembly and disassembly wherein heterodimers of tubulin are polymerized and form microtubule. Microtubules play a key role in the regulation of cell architecture, metabolism, and division and in their dynamic state are critical to normal cell function. With respect to cell division, tubulin is polymerized into microtubules that form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Accordingly, agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis, comprise some of the most effective cancer chemotherapeutic agents in clinical use. Thus agents which have the ability to disrupt the microtubule system are useful for cancer treatment.
Certain cryptophycin compounds are disclosed in U.S. Pat. Nos. 4,946,835, 4,845,085, 4,845,086, and 4,868,208; however, compounds having greater metabolic stability and longer duration of action are desired for most therapeutic uses. Thus there is still a need for compounds which inhibit mitosis.
SUMMARY OF THE INVENTION
In one embodiment of the invention is disclosed compounds having Formula I
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R
A
, R
B
, and R
C
are independently selected from the group consisting of
(1) alkyl,
(2) alkoxy,
and
(3) thioalkoxy;
R
D
and R
E
are independently selected from the group consisting of
(1) hydrogen
and
(2) alkyl;
R
2
is selected from the group consisting of
(1) aryl,
(2) heterocycle,
wherein (1) and (2) can be optionally substituted with one, two, three, four, or five substituents independently selected from -L R
6
wherein L
1
is selected from the group consisting of
(a) a covalent bond,
(b) —C(X)—, wherein X is O or S,
(c) —S(O)
t
—, wherein t is 0, 1, or 2,
(d) —NR
3
—, wherein R
3
is selected from the group consisting of
(i) hydrogen,
(ii) carboxaldehyde,
(iii) alkanoyl,
(iv) alkoxycarbonyl,
(v) —C(O)OR
11
, wherein R
11
is alkyl which can be optionally substituted with one or two aryl substituents,
(vi) cycloalkyl,
(vii) alkyl, wherein the alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of
(1′) alkoxy,
(2′) cycloalkyl,
and
(3′) aryl, wherein the aryl can be optionally substituted with one or two substituents independently selected from the group consisting of
(a′) alkanoyloxy,
(b′) hydroxy,
and
(c′) alkoxy,
(viii) alkenyl,
(ix) alkynyl,
(x) —OR
5
wherein R
5
is selected from the group consisting of
(1′) hydrogen, and
(2′) alkyl, wherein the alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of
(a′) aryl,
(b′) cycloalkyl,
and
(c′) hydroxyl,
(xi) a nitrogen protecting group,
(xii) aryl,
and
(xiii) —C(O)R
13
, wherein R
13
is perfluoroalkyl,
(e) —O—,
(f) —X′C(X)—, wherein X is defined previously and X′ is O or S,
(g) —C(X)X
′
—,
(h) —N(R
3′
)C(O)N(R
4′
)— wherein R
3′
and R
4′
are independently selected from the
group consisting of
(i) hydrogen
and
(ii) alkyl,
(i) -N(R
3′
)C(X)—,wherein R
3′
is defined above,
(i) —C(X)N(R
3′
)—, wherein R
3′
is defined above,
(k) —NR
3′
S(O)
t
—, wherein R
3′
is defined above,
and
(l) —S(O)
t
NR
3′
— wherein t and R
3′
are defined above,
wherein (a)-(l) are drawn with their left ends attached to R
2
and their right ends attached to R., and R is selected from the group consisting of
(a) -CO
2
O
5
, wherein R
5
is defined above,
(b) —C(O)R
5
, wherein R
5
is defined above,
(c) —OC(O)R
10
, wherein R
10
is alkyl which can be optionally substituted with one or two substituents selected from the group consisting of
(i) alkoxy
and
(ii) hydroxy,
(d) cyano,
(e) nitro,
(f) —XH,
(g) halo,
(h) —S(O)
t′
NR
3
R
4
, wherein R
3
is defined above, t′ is one or two, and R
4
is selected from the group consisting of
(i) hydrogen,
(ii) carboxaldehyde,
(iii) alkanoyl,
(iv) —C(O)OR
10
, wherein R
10
is defined above,
(v) —C(O)OR
11
, wherein R
11
is defined above,
(vi) cycloalkyl,
(vii) alkyl, wherein the alkyl can be optionally substituted with one or two substituents independently selected from the group consisting of
(1′) —OR
10
, wherein R
10
is defined above,
(2′) cycloalkyl,
and
(3′) aryl, wherein the aryl can be optionally substituted with one or two substituents independently selected from the group consisting of
(a′) —OC(O)R , wherein R is defined above,
(b′) hydroxyl,
and
(c′)—OR
10
, wherein R
10
is defined above,
(viii) alkenyl,
(ix) alkynyl,
and
(x) —OR
5
, wherein R
5
is defined above,
(i) —NR
3
R
4
, wherein R
3
and R
4
are defined above,
(j) perfluoroalkyl,
(k) alkenyl,
(l) alkynyl,
(m) aryl,
(n) heterocycle,
(o) alkyl,
(p) cycloalkyl,
and
(q) ═X, wherein X is defined above,
wherein (k)-(o) can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of
(i) hydroxyl,
(ii) halo,
(iii) —OR
10
, wherein R
10
is defined above,
(iv) —SR
10
, wherein R
10
is defined above,
(v) —CO
2
R , wherein R
5
is defined above,
(vi) carboxaldehyde,
(vii) ═X, wherein X is defined above,
(viii) azido,
(ix) ═C(H)NR
3
R
4
, wherein R
3
and R
4
are defined above,
(x) cyano,
(xi) ═NOR
3
, wherein R
3
is defined above,
(xii) —NR
3
R
4
, wherein R
3
and R
4
are defined above,
(xiii) —S(O)
t′
NR
3
R
4
, wherein R
3
and R
4
are defined above,
(xiv) nitro,
(xv) aryl,
and
(xvi) heterocycle,
(4) cycloalkyl,
and
(5) cycloalkenyl,
wherein (4) and (5) can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of
(a) alkyl,
(b) hydroxyl,
and
(c) aryl.
In another embodiment of the invention are disclosed methods of treating cancer comprising administering an effective amount of a compound having Formula I.
In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
Compounds of the invention include, but are not limited to,
2-(4-dimethylaminophenyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(3-hydroxy-4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(3,5-dimethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(3-acetylindol-5-yl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(1-methylindol-5-yl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(indol-3-yl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(indol-2-yl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(1xindol-yl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(4-amino-3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(indol-5-yl )-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(4-amino-3-methylphenyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(3-hydroxy-4-methoxyphenyl)-4-dimethyl-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(N-methyl-tetrahydroquinol-6-yl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3-oxazoline,
2-(2-methyl-cyclopropyl)-5-(3,4,5-trimethoxyphenyl)-&Dgr;2,3

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