Antitumor compositions and methods of treatment

Details Antitumor compositions and methods of treatment Antitumor compositions and methods of treatment

1999-03-29

2001-01-16

Kumar, Shailendra (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S039000, C564S042000

Reexamination Certificate

active

06174921

ABSTRACT:

BACKGROUND OF THE INVENTION
In recent years fundamental advances have been made in the development of chemical agents and regimens of therapy to combat neoplastic diseases. Despite these continuing advances, cancers continue to exact intolerable levels of human pain and suffering. The need for new and better methods of treating neoplasms and leukemias continues to fuel efforts to find new classes of antitumor compounds, especially in the area of inoperable or metastatic solid tumors, such as the various forms of lung cancer. Of the one million new cases of cancer diagnosed in the United States each year, more than 90% represent non-hematopoetic tumors, where improvements in five-year survival rates have been modest, at best. B. E. Henderson, et al.,
Science,
254:1131-1137 (1991).
The recent avalanche of information regarding the basic biological processes involved in neoplasms has led to a deeper understanding of the heterogeneity of tumors. Ongoing work has led to the realization that individual tumors may contain many subpopulations of neoplastic cells that differ in crucial characteristics, such as karyotype, morphology, immunogenicity, growth rate, capacity to metastasize, and response to antineoplastic agents.
It is because of this extreme heterogeneity among populations of neoplastic cells that new chemotherapeutic agents should have a wide spectrum of activity and a large therapeutic index. In addition, such agents must be chemically stable and compatible with other agents. It is also important that any chemotherapeutic regimen be as convenient and painless as possible to the patient.
This invention reports a series of novel sulfonylureas that are useful in the treatment of solid tumors. These compounds are orally active—which, of course, results in less trauma to the patient—and are relatively non-toxic. These compounds also have an excellent therapeutic index. The compounds and their formulations are novel.
Many sulfonylureas are known in the art. Certain of these compounds are known to have hypoglycemic activities, and have been used medicinally as such agents. In addition, some sulfonylureas have been taught to have herbicidal and antimycotic activities. General reviews of compounds of this structural type are taught by Kurzer,
Chemical Reviews,
50:1 (1952) and C. R. Kahn and Y. Shechter,
Goodman and Gilman's. The Pharmacological Basis of Therapeutics
, (Gilman, et al., 8th ed. 1990) 1484-1487.
Some diarylsulfonylureas have been reported as being active antitumor agents. e.g., U.S. Pat. No. 5,169,860, of F. Mohamadi and M. Spees, issued Dec. 8, 1992; U.S. Pat. No. 4,845,128 of Harper, et al., issued Jul. 4, 1989; U.S. Pat. No. 5,110,830 of Harper, et al., issued May 5, 1992; U.S. Pat. No. 5,116,874 of G. A. Poore, issued May 26, 1992; U.S. Pat. No. 5,216,026, of J. Howbert, issued Jun. 1, 1993; U.S. Pat. No. 5,216,027, of J. E. Ray, et al., issued Jun. 1, 1993; U.S. Pat. No. 5,260,338, of R. W. Harper, et al., issued Nov. 9, 1993; U.S. Pat. No. 5,594,028, of R. W. Harper, et al., issued Jan. 14, 1997; U.S. Pat. No. 5,302,724, of J. J. Howbert, et al., issued Apr. 12, 1994; U.S. Pat. No. 5,270,329, of W. L. Scott, et al., issued Dec. 14, 1993; U.S. Pat. No. 5,234,955, of J. E. Ray, et al., issued Aug. 10, 1993; U.S. Pat. No. 5,354,778, of J. E. Ray, et al., issued Oct. 11, 1994; U.S. Pat. No. 5,258,406, of J. E. Toth, et al., issued Nov. 2, 1993; U.S. Pat. No. 5,262,440, of W. J. Ehlhardt, et al., issued Nov. 16, 1993; U.S. Pat. No. 5,254,582, of G. B. Boder, et al., issued Oct. 19, 1993; U.S. Pat. No. 5,565,494, of G. B. Grindey, et al., issued Oct. 15, 1996; U.S. Pat. No. 5,387,681, of W. D. Miller, et al., issued Feb. 7, 1995; and U.S. Pat. No. 5,529,999, of J. E. Ray, et al., issued Jun. 25, 1996; the entirety of all of which are herein incorporated by reference.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I
wherein:
R
1
is C
2
-C
8
alkenyl;
R
1a
is hydrogen or hydroxy; and
R
2
and R
3
are independently selected from the group consisting of hydrogen, halo, C
1
-C
6
alkyl, and trifluoromethyl, provided that no more than one of R
2
and R
3
can be hydrogen;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
This invention also provides a method of treating a susceptible neoplasm in a mammal which comprises administering to a mammal in need of said treatment an effective amount for treating a susceptible neoplasm of a compound of Formula I.
In addition, this invention provides pharmaceutical formulations comprising an effective amount for treating susceptible neoplasms of a compound of Formula I, or a salt, solvate or prodrug thereof, in combination with a suitable pharmaceutical carrier, diluent, or excipient. These formulations are useful in the treatment of mammals suffering from susceptible neoplasms.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
As used herein, the term “halo” refers to fluoro, chloro, bromo, and iodo. The term “C
1
-C
6
alkyl” refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
The term “C
2
-C
8
alkenyl” as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to eight carbon atoms. Typical C
2
-C
8
alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-pentenyl, and the like.
Preferred methods of treatment employ compounds of Formula I in which R
1
is ethenyl or propenyl; and R
2
and R
3
are independently selected from the group consisting of hydrogen, chloro, fluoro, bromo, iodo, methyl, ethyl, and trifluoromethyl.
The compounds of Formulas I are generally referred to as derivatives of N-[[(substituted phenyl)amino]carbonyl]-(alkenylbenzene)sulfonamides. Alternatively, the compounds can be referred to as 1-(substituted phenyl)-3-(substituted phenylsulfonyl)ureas or N- and N′-substituted sulfonylureas.
The compounds of Formulas I can be prepared by methods known in the literature. Generally, these methods involve either the reaction of a sulfonamide with an isocyanate, a reaction of a sulfonylisocyanate with an appropriately substituted aniline, or a reaction of a sulfonylcarbamate with an appropriately-substituted aniline.
A preferred process for preparing a compound of Formula I comprises reacting a sulfonylisocyanate of Formula II
with an aniline derivative of Formula III
where R
1
, R
2
, and R
3
are the same as previously defined.
The reaction between compounds II and III is usually performed using equimolar amounts of the two reactants, although other ratios are operative. The reaction is preferably carried out in a solvent which is nonreactive under the reaction conditions such as benzene, toluene, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, methylene chloride, or acetone.
The reaction can be carried out at temperatures from about 0° C. up to about 100° C. At the preferred temperature range of from about 20° C. to about 30° C., the reaction produces a strong exotherm and the reaction is usually complete within one hour. The product thus obtained is recovered by filtration and can be purified, if desired, by any number of methods known to those skilled in the art, such as chromatography or crystallization.
An alternative preferred process for preparing a compound of Formula I comprises reacting an appropriately substituted sulfonamide of Formula IV
with an isocyanate of Formula V
to provide the corresponding compound of Formula I.
The reaction is generally performed in a mixture of water and a water-miscible, non-reactive solvent such as tetrahydrofuran or acetone in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium hydride and the like. Generally, an equimolar or slight molar excess of V is employed, although other ratios are op

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