Antitumor compositions and methods of treatment

A method is provided for treating a susceptible neoplasm in mammals which comprises administering to a mammal in need of said treatment an effective amount for treating the neoplasm of the compound N-[[(4-chlorophenyl)amino]carbonyl]-1-butanesulfonamide or a pharmaceutically acceptable salt thereof, wherein said neoplasm is selected from the group consisting of ovarian, non-small cell lung, gastric, pancreatic, renal cell, breast, colorectal, small-cell lung, melanoma, head and neck, Kaposi's sarcoma, and rhabdomyosarcoma.

BACKGROUND OF THE INVENTION 
According to the American Cancer Society about 494,000 people died from 
cancer in the United States in 1988. One of every five deaths from all 
cause in the United States is from cancer. Although chemotherapy has 
become one of the principal methods of treating cancer, the rate at which 
new drugs have become available for use in cancer chemotherapy has 
declined in recent years as reported by Horowitz et al. "Phase II Testing 
of Melphalan in Children with Newly Diagnosed Rhabdomyosarcoma: A Model 
for Anticancer Drug Development", Journal of Clinical Oncology, Vol. 6, 
No. 2, pp. 308-314 (1988). Accordingly, there is a substantial need for 
new drugs which are effective in inhibiting the growth of tumors. 
To be particularly useful, a new chemotherapeutic agent should have a wide 
spectrum of activity, a large therapeutic index, and be chemically stable 
and compatible with other agents. Additionally, it would be beneficial for 
the new agent to have oral activity so that initial treatment and 
subsequent maintenance therapy is more convenient and less traumatic to 
the patient. 
It has now been found that certain N-phenyl-N'-alkylsulfonylureas are 
particularly useful in the treatment of solid tumors. These compounds are 
relatively nontoxic and provide an excellent therapeutic index. 
Some N,N'-diarylsulfonylureas have been reported as being active antitumor 
agents e.g., U.S. Pat. No. 4,845,128 of Harper et al. (1989) and Grindey 
et al. American Association of Cancer Research, Vol. 27, pp. 277 (1986). 
There is no suggestion in these references of the 
N-phenyl-N'-sulfonylureas of the instant application or that these 
compounds would be useful as antitumor agents. 
Certain arylalkylsulfonylureas have been reported in the literature. U.S. 
Pat. No. 2,979,437 of McLamore et al. (1961) discloses compounds of the 
general formula RCH.dbd.CHSO.sub.2 NHCONHR' in which R can be a phenyl or 
substituted phenyl and R' can be p-chloro-or p-bromophenyl as having 
hypoglycemic activity. Chemical Abstracts, Vo. 54, 5532d (1960) cites an 
article by Palazzo et al. (Farmaco. Ed. Sci., 14, 358-62 (1959)) which 
discloses N-(p-chlorophenyl)-N'-butylsulfonylurea. The compound is 
disclosed as producing hypoglycemia in rabbits after oral administration. 
Giorgetti in Bulletin De La Societe Chimique. De France, 1971, No. 10, pp. 
3600 discloses the preparation of a sulfonylurea with formula CH.sub.2 
.dbd.CHSO.sub.2 NHCONHR where R is 3,4-dichlorophenyl. 
Holland in U.S. Pat. No. 3,983,107 (1976) also discloses certain 
2-phenylethenesulfonamide derivatives of the general formula 
RCH.dbd.CHSO.sub.2 NHCONR.sup.1 R.sup.2 where R is a phenyl and R.sup.1 
and R.sup.2 can be hydrogen or a substituted phenyl. These compounds are 
disclosed as being useful for reducing elevated serum lipid levels in 
mammals. 
Hainaut et al. in U.S. Pat. No. 4,045,209 (1977) disclose compounds of the 
formula XSO.sub.2 (CH.sub.2).sub.n NCH.sub.2 CONYR where n is 0 or 1, X 
can be a C.sub.1 -C.sub.6 alkyl, Y can by hydrogen and R is a phenyl group 
which can be substituted with hydrogen, chlorine or bromine. These 
compounds having a methyl substituent on the nitrogen adjacent to the 
sulfonyl group are disclosed as being useful as herbicides. 
None of these references suggest or disclose the antitumor activity of the 
sulfonylurea compounds of the instant invention. Additionally, there is no 
suggestion or disclosure of the claimed compounds of the instant 
invention. 
SUMMARY OF THE INVENTION 
A Method is provided for treating a susceptible neoplasm in mammals which 
comprises administering to a mammal in need of said treatment an effective 
amount for treating the neoplasm of the compound 
N-[[(4-chlorophenyl)amino]carbonyl]-1-butanesulfonamide or a 
pharmaceutically acceptable salt thereof, wherein said neoplasm is 
selected from the group consisting of ovarian, non-small cell lung, 
gastric, pancreatic, renal cell, breast, colorectal, small-cell lung, 
melanoma, head and neck, Kaposi's sarcoma, and rhabdomyosarcoma. 
Detailed Description 
As used herein the term "halo" refers to fluoro, chloro, bromo and iodo. 
The term "C.sub.2-C.sub.7 alkyl" refers to straight and branched chain 
alkyl groups including ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 
s-butyl, n-pentyl, isopentyl, 2-methylbutyl, n-hexyl, 2-methylpentyl, and 
the like. The term "alkenyl" refers to unsaturated alkyl groups with the 
term "C.sub.2-C.sub.7 alkenyl" referring to vinyl, 1-propenyl, 
1-methylvinyl, 1-butenyl, 1-methyl-1-propenyl, 1-hexenyl, and the like. 
The term "C.sub.4 -C.sub.8 cycloalkyl" refers to cyclic alkyl groups such 
as cyclobutyl, cyclopentyl, cyclohexyl, and lower alkyl substituted 
cyclopentyl and cyclohexyl groups such as methylcyclopentyl, etc. The term 
"phenyl-substituted C.sub.1 -C.sub.4 alkyl" refers to C.sub.1 -C.sub.4 
alkyl groups which are substituted with phenyl groups such as 
phenylmethyl, phenylethyl and the like. The term "phenyl-substituted 
alkenyl" refers to phenyl-substituted lower alkenyl groups such as C.sub.6 
H.sub.5 CH.dbd.CH-- (i.e., styryl) C.sub.6 H.sub.5 CH.sub.2 CH.dbd.CH--, 
and the like. The term "alkylsulfonylurea" is used herein to generically 
encompass all of the foregoing substituents on the sulfonyl group. 
The compounds of Formula I and Formula II can be referred to as derivatives 
of N-[[(substituted phenyl)amino]carbonyl]alkylsulfonamides. Alternatively 
the compounds can be referred to as 1- and 3-substituted sulfonylureas or 
N- and N'-substituted sulfonylureas. 
Preferred compounds of the instant method are those in Formula I in which 
X.sup.1 is chloro, bromo or fluoro, X.sup.2 is hydrogen or chloro and A is 
C.sub.3 -C.sub.6 alkyl, C.sub.5 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.6 
alkenyl, styryl, phenylthiomethyl, or ethoxyethyl. 
More preferred compounds of Formula I include: 
N-[[(3-chloro-4-fluorophenyl)amino]carbonyl]-2-propane-sulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-methyl-1-propanesulfonamide; 
N-[[(4-fluorophenyl)amino]-carbonyl]-cyclopentanesulfonamide; 
N-[[(4-fluorophenyl)-amino]carbonyl]-2-butanesulfonamide; 
N-[[(3,4-dichlorophenyl)amino]carbonyl]-2-propanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-propanesulfonamide; 
N-[[(4-bromophenyl)amino]carbonyl]-2-propanesulfonamide; 
N-[[(3-trifluoromethyl-4-chlorophenyl)amino]carbonyl]2-propanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-cyclohexanesulfonamide; 
N-[[(4-bromophenyl)amino]carbonyl]cyclopentanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-ethoxyethanesulfonamide; 
N-[[(3,4-dichlorophenyl)amino]carbonyl]-2-butanesulfonamide; and 
N-[[(4-chlorophenyl)amino]carbonyl]-2-butene-2-sulfonamide. 
Most preferred compounds of the instant method include: 
N-[[(4-chlorophenyl)amino]carbonyl]-2-butanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-1-butanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-cyclopentanesulfonamide; 
N-[[(4-chlorophenyl)amino]-carbonyl]-2-phenylethenesulfonamide; 
N-[[(4-chlorophenyl)-amino]carbonyl]phenylmethanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]phenylthiomethanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-1-butene-1-sulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-1-pentanesulfonamide; and 
N-[[(4-chlorophenyl)amino]carbonyl]-1-hexanesulfonamide. 
Preferred compounds of Formula II include those in which: X.sup.1 is 
chloro, bromo or fluoro; X.sup.2 is hydrogen, chloro, or trifluoromethyl; 
B is: (a) C.sub.3 -C.sub.6 alkyl with the proviso that when the alkyl is 
n-butyl then X.sup.1 is bromo or X.sup.2 is not hydrogen; (b) C.sub.4 
-C.sub.5 alkenyl; (c) phenyl-substituted C.sub.1 -C.sub.2 alkyl; (d) 
phenyl-substituted C.sub.2 -C.sub.3 alkenyl with the proviso that when the 
alkenyl group is C.sub.2 and X.sup.1 is chloro then X.sup.2 is not 
hydrogen of chloro and when X.sup.1 is bromo then X.sup.2 is not hydrogen; 
(e) C.sub.5 -C.sub.6 cycloalkyl; or (f) RZR.sup.1 - where R is phenyl or 
C.sub.1 -C.sub.2 alkyl, R.sup.1 is CH.sub.2 or C.sub.2 H.sub.4, and Z is 0 
or S; and pharmaceutically acceptable salts thereof. 
More preferred compounds of Formula II include: 
N-[[(3-chloro-4-fluorophenyl)amino]carbonyl]-2-propanesulfonamide; 
N-[[(4-fluorophenyl)amino]carbonyl]-2-butanesulfonamide; 
N-[[(3,4-dichlorophenyl)-amino] carbonyl]-2-propanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-propanesulfonamide; 
N-[[(4-bromophenyl)amino]carbonyl]-2-propanesulfonamide; 
N-[[(3-trifluoromethyl-4-chlorophenyl)amino]carbonyl]-2-propanesulfonamide 
; N-[[(4-chlorophenyl)amino]carbonyl]-cyclohexanesulfonamide; 
N-[[(4-bromophenyl)-amino]carbonyl]cyclopentanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-ethoxyethanesulfonamide; 
N-[[(3,4-dichlorophenyl)amino]carbonyl]-2-butanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-butene2-sulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-butanesulfonamide; 
N-[[(4-chlorophenyl)amino]-carbonyl]cyclopentanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]phenylmethanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]phenylthiomethanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-1-butene-1sulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-2-methyl-1-propanesulfonamide; 
N-[[(4-fluorophenyl)amino]carbonyl]-cyclopentanesulfonamide; 
N-[[(4-chlorophenyl)amino]carbonyl]-1-pentanesulfonamide; and 
N-[[(4-chlorophenyl)amino]carbonyl]-1-hexanesulfonamide. 
This invention includes the pharmaceutically acceptable salts of the 
compounds of Formula I and Formula II. The compounds of this invention can 
be contacted with basic materials such as alkali metal or alkaline earth 
metal hydroxides, carbonates, and bicarbonates, including sodium 
hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, 
sodium bicarbonate, etc., to form the corresponding metal salt such as the 
sodium, potassium, lithium or calcium salt. Nontoxic organic bases can 
also be used including primary, secondary and tertiary alkyl amines such 
as methylamine, triethylamine, and the like. 
The compounds of Formula I and Formula II can be prepared by any of the 
methods known in the literature. Generally these methods involve either 
the reaction of a sulfonamide with an isocyanate or a reaction of a 
sulfonylcarbamate with an amine. A preferred method of preparing the 
instant compounds involves the reaction of a sulfonamide of Formula IIIa 
EQU A--SO.sub.2 NH.sub.2 or B--SO.sub.2 NH.sub.2 IIIa 
with a basic material to provide the reactive anion of Formula III.sub.b 
EQU A-- or B--SO.sub.2 NH.sup.-, M+ IIIb 
wherein M+ is a counter ion, prior to contacting an arylisocyanate of 
Formula IV 
##STR1## 
where A, B, X.sup.1, and X.sup.2 are the same as previously defined. 
A basic material such as sodium hydroxide, potassium hydroxide, lithium 
hydroxide, sodium methoxide, sodium hydride and the like can be contacted 
with the sulfonamide and the resulting product III.sub.b then contacted 
with the isocyanate. The reaction between anion III.sub.b and isocyanate 
IV is usually performed using equal molar 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 condition such as 
benzene, toluene, acetonitrile, ethyl ether, dioxane, or most preferably 
acetone or tetrahydrofuran. The reaction can be carried out at 
temperatures from about 0.degree. C. normally up to the boiling point of 
the reaction mixture. At the preferred temperature range of about 
0.degree. to 50.degree. C., the reaction is usually complete within two 
hours. The resulting product is preferably neutralized with an acid such 
as hydrochloric acid and recovered by filtration. If desired, the product 
can be purified by any number of methods known to those skilled in the art 
such as chromatography or crystallization. 
The sulfonamide of Formula III.sub.a can be prepared by one of several 
methods. Generally, the sulfonamides can be prepared by ammonolysis of the 
appropriate sulfonyl chloride: 
##STR2## 
This preparation can be performed using ammonia, with or without a 
cosolvent such as tetrahydrofuran, or using aqueous ammonia, with or 
without a cosolvent such as tetrahydrofuran, dichloromethane, etc. 
Arylthiomethane sulfonamides can be prepared using the method disclosed in 
J. Chem. Engineering Data, 21, 237 (1976). Alkenylsulfonamides can be 
prepared according to the method disclosed in J. Org. Chemi., 49, 1700 
(1984). These articles are incorporated herein by reference in their 
entirety. 
Styrene sulfonyl chlorides can be prepared using the method of Culbertson 
and Dietz, J. Chem. Soc. [C], 992 (1968) with dimethylformamide (DMF) and 
sulfonyl chloride as follows: 
##STR3## 
Benzyl and alkyl sulfonyl chlorides can be prepared by chlorination of 
isothiouronium salts, which are derived from the corresponding benzyl or 
alkyl halides: 
##STR4## 
where X is Cl, Br, or I. Chlorination of other thio-containing compounds 
can also be used. This procedure as well as other general preparations of 
sulfonyl halides are disclosed in Advanced Organic Chemistry, 3rd Ed., 
Jerry March, John Wiley & Sons (1985), indexed on page 1172 and all are 
incorporated herein by reference. 
The starting materials and intermediates for these preparations are 
commercially available or can be readily prepared by the above-described 
methods or other methods known in the literature. 
The terms and abbreviations used in the instant examples have their normal 
meaning unless otherwise designed, for example, "THF" means 
tetrahydrofuran; ".degree. C" refers to degrees celsius; "N" refers to 
normal or normality; "mmole" refers to millimole; "g" refers to gram; "ml" 
means milliliter; "M" refers to molar; "NMR" refers to proton nuclear 
magnetic resonance; and "m.s." refers to mass spectrometry. 
The following examples further illustrate the preparation of the compounds 
of this invention. The examples are provided for purposes of illustration 
only and are not to be construed as limiting the scope of the instant 
invention in any way. 
Experimental 
Procedure A 
The sulfonamide was dissolved in acetone. An aqueous solution of 1.0N 
sodium hydroxide was added at room temperature. Additional water and 
acetone was added as necessary to dissolve any solid formed. An acetone 
solution of the isocyanate was added. The mixture was stirred, and the 
solvent was removed to provide a residue. Water was added to the residue, 
the mixture was acidified, and the solid product was collected. 
Procedure B 
Same as Procedure A except the sulfonamide was dissolved in methanol and a 
solution of sodium methoxide in methanol was used instead of sodium 
hydroxide. The methanol was removed and tetrahydrofuran (THF) was added to 
the residue. The isocyanate was added to the mixture and stirred. After 
removing the tetrahydrofuran the residue was dissolved in water, filtered, 
and the water removed to provide the sodium salt of the product.