ANTITUMOR 2-AMINOCARBONYL-1,2-BIS(METHYLSULFONYL)-1-(SUBSTITUTED)HYDRAZINES

Abstract: The present invention relates to novel 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines and 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-methylhydrazines, and their use to treat malignant tumors. The agents are especially useful in the treatment of animal and human cancers. Two preferred agents in this class, especially for use in the treatment of tumors are 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(2-chloroethyl)aminocarbonylhydrazine and 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-methylaminocarbonylhydrazine. These agents are characterized by the following: they are incapable of undergoing inactivation by the denitrosation mechanism proposed for the inactivation of the CNUs roethylation or methylation and carbamoylation.

Description: Antitumor 2-Aminocarbonyl-l,2-Bis(Methylsulfonyl)-1- (Substitu ed)hydrazines Field of the Invention The present invention relates to 2-aminocarbonyl-l,2- bis(methylsulfonyl) -1-(substituted)hydrazines exhibiting antitumor activity in mammals. Methods of treating neoplasia, especially including solid tumors are additional aspects of the present invention. This work was supported by a National Institutes of Health Grant. The United States Government retains certain rights in the invention. Background of the Invention The search for compounds exhibiting enhanced anti¬ neoplastic activity has focused some attention on nitrosourea compounds such as 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and related agents. Several N-(2-chloroethyl) -N-nitrosoureas (CNUs) have been evaluated clinically and have been shown to possess significant antineoplastic activity against brain tumors, colon cancer and lymphomas (See, DeVita, et al., Can¬ cer Res. 1965, 25, 1876-1881; Nissen, et al., Cancer 1979, 43, 31-40) . Characterization of the decomposition products of the clinically used CNUs, such as BCNU and 1-(2-chloroethyl) -3- cyclohexyl-l-nitrosourea (CCNU) , has resulted in the identifi¬ cation of several reactive products, including chloroethylat- ing, carbamoylating and hydroxyethylating species (See, for example, Montgomery, et al., J. Med. Chem. 1967, 10, 668-674; Montgomery, et al., J. Med. Chem. 1975, 18, 568-571; einka and Lin, J. Med. Chem. 1979, 22, 1193-1198; and Brundrett, R. B., J. Med. Chem. 1980, 23, 1245-1247). The antitumor activity of the CNUs has been suggested to result from chloroethylation and subsequent crosslinking of DNA (See Kohn, K.W. in Recent Results in Cancer Research (Eds. Carter, S.K., Sakurai, Y., and Umezawa, H.), vol. 76, p. 14i, Springer, Berlin (1981)) . In support of this view is the IIIE 26 observation that many chloroethylating agents with no car- bamoylating activity (e.g., clomesone, as discussed by Shealy, et al., J. Med. Chem. 1984, 27, 664-670) possess excellent antineoplastic activity. In addition, replacement of the chloro group in CNUs by a hydroxyl group has resulted in a considerable decrease in antineoplastic activity (Montgomery, J. A., personal communication; cited by Gibson, et al., Can¬ cer Res. 1986, 46, 553-557) . Furthermore, there is some evi¬ dence that hydroxyethylation of DNA is a carcinogenic and/or mutagenic event (Pelfrene, et al., J. Natl. Cancer Inst. 1976, 56, 445-446; and Swenson, et al. , J. Natl. Cancer Inst. 1979, 63, 1469-1473). While hydroxyethylation seems to have no salutary effect on the antineoplastic activity of the CNUs, there appears to be some uncertainty regarding the role played by the carbamoylating species (i.e., the isocyanate). The isocyanate generated from the CNUs reacts with thiol and amine functionalities on proteins and inhibits DNA polymerase (Baril, et al., Cancer Res. 1975, 35, 1-5.), the repair of DNA strand breaks (Kann, et al., Cancer Res. 1974, 34, 398-402), and RNA synthesis and processing (Kann, et al., Cancer Res. 1974, 34, 1982-1988). In addition, BCNU has been shown to inhibit glutathione reductase, ribonucleotide reductase and thioredoxin reductase (Schallreuter, et al., Biochim. Biophys. Acta 1990, 1054, 14-20). Although it is believed by many that some of these same properties contribute to the toxic side effects of CNUs (Colvin, et al., Biochem. Pharmacol. 1976, 25, 695-699; Wheeler, et al., Cancer Res. 1974, 34, 194-200; and Panasci, et al. , Cancer Res. 1977, 37, 2615-2618) , it is entirely possible, as speculated by Gibson and Hickman (Gibson and Hickman, Biochem. Pharmacol. 1982, 31, 2795-2800) in their study of the effects of BCNU on the TLX tumor in mice, that intracellular release of isocyanates plays a role in modulating the biological activity of the CNUs against some specific tumor types. Caracemide, an investiga- tional antitumor agent developed by the Dow Chemical Company (Newman and Farquhar, Invest. New Drugs 1987, 5, 267-271 and Slatter, et al., Chem. Res. Toxicol. 1993, 6, 335-340) is thought to act as a latent form of methyl isocyanate. This agent was shown to be active in a number of National Cancer Institute tumor models, including the mammary MX-1 and colon CX-1 human tumor xenografts implanted in the subrenal capsules of athymic mice (Clinical brochure "Caracemide NSC 253272", Division of Cancer Treatment, National Cancer Institute, 1983) . The hydroxyethylating species generated from the CNUs, 2-hydroxyethyldiazohydroxide, is thought to be formed from 4,5-dihydro-l,2,3-oxadiazole which, in turn, has been hypothesized to be the result of an internal cyclization reac¬ tion involving the N-nitroso group (Brundrett, R. B., J. Med. Chem. 1980, 23, 1245-1247). The N-nitroso group is also involved in the enzymatic inactivation of the CNUs. For exam¬ ple, BCNU can be inactivated by denitrosation by liver micro¬ somal enzymes in an NADPH-dependent reaction, with the forma¬ tion of 1, 3-bis(2-chloroethyl)urea (Hill, et al., Cancer Res. 1975, 35, 296-301 and Lin and Weinkam, J. Med. Chem. 1981, 24, 761-763) . The denitrosation reaction is catalyzed by NADPH:cytochrome P450 reductase in the case of CCNU (Potter and Reed, Arch. Biochem. Biophys. 1982, 216, 158-169 and Pot¬ ter and Reed, J. Biol. Chem. 1983, 258, 6906-6911). BCNU has also been shown to undergo glutathione-dependent denitrosation catalyzed by rat (Smith, et al., Cancer Res. 1989, 49, 2621- 2625) and human (Berhane, et al., Cancer Res. 1993, 53, 4257- 4261) glutathione S-transferase mu isoenzymes. Since tumor cell-catalyzed denitrosation could con¬ ceivably be a potential mechanism of resistance to the CNUs, our aim was to synthesize a series of compounds that (a) were capable of generating a chloroethylating or methylating species; (b) were capable of forming a carbamoylating species; (c) were devoid of hydroxyethylating activity; and (d) were free from structural features that would make them highly prone to metabolic inactivation. We believed that 2-aminocarbonyl-l,2- bis(methylsulfonyl) - 1-(substituted)hydrazines (I) might satisfy the above conditions for the following reasons: (a) Base-catalyzed elimination of compounds I would result in the formation of a chloroethylating or methylating species and a carbamoylating agent as shown below. Y CH3SO2-N-NSO2CH3 > CH 3 S0 2 N-NY + RNCO + CH 3 S0 2 H C N-R II 0 H I (Y is Methyl or 2-Chloroethyl) (b) At least three classes of prodrugs of species II, i.e., 1,2-bis(methylsulfonyl) -1-(2-chloroethyl)hydrazine, 1- (2-chloroethyl) -1,2,2-tris(methylsulfonyl)hydrazine (Shyam, et al., J. Med. Chem. 1990, 33, 2259-2264), and l-acyl-1,2- bis(methylsulfonyl) -2-(2-chloroethyl)hydrazine (Shyam, et al., J. Med. Chem. 1993, 36, 3496-3502) , with potent antitumor activity, have been identified. (c) The formation of a 4,5-dihydro-l,2,3-oxadiazole intermediate may be prevented by the absence of an N-nitroso moiety. This, in turn, may prevent the formation of a 2- hydroxyethylating agent. The absence of an N-nitroso group may also make the compounds less prone to metabolic inactivation. Objects of the Invention It is an object of the invention to provide effective antineoplastic agents effective for treating numerous can¬ cerous conditions, including solid tumors in animals and humans. It is another object of the invention to provide antineoplastic agents which are capable of generating a car¬ bamoylating and chloroethylating chemical species. It is yet a further object of the invention to provide effective antineoplastic agents which are less prone to metabolic inactivation than compounds of related structure. It is an additional object of the invention to provide pharmaceutical compositions based upon the use of these novel antineoplastic agents. It is still another object of the invention to provide methods of treating neoplasia, including solid tumors, in animals and humans. These and/or other objects of the invention may be readily gleaned from the description of the invention which follows. Summary of the Invention The present invention relates to 2-aminocarbonyl-l,2- bis(methylsulfonyl)-1-(substituted)hydrazine compounds of the formula: CH 3 S0 2 N(Y)N(CONHR) S0 2 CH 3 where Y is -CH 3 or -CH CH 2 C1; and R is C1-C7 alkyl, cyclohexyl, ethylcyclohexyl, -CH 2 CH=CH 2 , -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 C1, -CH 2 COOC 2 H 5 , -CH(CH 3 ) COOC 2 H 5 or -CH(CH 2 C 6 H5)COOC 2 H 5 . In preferred compounds according to the present inven¬ tion, Y is -CH 2 CH 2 C1 and R is -CH 2 CH 2 C1, -CH 2 CH=CH 2 or -CH 3 . R is most preferably -CH 2 CH 2 Cl or -CH 3 . The Ci^C alkyl sub¬ stituent is preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t- butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and substituted hexyl. The compounds according to the present invention are produced by synthetic methods which are readily known to those of ordinary skill in the art and include the disclosed chemi¬ cal synthetic methods. The present invention also relates to pharmaceutical compositions comprising an antineoplastic effective amount of a 2-aminocarbonyl-l,2-bis(methylsulfonyl)-1- (substituted)hydrazine compound as set forth above. These pharmaceutical compositions preferably also include a phar aceutically acceptable additive, carrier or excipient. The present invention also relates to a method for treating neoplasia in mammals comprising administering an antineoplastic effective amount of 2-aminocarbonyl-l,2- bis(methylsulfonyl)-1-(substituted)hydrazine compound to a patient suffering from cancer. The treatment of solid malig¬ nant tumors comprising administering to a patient an antitumor effective amount of one or more of these agents is a preferred embodiment of the present invention. The treatment of leukemias, lung carcinomas, melanoma, reticulum cell sarcoma, among various other related disease states may also be effected using the compounds of the present invention. Detailed Description of the Invention The term "neoplasia" is used throughout the specifica¬ tion to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organi¬ zation and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. The term antineoplastic effective amount is used throughout the specification to describe an amount of the present compounds which is used to treat a patient suffering from a cancerous tumor to prevent the further growth of the neoplasms, bring that growth under control and preferably, produce a remission of the tumor. The term "therapeutically effective amount" is used throughout the specification to describe that amount of the compound according to the present invention which is administered to a mammalian patient, especially including a human patient, suffering from cancer, to reduce or inhibit the growth or spread of the hematogenous, ascitic or solid tumor. Preferably, the compounds according to the present invention will result in a remission of the malignant hematogenous, ascitic or solid tumor. In the case of solid tumors, the com¬ pounds according to the present invention will inhibit the further growth of the tumor tissue and shrink the existing tumor. The present invention is directed to 2-aminocarbonyl- 1,2-bis(methylsulfonyl) -1-(substituted)hydrazine compounds of the formula: CH 3 S0 2 N(Y)N(CONHR) S0 2 CH 3 where Y is -CH 3 or -CH 2 CH 2 C1; and R is Ci-Cy alkyl, cyclohexyl, methylcyclohexyl, -CH 2 CH=CH 2 , -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 C1, -CH 2 C00C 2 H 5 , -CH(CH 3 )C00C 2 H 5 or -CH(CH 2 C 6 H 5 )COOC 2 H 5 . In preferred compounds according to the present inven¬ tion, Y is -CH 2 CH 2 C1 and R is -CH 2 CH 2 C1, -CH 2 CH=CH 2 , or -CH 3 . R is most preferably -CH 2 CH 2 C1 or -CH 3 . Where R is Ci-Cy alkyl, R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n- pentyl, isopentyl, n-hexyl, isohexyl or substituted hexyl. These compounds, which contain a 2-aminocarbonyl group, exhibit enhanced activity against a broad spectrum of neoplastic disease states, including, for example, numerous solid tumors. In in vivo screening tests, these agents have exhibited broad spectrum activity against a wide range of neoplastic disease states. In one case, where R is CH 2 CH 2 C1, this compound exhibited unexpectedly greater antineoplastic activity than mitomycin C or cyclophosphamide, among the most effective commercial antineoplastic alkylating agents. The present compounds represent prodrug forms of intermediates which are believed to exhibit their activity through chloroethylation, methylation and/or carbamoylation mechanisms. The compounds according to the present invention are primarily useful for their antineoplastic activity, including their activity against solid tumors. In addition, these com¬ positions may also find use as intermediates in the chemical synthesis of other useful antineoplastic agents which are, in turn, useful as therapeutic agents or for other purposes. Compounds according to the present invention are synthesized by the adaptation of techniques which are well known in the art. 2-Aminocarbonyl-l,2-bis(methylsulfonyl)-1- (substituted)hydrazines (I, Y is -CH 3 or -CH 2 CH 2 C1) are synthesized by reacting 1,2-bis(methylsulfonyl)-1- methylhydrazine or 1,2-bis(methylsulfonyl)-1-(2- chloroethyl)hydrazine with the appropriate isocyanate (where R is of the indicated structure or a related alkyl structure) in dry acetonitrile in the presence of triethylamine as shown below. The synthesis of the appropriate isocyanate derivative for use in this reaction scheme is well known in the art and uses standard chemical techniques. CH 3 S0 2 N(Y)NHS0 2 CH 3 + RNCO (where Y is -CH 3 or CH 2 CH 2 C1) NEt 3 CH 3 CN CH 3 S0 2 N(Y)N(CONHR)S0 2 CH 3 III. R = -CH 2 CH 2 C1 IV. R = -CH 3 V. R = -CH 2 CH=CH 2 VI. R = -CH 2 CH 2 CH 2 C1 VII. R = -CH 2 COOC 2 H 5 VIII. R = -CH(CH 3 )COOC 2 H 5 IX. R = -CH(CH 2 C 6 H 5 )COOC 2 H 5 X. R = -C 2 -C 7 alkyl, cyclohexyl or methy1eye1ohexy1 After synthesis, the residue generally is triturated, washed with dilute acid, dried, triturated again and recrystallized from an appropriate solvent, for example, ethanol or ethanol/petroleum ether. Modification of the dis¬ closed chemical synthetic methods may be readily made by those of ordinary skill in the art in order to provide alternative synthetic pathways to the present compounds. The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a 2-aminocarbonyl-l,2-bis(methylsulfonyl)-1- (substituted)hydrazine compound as set forth above. A therapeutically effective amount of one or more of these com¬ pounds is that amount which may be used to treat patients suf¬ fering from cancer such as a malignant tumor. These pharmaceutical compositions preferably also include a pharmaceutically acceptable additive, carrier or excipient. In pharmaceutical compositions according to the present inven¬ tion which relate to the treatment of malignant solid tumors, those compositions comprise an amount of one or more 2- aminocarbonyl-1,2-bis(methylsulfonyl)-l-(substituted)hydrazine compounds as set forth above effective to inhibit the growth of the treated tumor and, in certain cases, to actually shrink the treated tumor. One of ordinary skill in the art will recognize that a therapeutically effective amount of the compounds according to the present invention to be used to treat malignant tumors will vary with the disease state or condition to be treated, its severity, the treatment regimen to be employed, the result desired (remission, shrinkage of tumor in combination with surgical techniques or radiation) , the type of administration used to deliver the compounds, the pharmacokinetics of the compounds used, as well as the patient (animal or human) treated. In the pharmaceutical aspect according to the present invention, one or more compounds according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable additive, carrier or excipient. In general, it is preferable to administer the pharmaceutical composition in parenteral-administrable form (preferably, intravenous) , but consideration should be given to other for¬ mulations administered via intramuscular, transdermal, buccal, subcutaneous, suppository, oral or other route. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising the therapeutic activity. For example, modifying the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formula¬ tion, esterification, etc.) which are well within the ordinary skill in the art. It is also within ordinary skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the pres¬ ent compounds for maximum beneficial effect in the patient to be treated. Sustained and/or controlled release forms of the pharmaceutical compositions are also contemplated by the pres¬ ent invention. The present compounds are prodrug forms of reactive intermediates. In certain pharmaceutical dosage formε, the present compounds may be modified to other prodrug forms to take advantage of a particular route of administration of the active compounds. One of ordinary skill in the art will recognize how to readily modify the present compounds to alternative prodrug forms to facilitate delivery of active compounds to a targeted site within the patient. The individ¬ ual of ordinary skill also will take advantage of favorable pharmacokinetic parameters of the prodrug formε, where appli¬ cable, in delivering the present compounds to a targeted εite within the patient to maximize the intended antineoplaεtic effect of the compound. The amount of compound included within the therapeuti¬ cally active formulations according to the present invention is an effective amount for treating the malignant tumor. In general, a therapeutically effective amount of the compound according to the preεent invention in doεage form usually ranges from lesε than about 0.05 mg/kg to about 500 mg/kg of body weight of the patient to be treated, or conεiderably more, depending upon the compound used, the tumor type to be treated, the ability of the active compound to localize in the tisεue to be treated, the route of adminiεtration and the pharmacokineticε of the compound in the patient. In the case of treating solid tumors, the compound is preferably administered in amounts ranging from about 0.05 mg/kg to about 250 mg/kg or more at one time. This dosage range generally produces effective blood level concentrations of active com¬ pound ranging from about 0.01 to about 500 micrograms per ml of blood in the patient to be treated. The duration of treat¬ ment may be for one or more days or may last for several months or considerably longer (years) depending upon the dis¬ ease state treated. Administration of the active compound may range from continuous (intravenous drip) to intramuscular, to several oral administrationε per day (for example, Q.I.D.) and may include parenteral, including intravenouε and intramuscular, oral, topical, subcutaneous, transdermal (which may include a penetration enhancement agent) , buccal and suppoεitory admin- iεtration, among other routeε of adminiεtration. To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is preferably intimately admixed with a pharmaceuti¬ cally acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., parenteral or oral. For parenteral formulations, the carrier may comprise sterile water or aqueous sodium chloride solution in combina¬ tion with other ingredients which aid dispersion, such as ethanol and other pharmaceutically acceptable solventε, including DMSO, among others. Of course, where solutionε are to be uεed and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suεpenεionε may also be prepared, in which case appropriate liquid carriers, εuspending agents and the like may be employed. In preparing pharmaceutical compositionε in oral dosage form, any one or more of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensionε, elixirε and εolutionε, suitable carriers and additives including water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like may be used. For εolid oral preparationε such as powders, tablets, capsules, and for εolid preparations such as suppoεitorieε, εuitable carrierε and additives including starches, sugar car- rierε, εuch as dextrose, mannitol, lactose and related car¬ riers, diluents, granulating agents, lubricants, binders, dis¬ integrating agents and the like may be used. If desired, the tablets or capεuleε may be enteric-coated or sustained release by standard techniques. The compoundε and compoεitionε according to the preε¬ ent invention are uεed to treat cancer in mammalε, including humanε. Generally, to treat malignant tumorε, the composi¬ tions will be administered in parenteral, preferably intravenous dosage form in amounts ranging from about 25 microgramε up to about 500 mg or more one to four timeε per day. The preεent compounds are preferably administered parenterally, but they also may be administered in an alterna¬ tive manner, for example, orally or even topically or in sup¬ pository form. Compounds according to the present invention may be administered alone or in combination with other agentε, eεpe- cially including other compoundε of the present invention. In addition, the administration of one or more compoundε accord¬ ing to the present invention with other antineoplastic agents, in combination chemotherapy, such as antimetaboliteε, etopoεide, doxorubicin, taxol, vincriεtine, cyclophoεphamide or mitomycin C, among numerouε otherε, iε contemplated by the preεent invention. While not being limited by way of theory, it iε believed that the compoundε according to the preεent invention primarily induce their therapeutic effect in treating malig¬ nant tumors by functioning as combined chloroethylating and carbamoylating agents, without also providing hydroxyethylat¬ ing activity. The present invention is now described, purely by way of illustration, in the following examples. It will be under¬ stood by one of ordinary skill in the art that these exampleε are in no way limiting and that variationε of detail can be made without departing from the εpirit and εcope of the preε- ent invention. EXAMPLES Experimental Section Synthesiε. Melting pointε were determined in capillary tubeε on a Thomaε-Hoover melting point apparatus and are uncorrected. 1 H NMR spectra were recorded on a Varian EM-390 spectrometer with tetramethyl εilane aε an internal standard. Elemental analyses were performed by the Baron Consulting Co., Orange, CT and the data were within + 0.4% of the theoretical values for the 2-aminocarbonyl-l,2-bis(methylsulfonyl)-1-(2- chloroethyl)hydrazines. EXAMPLE 1 Synthesis Of 1,2-bis(methylsulfonyl)-l-(2-chloroethyl)-2- (2-chloroethyl)aminocarbonylhydrazine (III) To a stirred solution of 1,2-bis(methylsulfonyl)-1-(2- chloroethyl)hydrazine (Shyam, et al..J. Med. Chem.. 1990, 33, 2259-2264) (2.5 g, 0.010 mol) and 2-chloroethyl isocyanate (1.2 g, 0.011 mol) in dry acetonitrile (100 mL) was added triethylamine (1.1 g, 0.011 mol) at room temperature. After an additional 10 min, the reaction mixture was evaporated to dryness .in vacuo. The residue was triturated twice with 15 mL quantitieε of petroleum ether and the petroleum ether layer waε diεcarded each time. The residue was then taken up in ethyl acetate (150 mL) and washed with dilute hydrochloric acid (3 x 15 mL) . The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. Upon evaporation of the solvent, a semi-solid residue was obtained which, upon trituration with absolute ethanol, gave a white solid. Recrystallization from ethanol afforded 1.5 g (42.2 %) of the title compound: mp 96-97.5 °C; ^ NMR (acetone-d6) 1 .0 (br, 1 H, NH) , 3.7-4.2 (m, 4 H, S0 2 NCH 2 CH 2 C1) , 3.5-3.7 (m, 4 H, C0NHCH 2 CH 2 C1) , 3.5 and 3.3 (2 s, 6 H, 2 CH 3 ). Anal. (C 7 H 15 C l2 N 3 0 5 S 2 ) C, H, N. EXAMPLES 2-7 SYNTHESIS OF 2-AMINOCARBONYL-l,2-BIS(METHYLSULFONYL)-1- (2-CHLOROETHYL)HYDRAZINES The following compoundε were prepared uεing procedureε similar to the one described in example 1 for compound III. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2- methylaminocarbonylhydrazine (IV) was syntheεized according to the method of example 1. Compound IV waε recryεtallized from ethanol: yield 42.4 %; mp 146-147.5 °C; X H NMR (acetone-d6) & 6.7 (br, 1 H, NH) , 3.7-4.2 (m, 4 H, CH 2 CH 2 Cl) , 3.5 and 3.3 (2 s, 6 H, 2 CH 3 ), 2.9 (d, 3 H, NCH 3 ). Anal. (C 6 H 14 C1N 3 0 5 S 2 ) C, H, N. 2-Allylaminocarbonyl-l,2-bis(methylsulfonyl)-1-(2- chloroethyl)hydrazine (V) was syntheεized according to the method of example 1. Compound V waε recryεtallized from ethanol: yield 42.2 %; mp 105-106 °C; H NMR (acetone-d6) <_T 6.9 (br, 1 H, NH) , 5.6-6.1 (m, 1 H, CH=C) , 5.4, 5.2 and 5.1 (3 d, 2 H, C=CH 2 ), 3.7-4.2 (m, 6 H, NHCH 2 and CH 2 CH 2 C1) , 3.5 and 3.3 (2 ε, 6 H, 2 CH 3 ) . Anal. (C 8 H 16 C1N 3 0 5 S 2 ) C, H, N. 1,2-Biε(methylsulfonyl)-1-(2-chloroethyl)-2-(3- chloropropyl)aminocarbonylhydrazine (VI) was syntheεized according to the method of example 1. Compound VI waε recryεtallized from ethanol: yield 35.2 %; mp 85-86 °C; 1 H NMR (acetone-d6) c^6.8 (br, 1 H, NH) , 3.7-4.2 (m, 4H, S0 2 NCH 2 CH 2 C1) , 3.4-3.8 (m, 6 H, CH 2 CH 2 CH 2 C1) , 3.5 and 3.3 (2 ε, 6 H, 2 CH 3 ). Anal. (C 8 H 17 C1 2 N 3 0 5 S 2 ) C, H, N. 1,2-Biε(methylsulfonyl)-1-(2-chloroethyl)-2- (ethoxycarbonylmethyi)aminocarbonylhydrazine (VII) was synthesized according to the method of example 1. Compound VII was recrystallized from ethanol: yield 42.2%; mp 121-122 °C; l-H NMR (acetone-d6) « ■ & 7.1 (br, 1 H, NH) , 3.7-4.4 (m, 8 H, OCH 2 , NHCH 2 and CH 2 CH 2 C1) , 3.5 and 3.3 (2 s, 6 H, 2 CH 3 ), 1.2 (t, 3 H, CCH 3 ) . Anal. (C 9 H 18 C1N 3 0 7 S 2 ) C, H, N. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(1- ethoxycarbonylethyl)aminocarbonylhydrazine (VIII) was synthesized according to the method of example 1. Compound VIII was recrystallized from ethanol: yield 28.0%; mp 111-112 °C; NMR (acetone-d6) (f> " 6.9 (br, 1 H, NH) , 3.7-4.6 (m, 7 H, OCH 2 , NHCH and CH 2 CH 2 C1) , 3.5 and 3.3 (2 s, 6 H, 2 CH 3 ) , 1.4 (d, 3 H, CHCH 3 ), 1.2 (t, 3 H, CH 2 CH 3 ). Anal. (C 10 H 20 ClN 3 O 7 S 2 ) C, H, N. 1,2-Bis(methylsulfonyl) -1-(2-chloroethyl)-2-(1- ethoxycarbony1-2-phenylethyl)aminocarbonylhydrazine (IX) was synthesized according to the method of example 1. Compound IX was recrystallized from ethanol-petroleum ether: yield 12.8%; mp 106-107 °C; 3-H NMR (acetone-d6) & 7.1-7.3 (m, 5 H, C 6 H 5 ) , 6.8 (br, 1 H, NH) , 4.6 (m, 1 H, NHCH) , 3.6-4.3 (m, 6 H, OCH 2 and CH 2 CH 2 C1) , 3.5 (s, 3 H, CH 3 S0 2 ) , 3.0-3.3 (ε, m, 5 H, CH 2 C 6 H 5 , CH 3 S0 2 ), 1.2 (t, 3 H, CH 2 CH 3 ). Anal. (C 16 H 24 C1N 3 0 7 S 2 ) C, H, N. 2-Aminocarbonyl-l,2-biε(methylsulfonyl)-1- methylhydrazine compounds containing the same aminocarbonyl substituents are prepared by analogy by following the synthetic protocols described above. EXAMPLE 8 ANTITUMOR ACTIVITY Antitumor Activity was tested in several cell lines: L1210 leukemia, B16F10 melanoma, M5076 reticulum cell sarcoma, M109 lung carcinoma and LX-1 lung carcinoma. Leukemia L1210 Testing Leukemia L1210 cells were obtained from the Frederick Cancer Research Facility, Division of Cancer Treatment Tumor Repository of the National Cancer Institute, and were main¬ tained by serial passage in tissue culture. Every 8 weeks, tumor cells were injected intraperitoneally into five donor CD 2 Fι mice 8- to 10- weeks of age and were allowed to grow for 7 days. The peritoneal fluid was withdrawn and the suεpenεion was centrifuged for 5 min at 1600g. The supernatant was decanted and IO 5 cells/mL were εeeded into 10 mL of RPMI 1640 medium εupplemented with 10% fetal bovine εerum and 1% L- glutamine, and once again maintained in culture. To assay for antineoplastic activity, 0.1 mL of the cell suεpenεion con¬ taining IO 5 L1210 leukemia cells was injected ip into each recipient mouse. Test compounds were adminiεtered over a wide range of doεage levelε, beginning 24 h after tumor implanta¬ tion, and continued once daily for 6 conεecutive days. All drugs were administered ip as a solution in 100% dimethylsul¬ foxide (DMSO), in a volume not exceeding 0.025 mL. In each experiment, animals were distributed into groups of five mice of comparable weight and maintained throughout the course of the experiment on Purina Laboratory Chow pellets and water ad libitum. Control tumor-bearing animals given comparable volumes of vehicle were included in each experiment. Mice were weighed during the course of the experiments, and the percentage change in body weight from onset to termination of therapy waε uεed aε an indication of drug toxicity. Determina¬ tion of the sensitivity of neoplasmε to theεe agentε was based upon the prolongation of survival time afforded by the drug treatments. Results of L1210 Testing The tumor-inhibitory properties of compounds III-IX were determined in initial tests by measuring their effects on the εurvival time of mice bearing the intraperitoneally (ip) implanted L1210 leukemia; the reεults of these testε are sum¬ marized in Table 1, below. With the exception of compound VI, all of the agents synthesized produced "cures" (defined as tumor-free 60 days poεt-tumor implant) in 100 % of mice bear¬ ing the L1210 leukemia at one or more of the doεage levelε examined following ip adminiεtration. It is conceivable that compound VI failed to do so only because it was not evaluated at daily dosage levels greater than 15 mg/kg given for 6 con¬ secutive days. Compound VI did, however, produce a partial cure rate of tumor-bearing mice at the highest dosage level examined. Compounds III and IV appeared to have much better therapeutic potential than the amino acid ester derivatives, i.e., compounds VII, VIII and IX. Thuε, the methyl urea derivative (IV) produced a 40 % cure rate of tumor-bearing mice at 5 mg/kg adminiεtered for 6 conεecutive dayε with no body weight loεε. Thiε agent alεo cured 100 % of mice bearing the L1210 leukemia at 10 and 15 mg/kg x 6 with leεε than a 6% loεε of body weight. The 2-chloroethyl urea derivative (III) , which can be regarded as a structural analog of BCNU, cured 80 to 100 % of leukemic mice at 10 to 20 mg/kg x 6, although at the highest dose examined, i.e., 20 mg/kg, it appeared to be somewhat toxic, as evidenced by a 10.4 % loss in body weight. The allyl urea derivative (V) was also highly efficacious against this tumor, curing 100 % of mice receiving a daily dosage of 15 mg/kg given for 6 consecutive days. The amino acid ester derivatives (VII-IX) , in general, appeared to be considerably less potent than compounds III-V requiring daily dosage levels in the range of 25 to 100 mg/kg to achieve optimum cure rates, and early deaths of treated mice occurred at higher doεeε in each caεe. Table 1 Effects of 2-Aminocarbonyl-l ,2-bis(methylsulfonyl)-1- (2-chloroethyl)hydrazines On the Survival Time of Mice Bearing the L1210 Leukemia Compound Daily Dose Av.Wt. %T/C C % 60 Dav mg kg 3 Change % b Survivorε III 10 -4.7 -.----.--_ 100 15 -4.0 216 80 20 -10.4 239 80 IV 5 +9.9 234 40 10 -5.6 100 15 -2.1 ——— 100 5 -1.6 184 20 10 -2.1 394 40 15 -2.9 100 VI 5 -2.8 Ill ___ 10 -5.6 187 15 -8.8 192 20 VII 5 -1.5 151 ___ 10 -1.4 202 20 15 -0.5 202 20 -3.7 191 20 25 -0.5 100 50 -2.5 138 80 75 -1.5 119 60 100 -4.0 115 VIII 5 -2.0 170 10 -1.4 178 20 15 -0.5 185 20 -1.5 227 25 -2.5 239 60 50 -3.3 100 75 2.5 125 80 100 2.5 118 IX 5 2.5 147 -...---.--_ 10 0.5 165 15 1.9 160 20 1.9 174 25 0.9 177 50 2.0 225 60 100 2.0 100 150 5.0 169 20 a Administered ip once daily for εix conεecutive dayε, begin¬ ning 24 hours after tumor implantation, with 5-10 mice being used per group. ^Average percent change in body weight from onset to termination of therapy. C %T/C = average survival time of treated/control mice X 100; cures (>60-day survivors) are listed separately and are not included in this calcula¬ tion. B16F10 Melanoma, M5076 Reticulum Cell Sarcoma, M109 Lung Carcinoma and LX-1 Lung Carcinoma Testing B16F10 melanoma cells were grown in vitro as monolayers in minimum eεsential medium with Hank's salts sup¬ plemented with 10% fetal bovine εerum and 1% 200 mM L- glutamine solution. Solid tumors were produced in C57BL/6 female mice 12- to 14-weeks of age by the intradermal injec¬ tion in the right flank of each mouse of 0.1 mL of a cell suspenεion containing IO 6 B16F10 cellε/mL from freεhly tryp¬ sinized cultures. After 10-12 days, animals bearing approxi¬ mately 100 mm 3 tumorε were treated ip with compound III or IV diεεolved in 100 % DMSO for 6 conεecutive dayε, and tumor volumes were measured on alternate days until reaching 1000 mm 3 . The M5076 reticulum cell sarcoma was pasεaged biweekly by sc transfer of tumor fragments into C57BL/6 mice, and the M109 lung carcinoma waε εimilarly paεsaged in BALB/c mice. The LX-1 human lung carcinoma was pasεaged εc every two to three weekε in BALB/c-background athymic (nu/nu) mice. For uεe in theεe εystems, compound III was disεolved in: (a) 100 % DMSO and adminiεtered by iv injection in a fixed volume of 10 microliters; or (b) DMSO diluted with saline to a final con¬ centration of 10% DMSO and administered iv in a volume of 0.01 milliliter/g of body weight. These different modes of formula¬ tion resulted in differences in the optimum effective dose found in the various tumor syεtemε. Mitomycin C and cyclophosphamide were dissolved and administered in saline. BCNU and MeCCNU were dissolved in ethanol and diluted 1:9 (v/v) with water prior to administration. Five mice per group were employed in experiments with the B16F10 melanoma, and 8 mice per group with the M5076 sar¬ coma, the M109 carcinoma and the LX-1 carcinoma. A minimum of two dose levels per compound were included in each evaluation and drug therapy was initiated 24 h after tumor implantation for the M5076 sarcoma and M109 carcinoma. In the LX-1 experi¬ ment, tumor-bearing mice were selected and sorted into treat¬ ment and control groups on day 6 post-tumor implant such that all tumor weights ranged from 50-100 mg and median tumor weights per group were reasonably similar. Therapeutic results are presented in terms of: (a) increaseε in lifespan reflected by the relative median survival time (MST) of treated versuε control groups (i.e., %T/C values), and by long-term survivors, and (b) primary tumor growth inhibition (i.e., T-C values) determined by calculating the relative median times for treated (T) and control untreated (C) mice to grow tumors of a 0.5 g size for the LX-1 carcinoma or a 1 g size for the murine neoplasmε. Tumor weightε were inter¬ changeable with tumor εize on the baεiε of 1 mm 3 = 1 mg. The activity criterion for increased lifespan waε a T/C of > . 125%. The activity criterion for tumor inhibition waε a delay in tumor growth conεiεtent with one log^ cell kill (LCK) . The abεolute T-C value needed to attain thiε level of efficacy varied from experiment to experiment and depended upon the tumor volume doubling time of the control mice in each εtudy. Treated mice dying prior to day 10 in the ip M109 experiment, or dying before their tumorε achieved 0.5 g for the LX-1 car¬ cinoma or 1 g in εize for all other sc tumor models, were con¬ sidered to have died from drug toxicity. Groups of mice with more than one death due to drug toxicity were not used in the evaluation of antitumor efficacy. Statistical evaluations of data were performed using Gehan's generalized Wilcoxan test (Gehan, Biometrika. 1965, 52, 203-233). Results of B16F10 Melanoma, M5076 Reticulum Cell Sarcoma, M109 Lung Carcinoma and LX-1 Lung Carcinoma Testing One of the most active and potent compoundε in the εerieε aε teεted in the L1210 system as described above, com¬ pound III, was also evaluated against several other transplanted tumors (Table 2, below). When administered at the highest dose examined, i.e, three ip doseε of 50 mg/kg given at 4 day intervals in the ip-implanted M109 lung car¬ cinoma model, this compound produced a %T/C of 267. In the εame system, but in a different experiment, the acetyl deriva¬ tive (X) produced a comparable %T/C of 231 at the highest dosage level examined (60 mg/kg per injection) , when the drug was administered ip using the same schedule (Shyam, et al., J. Med. Chem. 1993, 36, 3496-3502). CH 3 S0 2 N(CH 2 CH 2 C1)N(COCH 3 ) S0 2 CH 3 TABLE 2 Summary of Optimal Antitumor Effects of 1,2- Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(2- chloroethyl)aminocarbonylhydrazine (III) on M109, M5076 and LX-1 Tumors Tumor. Treatment Optimal Effective %T/C. (Cures/Total) . Site Schedule. Route Doεe. mg/kg/injection and/or TT-C. davεl M109, ip q4dX3; d.l a ; ip 50 b c 267 M109, εc q4dx3; d.l a ; iv 50 c a) d 115[8.3] q3dx4; d.l a ; iv 24[32] c / e b) d 143[9.3] 64 f b) d 145[17.8] M5076, εc q2dx5; d.l a ; iv 48 f >157(6/8) LX-1, εc q2dx5; d.6 a ; iv 40 f [14.5] d Day treatment initiated. ^Higheεt doεe teεted. Administered in 10% DMSO in saline. d Each letter (a,b) signifies a different RULE .% experiment. e Dose in brackets producing the maximum T-C obtained. f Administered in 100% DMSO. Compound III was also evaluated against the M109 lung carcinoma implanted εubcutaneouεly (εc) . In the initial teεt uεing thiε model, a doεe of 50 mg/kg per injection of thiε com¬ pound waε administered intravenously (iv) in 10 % DMSO in saline every fourth day for a total of three injections. While the maxi mum %T/C achieved (115) was not considered to be an active result, a meaningful delay in tumor growth (T-C) of 8.3 days was observed under these conditions. Mitomycin C, used as a referenc drug, produced a maximum %T/C of 103 and a delay in tumor growth of 10 days (data not shown) . A subsequent evaluation of compoun III was performed using four different doseε on a εlightly dif¬ ferent εchedule, i.e., 24, 32, 48 and 64 mg/kg adminiεtered ever third day for four total injections, and two vehicles, 10 % DMSO in saline and 100 % DMSO. When administered in 10 % DMSO in saline, compound III produced a maximum %T/C of 143 and a maximu delay in tumor growth of 9.3 days at 24 and 32 mg/kg per injec¬ tion, respectively; the next higher dose evaluated, 48 mg/kg per injection, was excessively lethal. At the highest level evalu¬ ated, 64 mg/kg per injection, made possible by the use of 100% DMSO as the vehicle, compound III achieved a maximum %T/C of 145 and a delay in tumor growth of 17.8 days, without causing any treatment-associated lethalities. The latter antitumor effect was statiεtically superior (p<0.01) to the best T-C value achieved with this compound in 10 % DMSO in saline. Cyclophosphamide and mitomycin C were included as reference drugs in the last experi¬ ment. The former compound produced a maximum %T/C of 143 and a delay in tumor growth of 8.8 days, while mitomycin C produced a maximum %T/C of 134 and a T-C value of 9.3 days (data not shown). Aε reported earlier, compound X achieved a maximum %T/C of 136 and a maximum T-C value of 14.5 dayε againεt thiε tumor (Shyam, et al., J. Med. Chem.. 1993, 36, 3496). Compound III was also evaluated against the M5076 reticulum cell sarcoma implanted sc. When administered iv at a level of 48 mg/kg per injection in 100 % DMSO every other day fo five days, compound III cured 6 out of 8 mice and consequently, no median time (T-C value) to reach 1 gram size tumors was expresεed for thiε group. Tumor growth in mice receiving only 100 % DMSO waε indistinguishable from that of untreated control animals. 1-(2-Chloroethyl) -3-(4-methylcyclohexyl) -1-nitroεourea (MeCCNU) and BCNU were included in this experiment for com¬ parison. The former achieved a maximum %T/C of 128 and a delay in tumor growth of 33.5 days at 16 mg/kg per injection administered iv every fourth day for three total injections, while BCNU, administered iv on the same treatment schedule, pro¬ duced a %T/C in excesε of 157, with 2 out of 8 cureε, and a T-C of >62 days (data not shown) . Since compound X, a chloroethylat ing agent with no carbamoylating activity, is much leεε active than compound III or BCNU against this tumor, it see ε probable that the generation of an iεocyanate intermediate contributes to the antineoplastic properties of chloroethylating agents against the M5076 sarcoma. The human lung tumor, LX-1, xenografted sc in athymic mice, waε alεo uεed to examine the antineoplaεtic potential of compound III. Treatment waε initiated on day 6 post-implant whe the median weight of the tumors was approximately 100 mg. A dos of 40 mg/kg per injection of compound III administered iv in 100 % DMSO on an every other day schedule for a total of five injec¬ tions was optimal; this regimen produced a median delay of 14.5 dayε in the growth of thiε tumor to a target size of 0.5 g. This level of activity, 1.6 LCK, compared favorably with that obtained with BCNU in the same experiment, which produced a T-C of 11.8 days (1.3 LCK) at the optimum dosage of 20 mg/kg per injection when administered iv every fourth day for a total of three injec¬ tions. In addition, both compounds III and IV were evaluated in 100 % DMSO against the B16F10 melanoma implanted intradermally (id) in mice (Table III) . In an initial experiment, compound IV produced a T-C of 15.5 days at a daily dosage level of 20 mg/kg administered once daily for six consecutive days beginning on day 10 post-implant. In the same experiment, using the same treat¬ ment schedule, a growth delay of 11 days was obtained with com¬ pound III. In the second experiment, when the daily dose of com¬ pound IV was increaεed to 30 mg/kg, a more εubεtantial growth delay of 25.5 dayε was achieved, whereas compound III at the same daily dose of 30 mg/kg was less active, with the T-C value obtained being 13.5 days. Thus, the aminocarbonyl component in this class of agents influences the magnitude of the antitumor effects obtained against the B16F10 melanoma. TABLE 3 Antitumor Activity of 1,2-Bis(methylsulfonyl)-l-(2-chloroethyl)- 2-(2-chloroethyl)aminocarbonylhydrazine (III) and 1,2- Bis(methylsulfonyl)-1-(2-chloroethyl)-2- methylaminocarbonylhydrazine (IV) Against sc B16F10 Melanoma Compound Treatment Optimal Effective ' -C. Dayε Schedule, Route Doεe. mg/kg/iniection III qdX6; d.lO a ; ip 20 b a) c 11.0 qdX6; d.l2 a ; ip 20 b b) c 5.5 30 b b) c 13.5 rv qdX6; d.lO a ; ip 10 b a) c 5.0 20 b a) c 15.5 qdX6; d.l2 a ; ip 20 b b) c 10.0 30 b b) c 25.5 d Day treatment initiated. b Administered in 100% DMSO. u Each letter (a,b) signifies a different experiment. Summary In summary, 2-aminocarbonyl-l,2-bis(methylsulfonyl)-1-(2 chloroethyl)hydrazines were highly active against the L1210 leukemia in mice. A representative agent of this clasε, compound III, was found to have substantial activity in several more stringent distal site tumor models, that unexpectedly was better than or equal to some of the best clinically active alkylating agents used for comparison in these asεays. Furthermore, a com¬ parison of compoundε III and IV against the B16F10 melanoma demonstrated that the aminocarbonyl substituent influenced the degree of antineoplastic activity attainable. It is to be understood by those skilled in the art that the foregoing description and examples are illustrative of prac¬ ticing the present invention, but are in no way limiting. Varia tions of the detail presented herein may be made without depart¬ ing from the spirit and scope of the present invention as defined by the following claims.

Claims: Claims : 1. A compound of the formula: CH 3 S0 2 N(Y)N(CONHR) S0 2 CH 3 where Y is -CH 3 or -CH 2 CH 2 C1; and R is Cf-Cη alkyl, cyclohexyl, methylcyclohexyl, -CH 2 CH=CH 2 , -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 C1, -CH 2 COOC 2 H 5 , -CH(CH 3 ) COOC 2 H 5 or -CH(CH 2 C 6 H 5 )COOC 2 H 5 . 2. The compound according to claim 1 wherein Y is -CH 2 CH 2 C1 and R is -CH 2 CH 2 C1, -CH 2 CH=CH 2 or -CH 3 . 3. The compound according to claim 2 wherein R is -CH 2 CH 2 C1 or -CH 3 . 4. The compound according to claim 2 wherein R is -CH 2 CH 2 C1. 5. The compound according to claim 1 wherein εaid l~ 7 alkyl i Ξ εelected from the group conεiεting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or εubstituted hexyl. 6. A pharmaceutical composition for use in treating malignant tumors in mammals comprising a therapeutically effec¬ tive amount of a compound of the formula: CH 3 S0 2 N(Y)N(CONHR) S0 2 CH 3 where Y is -CH 3 or -CH 2 CH 2 C1; and R is Cχ-C 7 alkyl, cyclohexyl, ethylcyclohexyl, -CH 2 CH=CH 2 , -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 C1, -CH 2 COOC 2 H 5 , -CH(CH 3 )COOC 2 H 5 or - CH(CH 2 C 6 H 5 )COOC 2 H 5 . 7. The composition according to claim 6 further includ¬ ing a pharmaceutically acceptable excipient, additive or carrier. 8. The composition according to claim 6 wherein Y is -CH 2 CH 2 C1 and R is -CH 2 CH 2 C1, -CH 2 CH=CH 2 or -CH 3 . 9. The composition according to claim 8 wherein R is -CH 2 CH 2 C1 or -CH 3 . 10. The composition according to claim 9 wherein R is -CH 2 CH 2 C1. 11. The composition according to claim 6 wherein said Cι~C 7 alkyl is selected from the group consiεting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, iεopentyl, n-hexyl, iεohexyl and εubεtituted hexyl. 12. The compoεition according to claim 7 in intra- venouε doεage form. 13. The compoεition according to claim 7 in intramus- cular dosage form. 14. The composition according to claim 7 in oral dosage form. 15. Compositions for use in treating malignant tumors in mammals comprising administering a therapeutically effective amount of a compound of the formula: CH 3 S0 2 N(Y)N(CONHR) S0 2 CH 3 where Y is -CH 3 or -CH 2 CH C1; and R iε C ] _-C 7 alkyl, cyclohexyl, methylcyclohexyl, -CH CH=CH 2 , -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 C1, -CH 2 COOC 2 H 5 , -CH(CH 3 )COOC 2 H 5 or -CH(CH 2 C 6 H 5 ) COOC 2 H 5 . 16. The composition according to claim 15 wherein Y is -CH 2 CH 2 C1. 17. The composition according to claim 15 wherein said Cι~C 7 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl isopentyl, n-hexyl, isohexyl or substituted hexyl. 18. The composition according to claim 15 wherein Y is -CH 2 CH 2 C1 and R is -CH 2 CH 2 C1, -CH 2 CH=CH 2 or -CH 3 . 19. The compoεition according to claim 18 wherein R is -CH CH 2 C1 or -CH 3 .

Inventors: PENKETH PHILIP G, SARTORELLI ALAN C, SHYAM KRISHNAMURTHY, PENKETH, PHILIP, G., SARTORELLI, ALAN, C., SHYAM, KRISHNAMURTHY
Applicants: UNIV YALE, YALE UNIVERSITY
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P35, C07C311