ANTITUMOR COMPOSITIONS AND METHODS OF TREATMENT

Abstract: This invention provides certain substituted 2,3-dihydrobenzofurylsulfonamide derivatives and methods for using them in the treatment of susceptible neoplasms in mammals. Also provided are certain novel pharmaceutical formulations employing these benzenesulfonamide derivatives in combination with a carrier.

Description: Title ANTITUMOR COMPOSITIONS AND METHODS OF TREATMENT 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. (Giln an, et al.. 8th ed. 1990) 1484-1487. Some diarylsulfonylureas have been reported as being active antitumor agents. e&., U.S. Patent 5, 169,860, of F. Mohamadi and M. Spees, issued December 8, 1992; U.S. Patent 4,845, 128 of Harper, et al.. issued July 4, 1989; U.S. Patent 5, 110,830 of Harper, et al.. issued May 5, 1992; U.S. Patent 5, 116,874 of G.A. Poore, issued May 26, 1992; U.S. Patent 5,216,026, of J. Howbert, issued June 1, 1993; U.S. Patent 5,216,027, of J.E. Ray, et al.. issued June 1, 1993; U.S. Patent 5,260,338, of R.W. Harper, et al.. issued November 9, 1993; U.S. Patent 5,594,028, of R.W. Harper, et al.. issued January 14, 1997; U.S. Patent 5,302,724, of J.J. Howbert, et al.. issued April 12, 1994; U.S. Patent 5,270,329, of W.L. Scott, et al.. issued December 14, 1993; U.S. Patent 5,234,955, of J.E. Ray, et al.. issued August 10, 1993; U.S. Patent 5,354,778, of J.E. Ray, et al.. issued October 11, 1994; U.S. Patent 5,258,406, of J.E. Toth, et al.. issued November 2, 1993; U.S. Patent 5,262,440, of W.J. Ehlhardt, et al.. issued November 16, 1993; U.S. Patent 5,254,582, of G.B. Boder, et al.. issued October 19, 1993; U.S. Patent 5,565,494, of G.B. Grindey, et al.. issued October 15, 1996; U.S. Patent 5,387,681, of W.D. Miller, et al.. issued February 7, 1995; and U.S. Patent 5,529,999, of J.E. Ray, et al. issued June 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 l is oxo, hydrogen, or hydroxy; R la is oxo, hydrogen, or hydroxy; and R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, alkyl, and triQuoromethyl, provided that no more than one of R 2 and R 3 can be hydrogen; provided that no more than one of R 1 and R la is hydrogen; and further provided that no more than one of R 1 and R la is oxo; or a pharmaceutically acceptable salt or solvate 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 -C6 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 "C2-C8 alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to eight carbon atoms. Typical C2-C8 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-l-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 triQuoromethyl. 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 Uterature. 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 III where R 1 , R la , 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 nonre active 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 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, Uthium hydroxide, sodium methoxide, sodium hydride and the Uke. GeneraUy, an equimolar or sUght molar excess of V is employed, although other ratios are operative. UsuaUy, the amount of base used is approximately equimolar to the amount of IV. The reaction is generally carried out from about 0°C up to about 100°C. At the preferred temperature of about 20°C to about 30°C, the reaction is usuaUy complete within about three hours. A preferred process for preparing a compound of Formula I involves reacting a sulfonamide of Formula IV with an alkyl haloformate of the formula XCOOR 4 > where X is bromo or chloro and R 4 is C 1 -C3 alkyl, to provide the carbamate of Formula VI and then reacting it with an aniUne derivative of Formula III to provide the corresponding product of Formula I. The transformation of IV into VI is usually accompUshed in a non-reactive solvent, such as acetone or methyl ethyl ketone, in the presence of an acid scavenger, such as an alkaU metal carbonate, for example potassium carbonate. A molar excess of the haloformate is usuaUy added, although other ratios are operative. The reaction mixture is heated to a temperature from about 30°C up to the reflux temperature of the mixture for a period of about 1-6 hours to provide the desired intermediate VI. Intermediate carbamate VI and the substituted aniUne III are then heated together in an inert high-boihng solvent, such as dioxane, toluene, or diglyme, at temperatures from about 50°C up to the reflux temperature of the mixture to provide the desired product of Formula I. The carbamate of Formula VI can also be synthesized by the procedure described by Atkins and Burgess. G. Atkins and E. Burgess, Journal of the American Chemical Society. 94:6135 (1972). In this process triethylamine and a substituted aniline are mixed in the presence of a solvent such as benzene. To this mixture a sulfamoyl chloride is added to produce the carbamate of Formula VI. Intermediates II, III, IV, V, and VI, and any other reagents required for these methods of preparation are commercially available, are known in the Uterature, or can be prepared by methods known in the art. This invention encompasses the pharmaceuticaUy acceptable salts of the compounds defined by Formula I. Although generaUy neutral, a compound of this invention can possess a sufficiently acidic functional group, and accordingly react with any of a number of organic or inorganic bases to form a pharmaceuticaUy acceptable salt. The term "pharmaceuticaUy acceptable salt" as used herein, refers to salts of the compounds of Formula I which are substantiaUy non- toxic to Uving organisms. Typical pharmaceuticaUy acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceuticaUy acceptable organic or inorganic base. Such salts are known as base addition salts. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the Uke. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the Uke. The potassium and sodium salt forms are particularly preferred. Organic bases can also be used, including primary, secondary, and tertiary alkyl amines such as methylamine, triethylamine, and the Uke. It should be recognized that the particular counterion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmacologicaUy acceptable and as long as the counterion does not contribute undesired quaUties to the salt as a whole. This invention further embraces the pharmaceuticaUy acceptable solvates of the compounds of Formulas I. The Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceuticaUy acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate. This invention also encompasses the pharmaceuticaUy acceptable prodrugs of the compounds of Formula I. A prodrug is a drug which has been chemicaUy modified and may be biologicaUy inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form. This prodrug should have a different pharmacokinetic profile than the parent, enabUng easier absorption across the mucosal epitheUum, better salt formation or solubility, or improved systemic stability (an increase in plasma half-life, for example). TypicaUy, such chemical modifications include: 1) ester or amide derivatives which may be cleaved by esterases or Upases; 2) peptides which may be recognized by specific or nonspecific proteases; or 3) derivatives that accumulate at a site of action through membrane selection of a prodrug form or a modified prodrug form; or any combination of 1 to 3, supra. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H, Bundgaard, Design of Prodrugs. (1985). The terms and abbreviations used in the instant examples have their normal meanings unless otherwise designated. For example "_C" refers to degrees Celsius; "N" refers to normal or normaUty; "mmole" refers to milUmole; "g" refers to gram or grams; "ml" means miUiliter or miUiUters; "M" refers to molar or molarity; "FDMS" refers to field desorption mass spectrometry; "m.p." refers to melting point; and "NMR" refers to nuclear magnetic resonance. The following examples further illustrate the preparation of the compounds of Formula I. These examples are lustrative only and are not intended to Umit the scope of the invention in any way. Preparation 1 Preparation of 2,3-dihydrobenzofuran-5-sulfonyl chloride To a 250 ml, 3-neck flask under nitrogen purge was added 9.2 grams (60 mmoles) of suffur trioxide-N,N-dimethy]formamide complex and 20 ml of 1,2-dichloroethane. The slurry was stirred at room temperature and 2,3-dihydrobenzofuran (6.0 g, 50 mmoles) was added dropwise at room temperature. The slurry was slowly heated to 85_C and aUquots were monitored for the progress of the reaction. After one hour the reaction was complete. The reaction slurry was aUowed to come to room temperature, at which time thionyl chloride (7.2 g, 60 mmoles) was added dropwise. The reaction mixture was slowly heated over the course of one hour, by which time it had reached 75_C. The mixture was aUowed to cool to room temperature. Water (100 ml) was then added to the slurry. The aqueous layer was extracted with 1,2-dichloroethane (3 x 25 ml). The 1,2-dichloroethane layers were combined and washed with water (25 ml) and dried over magnesium sulfate. The magnesium sulfate was filtered and washed with 1,2-dichloroethane. The 1,2-dichloroethane was removed under vacuum to give 11 grams of the title compound (>99% yield). Nuclear magnetic resonance assays confirmed the identity of the title compound. FDMS (MeOH) m/e 218 (M + ). Analysis for C8H7CIO3S: Theory: C, 43.94; H, 3.23. Found: C, 44.13; H, 3.34. Preparation 2 Preparation of 2,3-dihydrobenzofuran-5-sulfonamide. Into a 250 ml, 3-necked flask under nitrogen purge were added sulfur trioxide-N,N-dimethylformamide complex (9.2 g, 60 mmoles) and 1,2-dichloroethane (20 ml). The slurry was stirred at room temperature and 2,3-dihydrobenzofuran (6.0 g, 50 mmoles) was added dropwise at room temperature. The purple slurry was slowly heated to 85_C over the course of one hour. The progress of the reaction was monitored using thin layer chromatography. Once the reaction was completed, the reaction mixture was aUowed to cool to room temperature and thionyl chloride (7.2 g, 60 mmoles) was added dropwise. The reaction mixture was slowly heated to 75_C and maintained at that temperature untU the reaction had completed, as determined by thin layer chromatography. The reaction mixture was aUowed to cool to room temperature and water (100 ml) was added. The aqueous layer was coUected and extracted with 1,2-dichloroethane (3 x 25 ml). The combined 1,2-dichloroethane layers were washed with water (25 ml) and dried over magnesium suUate. The magnesium suUate was filtered and washed with 1,2-dichloroethane. This 1,2-dichloroethane solution containing the desired suUonyl chloride was added to a solution of 1,2-dichloroethane (20 ml) and gaseous ammonia (14.7 g) cooled by a dry ice/acetone bath. This reaction was aUowed to stir overnight, eventuaUy coming to room temperature. The precipitate was filtered and washed with 1,2- dichloroethane, foUowed by a wash with water and, finaUy, a wash with ether. The precipitate was vacuum dried to give 6.9 g of the title product. The 1,2-dichloroethane filtrate was evaporated under vacuum to give 2.0 g of soUd with was slurried with 25 ml of water. This precipitate was filtered and washed with water and ether, the ether being removed by vacuum-drying. The 1.2 g of soUd title compound recovered by this extraction of the filtrate (Sample B), when combined with the 6.9 g of title compound in the earUer precipitate (Sample A) results in an overall 81% yield of the title compound. Nuclear magnetic resonance assays confirmed the identity of the title compound. Analysis for C8H9NO3S: Sample A FDMS (MeOH) m/e 199 (M + ). Theory: C, 48,23; H, 4.55; N, 7.03. Found: C, 48.33; H, 4.47; N, 6.96. Sample B FDMS (MeOH) m/e 199 (M + ). Theory: C, 48,23; H, 4.55; N, 7.03. Found: C, 48.33; H, 4.49; N, 7.01. Preparation 3 Preparation of N-ethoxycarbonyl-2,3-dihydrobenzofur-5-ylsuUonamide To a solution of 2,3-dihydrobenzofur-5-ylsuUonamide (8.0 g , 40.2 mM) in 120 ml methyl ethyl ketone was added pulverized potassium carbonate (6.3 g, 45.6 mM) and the mixture brought to reflux under nitrogen with vigorous stirring. After 30 minutes, ethyl chloroformate (4.3 ml, 43 mM) was added through the condenser dropwise to the reaction mixture and refluxing continued for 16 hours. The reaction mixture was cooled, dUuted with water (350 ml), placed in a separatory funnel and washed with ethyl acetate (2 x 100 ml); the ethyl acetate washes were back-extracted with water (1 x 100 ml) and this was added to the main aqueous phase. The combined aqueous layers were acidified with IN hydrochloric acid (100 ml) and extracted with ethyl acetate (4 x 100 ml). After washing with water (1 x 50 ml) and brine (1 x 50 ml), the organic layer was dried over suUuric acid, filtered and evaporated to 8.9 g (82%) product as a white soUd. A sample was recrystaUized from toluene to give an analytical sample. Analysis of the title compound gave the foUowing results: mp=118-119°C; R f (1/1 EtOAc hexanes) = 0.25; 1H NMR (300 MHz, DMSO-d 6 ) δ 1.10 (t, 3H, J = 7 Hz , CH 3 ), 3.24 (dd, 2H, J = 8.8 Hz , CH 2 ), 3.96 (q, 2H, J = OCH 2 CH 3 ), 4.63 (dd, 2H, J = 8.8Hz, CEb), 6.91 (d, IH, J = 8.5Hz, Ar-H), 7.63 (d, 1 H, J = 8.5Hz, Ar-H), 7.70 (s, IH, Ar-H) and 11.7 (bs, IH, NH); IR(KBr) 3255, 1749, 1483, 1434, 1325, 1229, 1179, 1063, 921, 830 775 cm " *; UV(EtOH) λmax(ε) 279.2 (2804), 246.6 (12255) and 205.8 (30265) nm; FDMS (MeOH) m/e 27KTVT . Analysis for C 11 H 1 3NO5S: Theory: C, 48.70; H, 4.83; N, 5.16. Found: C, 48.83; H, 4.64; N, 5.16. Preparation 4 Preparation of N-ethoxycarbonyl-2,3-dihydro-3-oxo-benzofur-5- ylsuUon amide The su nylcarbamate (7.0 g, 26 mM) in 350 ml glacial acetic acid was treated with 100 ml (105 mM) of a solution of chromium trioxide (21 g) in glacial acetic acid (190 ml) and water (10 ml), keeping the internal temperature less than 30°C. After 4.5hrs, HPLC (Radial-pak Ci8, 50/50/0.2% CH 3 CN/H 2 O/H3PO 4 ) shows complex mixture with only 60% conversion. DUute with water (2000 ml) and extract with ethyl acetate (6 x 200 ml). The combined organic extracts were washed with water (2 x 100 ml) and brine (1 x 100 ml) and dried over sodium suUate. Evaporation gave 7.8 g dark oU. Chromatography (Prep 2000, siUca, 20% ethyl acetate/hexanes gradient to 100% ethyl acetate) gave recovered starting material, 780 mg and 1.0 g product (14% based on recovered starting material). Analysis of the title compound gave the foUowing results: mp=l 18- 119°C; R f (1/1 EtOAc/hexanes) = 0.25; 1H NMR (300 MHz, DMSO-d 6 ) δ 1.10 (t, 3H, J = 7 Hz , CH3), 3.96 (q, 2H, J = OCH 2 CH 3 ), 4.95 (s, 2H, CH^CO), 7.49 (d, IH, J = 8.8Hz, Ar-H), 8.01 (s, 1 H, Ar-H), 8.13 (d, IH, J =8.8Hz, Ar-H) and 12.1 (bs, IH, NH); IR(KBr)3200, 1737, 1703, 1613, 1472, 1458, 1351, 1211, 1159, 1125, 1081, 1047, 993, 873 and 649 cm "1 ; UV(EtOH) λmax(ε) 320.0 (3683), 245.0 (8902) and 224.5 (38095) nm; FDMS (MeOH) m/e (285, M + ). Analysis for CπHnNOeS: Theory: C, 46.31; H, 3.89; N, 4.91. Found: C, 46.53; H, 4.04; N, 4.88. Example 1 Preparation of N-[[[3,4-dichlorophenyl]amino]carbonyl]-2,3-dihydro-3-oxo- benzofur- 5 -ylsuUonamide A solution of N-ethoxycarbonyl-2,3-dihydro-3-oxo-benzofur-5- ylsuUonamide (4.5 g, 15.8 mM) and 3,4-dichloroaniUne (2.9 g,17.5 mM) in 180 ml toluene was prepared and heated at reflux under nitrogen with removal of toluene/ethanol azeotrope by use of a Dean-Stark trap. After 5 hours and removal of about 50 ml azeotrope, thin layer chromatography (100% ethyl acetate) shows complete loss of starting material. CooUng in an ice-bath, foUowed by filtration gave a soUd which was rinsed with toluene (50 ml) and diethyl ether (50 ml). Vacuum drying gave 5.2 g (83%) of the title compound Analysis of the title compound gave the foUowing results: mp=209-211°C; R f (100% THF) = 0.43; 1H NMR (300MHz, DMSO-d 6 ) δ 4.94 (s, 2H, CH^CO), 7.28 (d, IH, J = 8.8Hz, Ar-H), 7.51 (m, 2H, Ar-H), 7.66 (s, IH, Ar-H),8.12 (s, IH, Ar-H), 8.23 (d, IH, J = 8.8Hz, Ar-H), 9.32 (s, IH, NH) and 11.08 (bs, IH, NH); IR(KBr) 3364, 3254, 1744, 1713, 1614, 1591, 1534, 1467, 1444, 1347, 1208, 1147, 1121, 1026, and 1001 cm "1 ; UV(EtOH) λmax(ε) 320.0 (4086), 296.5 (2836), 249.5 (31372) and 213.0 (48434) nm; FDMS (MeOH) m/e 402 (M + +2), 400 (M + ), 239 (M + - 161). Analysis for C15H 1 0CI2N 2 O5S: Theory: C, 44.90; H, 2.51; N, 6.98. Found: C, 45.17; H, 2.59; N, 6.97. Example 2 Preparation of N-[[[3,4-dichlorophenyl]amino]carbonyl]-2,3-dihydro-3- hy dr oxy -b enzofur- 5 -ylsuUon amide The N-[[[3,4-dichlorophenyl]amino]carbonyl]-2,3-dihydro-3- oxo-benzofur-5-ylsuUonamide (2.9 g, 7.2 mM) in 60 ml methanol at 0°C was treated with sodium borohydride (820 mg, 22 mM) in portions over 5 minutes. The ice-bath was removed and the reaction stirred under nitrogen for 15 minutes. After quenching with 4 ml 5N hydrochloric acid at 0°C the reaction mixture was concentrated to about 4 ml and dUuted with ethyl acetate (300 ml). The ethyl acetate solution was washed with water (3 x 50 ml); the combined aqueous washes were back-extracted with fresh ethyl acetate ( 1 x 100 ml). The combined organic layers were washed with brine (1 x 50 ml), dried over sodium suUate, filtered and evaporated to 2.2 g. This residue was dissolved in 50 ml water, 5 ml IN sodium hydroxide added, and the solution filtered through CELITE™. After cooUng to 0°C, the clear solution was treated with 5N hydrochloric acid (1.2 ml), and the resulting precipitate coUected by filtration and washed with water (20 ml). Vacuum-drying gave the product as a white soUd, 1.56 g (54%). Analysis of the title compound gave the foUowing results: mp=109-112°C; R f (1/1 EtOAc/hexanes) = 0.25; 1H NMR (300MHz, DMSO-dβ ) δ 4.30 (m, IH, CHaCO), 4.63 (m, IH, CH 2 CO), 5.32 (m, IH, CHOH), 5.86 (bs, IH, exchanges with D 2 0, OH), 7.02 (d, IH, J = 8.6Hz, Ar-H), 7.25 (m, IH, Ar-H), 7.47 (d, IH, J = 8.6Hz, Ar-H), 7.67 (m, 1 H, Ar-H), 7.84 (d, IH, J =8.6Hz, Ar-H), 7.93 (s, IH, Ar- H), 9.13 (s, IH, NH) and 10.92 (bs, IH, NH); IR(KBr) 3344, 3111, 1702, 1593, 1535, 1479, 1384, 1342, 1244, 1204, 1176, 1146, 1121, 1075, 1034, 952 and 870 cm "1 ; FDMS (MeOH) m/e 402^ + ), 404 (M + + 2), 406(M + + 4). Analysis for C 1 5H 12 CI 2 N2O5S: Theory: C, 44.68; H, 3.00; N, 6.95. Found: C, 44.48; H, 2.84; N, 6.84. Preparation 5 Preparation of N-ethoxycarbonyl-4-hydroxy-3-(prop-2-en- 1- yl)phenylsuUonamide To a solution of 3-aUyl-4-hydroxybenzenesuUonamide (2 g, 9.4 mM) [prepared as described in Patent Cooperation Treaty PubUcation WO 96/09818, pubUshed April 4, 1996] in 100 ml methyl ethyl ketone was added potassium carbonate (1.4 g, 10 mM) and the mixture heated under nitrogen to reflux. After 10 minutes, ethyl chloroformate (1.8 ml, 18.8 mM, 2 equivalents) was added dropwise and the mixture refluxed for 3 hours. The cooled reaction was acidified with IN hydrochloric acid (50 ml) and the layers separated. An additional wash with water (1 x 50 ml) and brine (1 x 24 ml), foUowed by drying over sodium sulfate and evaporation gave 3.3 g of the di-acylated product. The crude oU was dissolved in water (90 ml), IN sodium hydroxide (29 ml) added and the mixture heated to refiux 2 hours. After cooUng in an ice-bath, IN hydrochloric acid (30 ml) was added and the resulting soUd coUected and dried to 1.87 g. Chromatography (siUca gel, 100% methylene chloride to 5% methanol/methylene chloride) gave the product as a white soUd, 1.3 g (49%). Analysis of the title compound gave the foUowing results: R f (1/9 MeOH/CHCla) = 0.29; 1H NMR (300 MHz, DMSO-d 6 ) δ 1.05 (t, 3H, J=6.9 Hz, OCHsCHa), 3.30 (d, 2H, J=6.7Hz, CH 2 =CHCH 2 ), 3.95 (q, 2H, J=6.9Hz, OCHaCHs), 5.05 (s, IH, CH 2 =CHCH 2 ), 5.05 (d, IH, J= 4Hz, CH 2 =CHCH 2 ), 5.85-5.94 (m, IH, CH 2 =CHCH 2 ), 6. 91 (d, IH, J=8.4Hz, Ar-H), 7.50-7.60 (m, 2H, Ar-H), 10.6(bs, IH, exchanges with D 2 0, OH), and 11.63(bs, IH, exchanges with D 2 0, NH); IR(KBr) 3409, 3212, 1728, 1592, 1488, 1425, 1366, 1348, 1290, 1239, 1159, 1129, 835 and 772 cm "1 ; UV(EtOH) λmax(ε) 244.5 (13070) and 207.0 (31769) nm; FDMS (MeOH) m/e 285 ( 4 ). Analysis for C 1 2H 1 5NO5S: Theory: C, 50.52; H, 5.30; N, 4.91. Found: C, 50.39; H, 5.20; N, 4.66. Preparation 6 Preparation of N-[[[3,4-dichlorophenyl]amino]carbonyl]-4-hydroxy-3- (prop-2-en-l-yl)phenylsuUonamide A solution of N-ethoxycarbonyl-4-hydroxy-3-(prop-2-en-l- yl)phenylsuUonamide (500 mg, 1.75 mM) and 3,4-dichloroaniUne (340 mg, 2.06 mM, 1.2 equivalents) was prepared in toluene (25 ml) and heated to reflux under nitrogen, removing the toluene/ethanol azeotrope by use of a Dean-Stark trap. After 4.5 hour and removal of about 10 ml azeotrope, the solution was cooled in an ice-bath and the resulting precipitate coUected and rinsed with cold toluene (10 ml). Vacuum dry to a white soUd, 536 mg (76%). Analysis of the title compound gave the foUowing results: Rf (1/9 MeOH/CHCl 3 ) = 0.19; 1H NMR (300MHz, DMSO-d6)δ 3.31 (d, 2H, J=6.7Hz, CH^CHCH^), 5.01 (s, IH, CH 2 =CHCH 2 ), 5.06 (d, IH, J= 7.9Hz, CH 2 =CHCH 2 ), 5.85-5.94 (m, IH, CH 2 =CHCH 2 ), 6. 91 (d, IH, J=8.4Hz, Ar-H), 7.22 (m, IH, Ar-H), 7.45 (d, IH, J=8.8Hz, Ar-H), 7.50-7.65 (m, 3H, Ar-H), 9.03 (bs, IH, exchanges with D 2 0, CONH), 10.6(bs, IH, exchanges with D 2 0, OH), and 10.8(bs, IH, exchanges with D 2 0, NH); ; IR(KBr) 3383, 3206, 1712, 1700, 1591, 1521, 1460, 1432, 1394, 1339, 1279, 1239, 1152, 1123, 1056, 864 and 706cm "1 ; FDMS (MeOH) m/e 400,402 (M + , M + +2). Analysis for C16H14CI2N2O4S: Theory: C, 47.89; H, 3.52; N, 6.98. Found: C, 47.78; H, 3.61; N, 6.72. Preparation 7 Preparation of N-ethoxycarbonyl-2,3-dihydro-2-hydroxy-benzofur-5- ylsuUon amide A solution of the aUyl phenol (1.0 g, 3.5 mM) in 50 ml ethyl acetate at -70°C was treated with ozone until the reaction was blue in color. After stirring another 5 minutes, the excess ozone was purged with nitrogen and the reaction mixture was treated with dimethyl sulfide (6 ml, 82 mM) and aUowed to come to room temperature and stir for 48 hours. The reaction mixture was diluted to 100 ml with ethyl acetate and washed with water (3 x 50 ml) and brine (1 x 25 ml); drying over sodium suUate foUowed by filtration and evaporation gave an oU. FUtration through coarse siUca, eluting with 700 ml ethyl acetate, gave the product as a yeUow soUd after evaporation, 840 mg (83%). Analysis of the title compound gave the foUowing results: R f (1/9 MeOH/CHCl 3 ) = 0.19; 1H NMR (300 MHz, CDC1 3 ) δ 1.20 (t, 3H, J=7.1, OCHaCHa), 3.10 (d, IH, J=15.6Hz, CHCHa-), 3.35(d, IH, exchanges with D 2 0, J=4.9Hz, OH), 3.45 (dd, IH, J=7.2,7.0Hz, CHCH 2 -), 4.10 (q, 2H, J=7.lHz, OCHaCHg), 6.21 (m, IH, CHCH 2 ), 7.15-7.25(m, 2H, Ar-H), 7.88(s, IH, Ar-H) and 7.9 l(s, IH, exchanges with D 2 0, NH); IR(KBr) 3432, 1725, 1484, 1453, 1371, 1355, 1300, 1242, 1192, 1156, 1129, 1081, 931, 911, 806 and 598 cm "1 ; FDMS (MeOH) m/e 287 (M + ). Analysis for C 11 H 1 3NO6S: Theory: C, 45.99; H, 4.56; N, 4.88. Found: C, 45.70; H, 4.74; N, 4.68. Example 3 Preparation of N-[[[3,4-dichlorophenyl]amino]carbonyl]-2,3-dihydro-2- hydroxy-benzofur-5-ylsuUonamide A solution of the aUyl phenol (800 mg, 2 mM) in 25 ml ethyl acetate was prepared and cooled to -70°C. Ozone was bubbled into the solution until the blue color persisted (5 minutes); the reaction mixture then was purged with nitrogen , treated with dimethylsulfide (5 ml, 68 mM) and aUowed to come to room temperature over 24 hours. The mixture was transferred to a separatory funnel with 100 ml ethyl acetate and washed with water (3 x 25 ml) and brine (1 x 20 ml). After drying over sodium suUate and evaporating, 840 mg of white foam was obtained. Chromatography (silica, 100% methylene chloride to 10% methanol/methylene chloride) gave the desired compound, 600 mg (75%). Analysis of the title compound gave the foUowing results: 1H NMR (300 MHz, DMSO-d 6 ) δ ; 3.15(m. 2 H, CHaCH), 5.99 (m, IH, CH 2 CHOH), 6.70-6.79 (m, IH, Ar-H), 7.20-7.40(m, 2H, Ar-H), 7.45- 7.59(m, 2 H, Ar-H), 7.80 (s, IH, Ar-H), 8.74 (IH, NH), 9.57(s, IH, OH) and 10.04 (s, IH, NH). IR(KBr) 3346, 1715, 1609, 1518, 1479, 1382, 1296, 1242, 1121, 1062, 922, 899, 819, 771, 715 and 578 cm "1 ; MS for C 16 H 1 4CI2N2O4S: Theory: 402.9922. Found: 402.9913. The compounds of Formula I have been shown to be active against human tumors in vitro. The in vitro data were obtained using CCRF-CEM ceUs, a human leukemia ceU Une. Foley et al.. Cancer. 18:522 (1965). These ceUs were grown using standard techniques. See, e.g., G.B. Grindey. et al.. Journal of Molecular Pharmacology. 16:601 (1979). Dose- response curves were generated for various compounds to determine the concentration required for 50% inhibition of growth (IC50). Cluster plates were prepared in dupUcate with the compound at various concentrations. Test compounds were dissolved initially in DMSO at a concentration of 4 mg/ml and further diluted with solvent to the desired concentration. CeUs in RosweU Park Memorial Institute 1640 media supplemented with 10% dialyzed fetal bovine serum, and 25 mM HEPES buffer were added to the weU at a final concentration of 4.8 X 10 4 ceUs/weU in a total volume of 2.0 ml. After 72 hours of incubation (95% air, 5% CO2), ceU numbers were determined on a ZBI Coulter counter. CeU number for indicated controls at the end of incubation was usuaUy (4-6) X 10 5 ceUs/weU. CeU viability was also measured by staining with 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyl-tetrazoUum bromide (MTT) using standard techniques. R.I. Freshney, Culture of Animal CeUs: A Manual of Basic Technique. 253-254 (2d ed. 1987). The compounds of Formula I have also been shown to be active against transplanted human tumors in vivo. To demonstrate the anti-tumor activity of the compounds of Formula I, these compounds are tested in mice bearing different aUograft and xenograft tumors. One of the tumor models used for showing the anti-neoplastic activity of the suUonylureas of this invention is the human colon xenograft HXGC3. JA. Houghton and D.M. Taylor, British Journal of Cancer. 37:213-223 (1978). This tumor is obtained from St. Jude's ChUdren's Research Hospital and has been widely used as a human tumor model. A second tumor model employed C3H mice bearing the widely used aUograft 6C3HED lymphosarcoma, also known as the Gardner lymphosarcoma (GLS). The 6C3HED lymphosarcoma is obtained from the Division of Cancer Treatment, National Cancer Institute, Tumor Bank, maintained at E. G. and G. Mason Research (Worcester, Massachusetts). First passage tumors are stored in Uquid nitrogen, using standard techniques. The transplanted tumor is reestabUshed from the Tumor Bank every six months or as needed. The tumor is maintained by serial passage twice weekly in the host mice. In the procedures utilized here, the tumor is removed from passage animals and minced into 1- to 3 -mm cubic fragments using sterile techniques. Tumor pieces are checked for sterility using both Antibiotic Medium 1 and Brain Heart Infusion (Difco, Detroit, Michigan). The xenograft tumor pieces are implanted into the recipient CDl Nu/Nu mice subcutaneously in an axillary site by trochar. The aUograft 6C3HED tumor pieces are implanted into the recipient C3H mice in an analogous fashion. Drug therapy on the appropriate schedule is initiated seven days after tumor implantation for the HXGC3 xenograft and the day after tumor implantation for the 6C3HED aUograft. The compound being tested is mixed with 2.5% Emulphor EL620 from GAF Corporation (1:40 dUution in 0.9% saUne). The total dosage volume for each administration is 0.5 ml. AU animals are weighed at the beginning and end of administration of the subject compounds. Food and water are provided ad Ubitum. Each control group and each dosage level of the treated groups consisted of 9 or 10 mice selected at random from the pool of implanted animals. The formulations are administered oraUy by gavage with the use of an 18-gauge needle. Compounds are dosed daily for 10 days for the studies using the human tumor xenografts and 8 days for the studies using the aUograft. The xenograft tumor is measured five days after treatment ended with two dimensional measurements (width and length) of the tumor taken using digital electronic caUpers interfaced to a microcomputer. J.F. WorzaUa, et al.. Investigational New Drugs. 8:241- 251 (1990). The aUograft is measured in a Uke manner the day after the dosing schedule ended. Tumor weights are calculated from these measurements using the foUowing formula: Tumor weight (mg) = tumor length (mm ) x [tumor width (mm)] 2 2 At least one control group of an equal number of mice is treated with the same volume of 2.5% Emulphor only. The percent inhibition is determined by subtracting the ratio of the mean tumor size of the test group relative to the control group from one and multiplying the result by 100. The compounds of Formula I are usuaUy administered in the form of pharmaceutical compositions. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Such compositions are useful in treating soUd tumors including carcinomas such as ovarian, non-smaU ceU lung, gastric, pancreatic, prostate, renal ceU, breast, colorectal, small ceU lung, melanoma, and head and neck; and sarcomas such as Kaposi's sarcoma and rhabdomyosarcoma. The Formula I compounds are preferably administered in the form of oral pharmaceutical compositions. Such compositions are prepared in a manner weU known in the pharmaceutical art and comprise at least one active compound. In another aspect, the present invention also includes novel pharmaceutical compositions which contain, as the active ingredient, the compounds of Formula I associated with pharmaceuticaUy acceptable carriers. In making the compositions of the present invention the active ingredient is usuaUy mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a soUd, semi-soUd, or Uquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, piUs, powders, lozenges, sachets, cachets, eUxirs, suspensions, emulsions, solutions, syrups, aerosols (as a soUd or in a Uquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, it may be necessary to miU the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantiaUy insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantiaUy water soluble, the particle size is normally adjusted by milling to provide a substantiaUy uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystaUine ceUulose, polyvinylpyrroUdone, ceUulose, water, syrup, and methyl ceUulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oU; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 500 mg, more usuaUy about 25 to about 300 mg, of the active ingredient. The term "unit dosage form" refers to physicaUy discrete units suitable as unitary dosages dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compounds are effective over a wide dosage range. For examples, dosages per day normaUy faU within the range of about 0.5 to about 600 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 50 mg/kg, in single or divided dose, is preferred. However, it will be understood that the amount of the compound actuaUy administered will be determined by a physician, in the Ught of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to Umit the scope of the invention in any way. Typical compositions of this invention are described in the foUowing examples: Formulation Example 1 Hard gelatin capsules containing the foUowing ingredients are prepared: Quantity Ingredient (mg/capsule Active Ingredient 250.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 560 mg quantities. Formulation Example 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablef) Active Ingredient 250.0 CeUulose, microcrystaUine 400.0 CoUoidal siUcon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 665 mg. Formulation Example 3 A dry powder inhaler formulation is prepared containing the foUowing components: Ingredient Weight % Active Ingredient 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaUng appUance. Formulation Example 4 Tablets, each containing 60 mg of active ingredient, are prepared as foUows: Quantity Ingredient (mg/tablefl Active Ingredient 60.0 mg Starch 45.0 mg MicrocrystaUine ceUulose 35.0 mg PolyvinylpyrroUdone (as 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 150 mg The active ingredient, starch and ceUulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrroUdone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formulation Example 5 Capsules, each containing 80 mg of medicament are made as foUows: Quantity Ingredient (mg/capsulel Active Ingredient 80.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 190.0 mg The active ingredient, ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 190 mg quantities. Formulation Example 6 Suppositories, each containing 225 mg of active ingredient are made as foUows: Ingredient Amount Active Ingredient 225 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and aUowed to cool. Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as foUows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl ceUulose (11%) MicrocrystalUne ceUulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor q.v. Color q.v. Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystaUine ceUulose and sodium carboxymethyl ceUulose in water. The sodium benzoate, flavor, and color are dUuted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. Formulation Example 8 Capsules, each containing 150 mg of medicament, are made as foUows: Quantity Ingredient (mg/capsule Active Ingredient 150.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 560.0 mg The active ingredient, ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.

Claims: We claim: A compound of the formula wherein: R 1 is oxo, hydrogen, or hydroxy; R la is oxo, hydrogen, or hydroxy; and R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, Ci-Cβ alkyl, and triQuoromethyl, provided that no more than one of R 2 and R 3 can be hydrogen; provided that no more than one of R 1 and R la is hydrogen; and further provided that no more than one of R 1 and R la is oxo; or a pharmaceuticaUy acceptable salt, solvate, or prodrug thereof. 2. A compound as claimed in Claim 1 wherein R 1 or R la is oxo. 3. A compound as claimed in Claim 2 wherein R 2 is halo. 4. A compound as claimed in Claim 3 wherein R 3 is chloro. 5. A compound as claimed in Claim 4 that is N-[[[3,4- dichlorophenyl]amino]carbonyl]-2,3-dihydro-2-oxo-benzofur-5- ylsuUonamide, N-[[[3,4-dichlorophenyl]ammo]carbonyl]-2,3-dihydro-3- oxo-benzofur-5-ylsuUonamide, N-[[[4-chlorophenyl]amino]carbonyl]-2,3- dihydro-2-oxo-benzofur-5-ylsuUonamide, or N-[[[4- chlorophenyl] amino]carbonyl] -2 , 3-dihydro-3-oxo-benzofur-5- ylsuffonamide, or a pharmaceuticaUy acceptable salt or solvate thereof. 6. A compound as claimed in Claim 1 wherein R 1 or R la is hydroxy. 7. A compound as claimed in Claim 6 wherein R 2 is halo. 8. A compound as claimed in Claim 4 that is N-[[[3,4- dichlorophenyl]amino]carbonyl]-2,3-dihydro-2-hydroxy-benzofur-5- ylsuUonamide, N-[[[3,4-dichlorophenyl]amino]carbonyl]-2,3-dihydro-3- hydroxy-benzofur-5-ylsuUonamide, N-[[[4-chlorophenyl]amino]carbonyl]- 2,3-dihydro-2-hydroxy-benzofur-5-ylsuUonamide, or N-[[[4- chlorophenyl] amino] carb onyl] -2,3- dihy dr o - 3 -hy droxy-b enzofur- 5 - ylsuUonamide, or a pharmaceuticaUy acceptable salt or solvate thereof. 9. A method of treating a susceptible neoplasm is a mammal which comprises administering to a mammal in need of said treatment an effective amount for treating the susceptible neoplasm of a compound as claimed in any one of Claims 1-8. 10. A pharmaceutical formulation comprising an effective amount of a compound as claimed in any one of Claims 1-8, or a pharmaceuticaUy acceptable salt, solvate, or prodrug, in combination with a suitable pharmaceutical excipient. 11. A process for preparing a suUonylurea as claimed in any one of Claims 1 to 8, which comprises reacting with a compound of the formula where R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, Ci-Cβ alkyl, and trifluoromethyl, provided that no more than one of R 2 and R 3 can be hydrogen; and Y is -NH 2 or -NCO; a sulfonyl compound of the formula wherein: R 1 is oxo, hydrogen, or hydroxy; R la is oxo, hydrogen, or hydroxy; and X is -NCO, -NH2, or -NH-COOR 4 in which R 4 is C 1 -C 3 alkyl, provided that if X is -NCO or -NH-COOR 4 , then Y is -NH 2 , and if X is - NH 2 , then Y is -NCO. 12. A compound as claimed in any one of Claims 1-8 for use in treating a susceptible neoplasm. 13. A pharmaceutical formulation for use in treating a susceptible neoplasm containing, as an active ingredient, a compound as claimed in any one of Claims 1-8.

Inventors: EHLHARDT WILLIAM J, RAY JAMES E, TOTH JOHN E, EHLHARDT, WILLIAM, J., RAY, JAMES, E., TOTH, JOHN, E.
Applicants: EHLHARDT WILLIAM J, LILLY CO ELI, RAY JAMES E, TOTH JOHN E, EHLHARDT, WILLIAM, J., ELI LILLY AND COMPANY, RAY, JAMES, E., TOTH, JOHN, E.
Application year: 1997
Main classification: C07D307
IPC codes: C07D307