IMPROVEMENTS IN OR RELATING TO BENZENESULFONAMIDO DERIVATIVES

Abstract: This invention provides the use of certain benzenesul­ fonamide derivatives of the formula (I) wherein: R₁ and R₃ are independently hydrogen, C₁-C₃ alkyl, halo, trifluoromethyl, or C₁-C₃ alkoxy; R₂ is halo, methyl, or trifluoromethyl; and R₄ is hydrogen, halo, methyl, or trifluoromethyl, in the treatment of susceptible neoplasms in mammals. Also provided are cer­ tain novel benzenesulfonamide derivatives and their phar­ maceutical formulations.

Description: Despite the development of numerous chemical agents and sophisticated regimens of drug therapy, the ravages of cancer continue to extract an ever-increasing human toll of suffering and death. Although many advances have been made, especially in the area of combination drug therapy, the need for new and better methods of treating neoplasms and leukemias has not diminished. This is especially evident in the area of inoperable or metastatic solid tumors, such as various forms of lung cancer. To be especially useful, new chemotherapeutic agents should have a wide spectrum of activity, a large therapeutic index, and be chemically stable and compatible with other agents. In addition, any new agents having oral activity would be especially useful so that initial treatment and subsequent maintenance therapy would be made easily and without inconvenience or pain to the patient. We have discovered a series of sulfonylureas which are useful in the treatment of solid tumors. The compounds are orally active and relatively non-toxic providing an excellent therapeutic index. Some of the compounds and their formulations are novel. Certain sulfonylureas used in this invention are known in the art. Compounds such as 1-(4-fluoro-, 4-chloro-, 4-bromo-, and 4-methyl-phenyl)-3-[phenyl-and (4-chloro-, 4-bromo-, and 4-methyl-phenyl-)sulfonyl]urea are taught in Chemical Abstracts 71:11457w (1969), Holland, et al., J. Med. Pharm. Chem. , 3 (1), 99 (1961), Gandhi, et al., Arzneim.-Forsch. , 21 , 968 (1971), Rajagopalan, et al., J. Org. Chem. , 3 0, 3369 (1965), and Petersen, Chem. Ber. , 83 , 551 (1950). In general, these compounds are taught to have oral hypoglycemic activity. In addition, some antimycotic activity is noted and the compounds have also been prepared as derivatives of carbodiimides. The Holland reference also teaches the preparation of 1-(3-trifluoromethylphenyl)-3-(4-methylphenylsulfonyl)urea, although the compound is taught to be lacking hypoglycemic activity. A general review of compounds of this structural type is taught by Kurzer, Chem. Rev. , 50 , 1 (1952). No anti-tumor activity is disclosed or inferred in any of the above references. According to a first aspect of the invention the compounds of formula (I) can be used for the manufacture of a medicament for use in the therapy of cancer or leukemia, said compounds having the formula: wherein: R₁ and R₃ are independently hydrogen, C₁-C₃ alkyl, halo, trifluoromethyl, or C₁-C₃ alkoxy; R₂ is halo, methyl, or trifluoromethyl; and R₄ is hydrogen, halo, methyl, or trifluoromethyl. According to a second aspect of the present invention there is provided a pharmaceutical formulation comprising as an active ingredient a compound of formula (I) provided that: (A) when R¹ is chloro, hydrogen or methyl and R³ is hydrogen; R² cannot (i) be halo when R⁴ is hydrogen; (ii) be methyl when R⁴ is hydrogen or methyl; (iii) be chloro when R⁴ is chloro, and (B) when R¹ is bromo and R³ is hydrogen, R² cannot be methyl when R⁴ is hydrogen, associated with one or more pharmaceutically-acceptable carriers, diluents or excipients. According to a third aspect of the invention, there is provided a compound of formula (I) provided that (A) when R¹ is chloro, hydrogen or methyl and R³ is hydrogen; R² cannot (i) be halo when R⁴ is hydrogen; (ii) be chloro when R⁴ is chloro; or (iii) be methyl when R⁴ is hydrogen or methyl, and (B) when R¹ is bromo and R³ is hydrogen, R² cannot be methyl or chloro when R⁴ is hydrogen. Such compounds are novel. One class of novel compounds of formula (I) which may be mentioned are those of formula: wherein R₁, R₃, and R₄ are the same as described above. In addition, this invention also provides for the novel compound N-([(4-chlorophenyl)amino]carbonyl)-3-methylbenzenesulfonamide (compound IIIa). This compound is one of the most active compounds of Formula I (R₁=R₄= hydrogen; R₃= methyl; R₂= chloro) in the treatment of susceptible neoplasms and has virtually no hypoglycemic liability. One class of pharmaceutical formulations of interest are pharmaceutical formulations comprising a compound of the formula: wherein R₁ and R₃ are the same as defined above and R 2a and R 4a are independently chloro or fluoro, in combination with a suitable pharmaceutical carrier, diluent, or excipient. These formulations are useful in the treatment of mammals suffering from susceptible neoplasms. The term "halo" refers to fluoro, chloro, bromo, and iodo. The term "C₁-C₃ alkyl" refers to methyl, ethyl, propyl, and isopropyl. The term "C₁-C₃ alkoxy" refers to methoxy, ethoxy, propoxy, and isopropoxy. The preferred compounds used according to this invention are those of Formula I wherein a) R₃ and R₄ are independently chloro, fluoro, methyl, or hydrogen, b) R₁ is hydrogen, halo, especially chloro, C₁-C₃ alkyl, especially methyl or ethyl, or C₁-C₃ alkoxy, especially methoxy, and c) R₂ is halo, especially chloro or fluoro, or trifluoromethyl. The especially preferred compounds used in this invention are those of formulas II and IIIa. Also especially preferred are compounds of formula I wherein R₁ is methyl or methoxy. The most preferred compounds are 4-methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, 4-methoxy-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, N-([(4-chlorophenyl)amino]carbonyl)-4-methylbenzenesulfonamide, and especially N-([(4-chlorophenyl)amino]carbonyl)-3-methylbenzenesulfonamide (compound IIIa). The compounds of formula I are generally referred to as derivatives of N-([(substituted phenyl)amino]carbonyl)benzenesulfonamides as used in the previous paragraph. Alternatively, the compounds are referred to as 1-(substituted phenyl)-3-(optionally substituted phenylsulfonyl)ureas. The compounds of formula I may be prepared by any number of methods known in the literature. These methods are generally summarized by Kurzer, Chem. Rev. , 50 , 1 (1952), especially pages 4-19. The compounds of formula (I) can be prepared by reacting a compound of formula: with a compound of formula: where X and Y are different and can each represent -NH₂ or -NCO. The preferred method of preparing the compounds of formula I is that of the reaction of a sulfonylisocyanate of the formula IV with an aniline derivative of the formula V where R₁, R₂, R₃, and R₄ are the same as previously defined. The reaction between compounds IV and V is usually performed using equimolar amounts of the two reactants, although other ratios are operative. The reaction is best carried out in an aprotic non-reactive solvent such as benzene, toluene, acetonitrile, ether, tetrahydrofuran, dioxane, or preferably methylene chloride. The reaction may be carried out at temperatures from about 0°C up to the boiling point of the reaction mixture, typically less than 100°C. At the preferred temperature range of about 20-30°C, the reaction produces a strong exotherm and the reaction is usually complete within 1 hour. The product thus obtained is recovered by filtration and may be purified, if desired, by any number of methods known to those skilled in the art, such as chromatography or crystallization. Alternatively, an appropriately substituted sulfonamide VI may be reacted with an isocyanate of the formula VII to provide the compounds of Formula I. The reaction is generally carried out in a water miscible, non-reactive organic solvent such as tetrahydrofuran or acetone. Generally, an equimolar amount or slight molar excess of VII is employed, although other ratios are operative. In addition, an aqueous solution of a base, such as sodium or potassium hydroxide, is employed. Usually the amount of base used is approximately equimolar to the amount of VI. The reaction is generally carried out from about 0°C up to the boiling point of the reaction mixture, typically less than 100°C. At the preferred temperature range of 20-30°C, the reaction is usually complete within about three days. Intermediates IV, V, VI, and VII, and any intermediates required for other methods of preparation are either commercially available, are known in the literature, or can be prepared by methods known in the art. The following examples further illustrate the preparation of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. Example 1 4-Methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide A solution of 8.0 g of 4-aminobenzotrifluoride in 10 ml of methylene chloride was added to a solution of 9.85 g of p-toluenesulfonyl isocyanate in 75 ml of methylene chloride with stirring. The mixture became quite warm and a heavy white precipitate formed. An additional 100 ml of methylene chloride were added. The reaction mixture was stirred an additional 15 minutes, and the precipitate was recovered by filtration affording 15.0 g of the title product as a white solid. A small amount of the material was crystallized from diethyl ether to provide 4-methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide with a melting point of 194-197°C. Analysis for C₁₅H₁₃F₃N₂SO₃: Calculated: C, 50.25; H, 3.66; N, 7.82; Found: C, 50.02; H, 3.63; N, 7.79. Examples 2-16 Following the general procedure of Example 1, the following compounds were prepared from the appropriate benzenesulfonyl isocyanate and aniline derivatives. Yields are expressed as percent molar yield. 2. N-([(4-chlorophenyl)amino]carbonyl)-4-methylbenzenesulfonamide, 87% yield, m.p. 174-176°C. Analysis for C₁₄H₁₃ClN₂O₃S: Calculated: C, 51.77; H, 4.03; N, 8.63; Found: C, 51.90; H, 4.08; N, 8.67. 3. 4-Methoxy-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, 58.9% yield, m.p. 188-189°C. Analysis for C₁₅H₁₃F₃N₂O₄S: Calculated: C, 48.13; H, 3.50; N, 7.48; Found: C, 48.38; H, 3.61; N, 7.53. 4. N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, 68.7% yield, m.p. 195-196°C. Analysis for C₁₄H₁₁F₃N₂O₃S: Calculated: C, 48.84; H, 3.22; N, 8.14; Found: C, 49.09; H, 3.28; N, 8.22. 5. 4-Methyl-N-([(4-methylphenyl)amino]carbonyl)benzenesulfonamide, 84.9% yield, m.p. 148-149°C. Analysis for C₁₅H₁₆N₂O₃S: Calculated: C, 59.19; H, 5.30; N, 9.20; Found: C, 59.00; H, 5.21; N, 8.96. 6. 4-Bromo-N-([(4-bromophenyl)amino]carbonyl)benzenesulfonamide, 68.0% yield, m.p. 213-215°C with decomposition. Analysis for C₁₃H₁₀Br₂N₂O₃S: Calculated: C, 35.97; H, 2.32; N, 6.45; Found: C, 36.21; H, 2.33; N, 6.48. 7. N-([(4-fluorophenyl)amino]carbonyl)-4-methylbenzenesulfonamide, 99% yield, m.p. 172-173°C. Analysis for C₁₄H₁₃FN₂O₃S·½CH₂Cl₂ (solvate with 0.5 mole of methylene chloride): Calculated: C, 49.65; H, 4.02; N, 7.99; S, 9.14; Found: C, 49.84; H, 3.97; N, 8.26; S, 8.97. 8. 1-(4-Bromophenyl)-3-(4-methylbenzenesulfonyl)urea, 88% yield, m.p. 188-189°C. Analysis for C₁₄H₁₃BrN₂O₃S: Calculated: C, 45.54; H, 3.55; N, 7.59; S, 8.68; Found: C, 45.30; H, 3.62; N, 7.49; S, 8.74. 9. N-([(4-chlorophenyl)amino]carbonyl)-4-methoxybenzenesulfonamide, 72% yield, m.p. 163-165°C. Analysis for C₁₄H₁₃ClN₂O₄S: Calculated: C, 49.34; H, 3.85; N, 8.22; S, 9.41, Cl, 10.40; Found: C, 49.06; H, 3.75; N, 8.16; S, 9.18; Cl, 10.36. 10. N-([(4-chlorophenyl)amino]carbonyl)benzenesulfonamide, 76% yield, m.p. 180-181°C. Analysis for C₁₃H₁₁ClN₂O₃S: Calculated: C, 50.25; H, 3.57; N, 9.01; S, 10.32; Cl, 11.41; Found: C, 50.05; H, 3.61; N, 8.92; S, 10.13; Cl, 11.21. 11. 1-(4-Chlorophenyl)-3-(4-chlorophenylsulfonyl)urea, 41.3% yield, m.p. 180-183°C. Analysis for C₁₃H₁₀Cl₂N₂O₃S: Calculated: C, 45.23; H, 2.92; N, 8.12; Found: C, 44.95; H, 2.82; N, 8.02. 12. N-([(4-iodophenyl)amino]carbonyl)-4-methylbenzenesulfonamide, 87% yield, m.p. 197°C with decomposition. Analysis for C₁₄H₁₃IN₂O₃S: Calculated: C, 40.04; H, 3.15; N, 6.73; S, 7.70; I, 30.49; Found: C, 40.22; H, 3.21; N, 6.49; S, 7.47; I, 30.70. 13. N-([(4-bromophenyl)amino]carbonyl)benzenesulfonamide, 77% yield, m.p. 191-192°C. Analysis for C₁₃H₁₁BrN₂O₃S: Calculated: C, 43.96; H, 3.12; N, 7.89; S, 9.03; Found: C, 43.76; H, 2.90; N, 7.73; S, 8.69. 14. 4-Chloro-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, 82.4% yield, m.p. 197-198.5°C. Analysis for C₁₄H₁₀ClF₃N₂O₃S: Calculated: C, 44.40; H, 2.66; N, 7.40; S, 8.47; Found: C, 44.23; H, 2.47; N, 7.28; S, 8.31. 15. N-([(3,4-dichlorophenyl)amino]carbonyl)-4-methylbenzenesulfonamide, 88.4% yield, m.p. 199-200°C. Analysis for C₁₄H₁₂Cl₂N₂O₃S: Calculated: C, 46.81; H, 3.37; N, 7.80; S, 8.93; Found: C, 46.71; H, 3.61; N, 7.59; S, 8.65. 16. 4-Chloro-N-([(4-fluorophenyl)amino]carbonyl)benzenesulfonamide, 98% yield, m.p. 201-202°C. Analysis for C₁₃H₁₀ClFN₂O₃S: Calculated: C, 47.50; H, 3.07; N, 8.52; Found: C, 47.31; H, 3.13; N, 8.33. Example 17 N-([(4-Bromophenyl)amino]carbonyl)-4-methoxybenzenesulfonamide To a solution of 9.97 g of 4-methoxybenzenesulfonamide in 54 ml of acetone were added 54 ml of a 1N sodium hydroxide solution. With stirring, a solution of 11.55 g of 4-bromophenylisocyanate in 50 ml of acetone was added. After stirring at room temperature for three days, the reaction mixture was filtered and 55 ml of 1N hydrochloric acid were added to the filtrate providing a fine white precipitate. Two hundred milliliters of water were added, and the solid was recovered by filtration to provide 18.85 g of the desired title product. Analysis for C₁₄H₁₃BrN₂O₄S: Calculated: C, 43.65; H, 3.40; N, 7.27; S, 8.32; Found: C, 43.52; H, 3.54; N, 7.32; S, 8.31. Examples 18-19 Following the procedure of Example 17, the following compounds were prepared from the appropriate sulfonamide and the corresponding isocyanate. 18. 3,4-Dichloro-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, 86% yield. Analysis for C₁₄H₉Cl₂F₃N₂O₃S: Calculated: C, 40.70; H, 2.20; N, 6.78; S, 7.76; Found: C, 40.70; H, 2.36; N, 6.61; S, 7.62. 19. 3-Trifluoromethyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide, 89.5% yield. Analysis for C₁₅H₁₀F₆N₂O₃S: Calculated: C, 43.70; H, 2.44; N, 6.79; S, 7.78; Found: C, 43.80; H, 2.18; N, 6.92; S, 8.04. Example 20 N-([(3,4-dichlorophenyl)amino]carbonyl)benzenesulfonamide The title compound was prepared in 83.5% yield from benzenesulfonyl isocyanate and 3,4-dichloroaniline following the procedure of Example 1, m.p. 194-195°C. Analysis for C₁₃H₁₀Cl₂N₂O₃S: Calculated: C, 45.23; H, 2.92; N, 8.12; S, 9.29; Found: C, 45.04; H, 3.07; N, 7.82; S, 9.34. Examples 21-31 Following the procedure of Example 17, the following compounds were prepared from the appropriate sulfonamide and the corresponding isocyanate. 21. 3,4-Dichloro-N-([(4-chlorophenyl)amino]carbonyl)benzenesulfonamide, 82% yield, m.p. 183-184°C. Analysis for C₁₃H₉Cl₃N₂O₃S: Calculated: C, 41.13; H, 2.39; N, 7.38; S, 8.45; Found: C, 40.85; H, 2.52; N, 7.14; S, 8.56. 22. 3-Chloro-N-([(4-chlorophenyl)amino]carbonyl)benzenesulfonamide, 79% yield, m.p. 135°C. Analysis for C₁₃H₁₀Cl₂N₂O₃S: Calculated: C, 45.23; H, 2.92; N, 8.12; S, 9.29; Found: C, 45.36; H, 2.74; N, 8.16; S, 9.51. 23. N-([(4-chlorophenyl)amino]carbonyl)-3-methylbenzenesulfonamide, 92.4% yield, m.p. 171-173°C. Analysis for C₁₄H₁₃ClN₂O₃S: Calculated: C, 51.77; H, 4.03; N, 8.63; Found: C, 51.53; H, 4.15; N, 8.63. 24. N-([(4-chlorophenyl)amino]carbonyl)-3-methoxybenzenesulfonamide, 91% yield, m.p. 152-154°C. Analysis for C₁₄H₁₃ClN₂O₄S: Calculated: C, 49.34; H, 3.85; N, 8.22; S, 9.41; Found: C, 49.49; H, 3.97; N, 8.06; S, 9.22. 25. N-([(4-chlorophenyl)amino]carbonyl)-3,4-dimethylbenzenesulfonamide, 82.9% yield, m.p. 149-151°C. Analysis for C₁₅H₁₅ClN₂O₃S: Calculated: C, 53.18; H, 4.46; N, 8.27; S, 9.46; Found: C, 53.44; H, 4.33; N, 8.03; S, 9.24. 26. N-([(4-chlorophenyl)amino]carbonyl)-4-ethylbenzenesulfonamide, 85.4% yield, m.p. 176-177°C. Analysis for C₁₅H₁₅ClN₂O₃S: Calculated: C, 53.18; H, 4.46; N, 8.27; Found: C, 53.04; H, 4.56; N, 8.13. 27. N-([(4-chlorophenyl)amino]carbonyl)-4-ethoxybenzenesulfonamide, 65% yield, m.p. 172-174°C. Analysis for C₁₅H₁₅ClN₂O₄S: Calculated: C, 50.78; H, 4.26; N, 7.90; S, 9.04; Found: C, 50.75; H, 4.23; N, 7.86; S, 9.06. 28. N-([(4-chlorophenyl)amino]carbonyl-)4-fluorobenzenesulfonamide, 67% yield. Analysis for C₁₃H₁₀ClFN₂O₃S: Calculated: C, 47.50; H, 3.07; N, 8.52; Cl, 10.78; F, 5.78; Found: C, 47.45; H, 3.25; N, 8.44; Cl, 11.02; F, 6.06. 29. N-([(4-chlorophenyl)amino]carbonyl)-3,4-diethylbenzenesulfonamide, 87% yield, m.p. 108-111°C. Analysis for C₁₇H₁₉ClN₂O₃S: Calculated: C, 55.66; H, 5.22; N, 7.64; S, 8,74; Found: C, 55.69; H, 5.13; N, 7.70; S, 8.57. 30. N-([(4-chlorophenyl)amino]carbonyl)-4-propylbenzenesulfonamide, 79% yield, m.p. 125°C. Analysis for C₁₆H₁₇ClN₂O₃S: Calculated: C, 54.47; H, 4.86; N, 7.94; S, 9.09; Found: C, 54.71; H, 5.00; N, 7.66; S, 9.34. 31. N-([(4-chlorophenyl)amino]carbonyl)-4-(1-methylethyl)benzenesulfonamide, 89% yield, m.p. 175-178°C. Analysis for C₁₆H₁₇ClN₂O₃S: Calculated: C, 54.47; H, 4.86; N, 7.94; S, 9.09; Found: C, 54.23; H, 4.75; N, 7.86; S, 8.85. Example 32 4-Chloro-N-([(3,4-dichlorophenyl)amino]carbonyl)benzenesulfonamide Following the procedure of Example 1, 5.04 g of 4-chlorobenzenesulfonyl isocyanate and 3.85 g of 3,4-dichloroaniline were allowed to react providing 8.06 g of the desired title product, m.p. 195-196°C. Analysis for C₂₃H₉Cl₃N₂O₃S: Calculated: C, 41.13; H, 2.39; N, 7.38; S, 8.45; Found: C, 40.92; H, 2.60; N, 7.12; S, 8.32. Example 33 N-([(4-bromo-3-methylphenyl)amino]carbonyl)-4-methylbenzenesulfonamide A solution of 5.58 g of 4-bromo-3-methylaniline in 20 ml of toluene and 5 ml of methylene chloride was added to a solution of 5.91 g of p-toluenesulfonyl isocyanate in 50 ml of toluene and 10 ml of methylene chloride under a nitrogen atmosphere. The mixture was stirred overnight and filtered, providing 9.19 g of the title product, m.p. 178-180°C. Analysis for C₁₅H₁₅BrN₂O₃S: Calculated: C, 47.01; H, 3.95; N, 7.31; S, 8.37; Found: C, 46.92; H, 4.04; N, 7.39; S, 8.54. The compounds of formula I have been shown to be active against transplanted mouse tumors in vivo . The compounds are active when administered orally or by the intraperitoneal route. The compounds are active in the test systems when administered according to a variety of dosage schedules. In general, the compounds were administered daily or twice daily for 8-10 days, or on days 1, 5, and 9 after inoculation with the appropriate tumor. In some additional tests, the compounds were active even though not administered until several days after inoculation with the tumor. To demonstrate the anti-tumor activity of the compounds of Formula I, the compounds were tested in animals bearing a 6C3HED lymphosarcoma, also known as the Gardner lymphosarcoma (GLS). Table 1 gives the results of several experiments in mice bearing this tumor. In the table, column 1 gives the example number of the compound; column 2, the method of administration; column 3, the dose level or dose level range and number of days this dosage was administered; and column 4, the percent inhibition of tumor growth. The results are compilations of one or more such tests which were performed with suitable control groups. In addition, certain of the compounds of Formula I were tested in additional test systems. These include the subcutaneous B-16 melanoma (B16-sc), the Yoshida rat sarcoma (Yoshida), the X5563 plasma cell myeloma (X5563), the M-5 ovarian carcinoma (M-5), the C3H mammary carcinoma (C3H), colon carcinoma-26 (C6), the CA-755 adenocarcinoma (CA755), the P1534J lymphatic leukemia (P1534J), the P388 lymphocytic leukemia (P388), and the Lewis Lung carcinoma (LL). A summary of these test results is provided in Table 2. The compounds of Formula I are antineoplastic agents and can be used for treating susceptible neoplasms and leukemia in afflicted mammals. A compound can be administered by various routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, being usually employed in the form of a pharmaceutical composition. It is a special feature of these compounds that they are effective following oral administration. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, in addition to the novel compounds of Formula II, the invention also includes pharmaceutical compositions comprising as active ingredient a compound of Formula II, III, or IIIa associated with a pharmaceutically acceptable carrier. In making the compositions of the present invention, as well as compositions containing other compounds of Formula I, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid 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. Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from 5 to 500 mg, more usually 25 to 300 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary 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 carrier. The active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of 0.5 to 1200 mg/kg of body weight. In the treatment of adult humans, the range of 1 to 50 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. The following formulation examples may employ as active compounds any of the compounds of Formulas II, III and IIIa. Example 34 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) 4-Methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide 250 Starch dried 200 Magnesium stearate 10 The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. Example 35 A tablet formula is prepared using the ingredients below: Quantity (mg/tablet) 4-Methoxy-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 The components are blended and compressed to form tablets each weighing 665 mg. Example 36 An aerosol solution is prepared containing the following components: Weight % 4-Chloro-N-([(3-chloro-4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide 0.25 Ethanol 29.75 Propellant 22 (Chlorodifluoromethane) 70.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. Example 37 Tablets each containing 60 mg of active ingredient are made up as follows: N-([(3,4-dichlorophenyl)amino]carbonyl)-4-methylbenzenesulfonamide 60 mg Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in water) 4 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a 350 µm (No. 45 mesh U.S.) sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a 1410 µ (No. 14 mesh U.S.) sieve. The granules so produced are dried at 50-60°C and passed through a 1000 µm (No. 18 mesh U.S.) sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a 250 µm (No. 60 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. Example 38 Capsules each containing 80 mg of medicament are made as follows: N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 350 µm (No. 45 mesh U.S.) sieve, and filled into hard gelatin capsules in 200 mg quantities. Example 39 Suppositories each containing 225 mg of active ingredient are made as follows: 4-Chloro-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide 225 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a 250 µm (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 g capacity and allowed to cool. Example 40 Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows: 4-Methyl-N-([(3,4-difluorophenyl)amino]carbonyl)benzenesulfonamide 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to 5 ml The medicament is passed through a 350 µm (No. 45 mesh U.S.) sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume. Example 41 Capsules each containing 150 mg of medicament are made as follows: N-([(4-chlorophenyl)amino]carbonyl)-3-methylbenzenesulfonamide 150 mg Starch 164 mg Microcrystalline cellulose 164 mg Magnesium stearate 22 mg Total 500 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a 350 µm (No. 45 mesh U.S.) sieve, and filled into hard gelatin capsules in 500 mg quantities.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE The use of a compound of the formula (I): wherein: R₁ and R₃ are independently hydrogen, C₁-C₃ alkyl, halo, trifluoromethyl, or C₁-C₃ alkoxy; R₂ is halo, methyl, or trifluoromethyl; and R₄ is hydrogen, halo, methyl, or trifluoromethyl; for the manufacture of a medicament for use in the therapy of cancer or leukemia. A pharmaceutical formulation comprising as an active ingredient a compound of formula (I) as defined in claim 1 provided that: (A) when R¹ is chloro, hydrogen or methyl and R³ is hydrogen; R² cannot (i) be halo when R⁴ is hydrogen; (ii) be methyl when R⁴ is hydrogen or methyl; (iii) be chloro when R⁴ is chloro, and (B) when R¹ is bromo and R³ is hydrogen, R² cannot be methyl when R⁴ is hydrogen, associated with one or more pharmaceutically-acceptable carriers, diluents or excipients. A pharmaceutical formulation as claimed in claim 2 wherein the active ingredient is a compound of the formula: wherein R₁ and R₃ are as defined in claim 1 and R 2a and R 4a are independently chloro or fluoro. A compound of formula (I) as defined in claim 1 provided that: (A) when R¹ is chloro, hydrogen or methyl and R³ is hydrogen; R² cannot (i) be halo when R⁴ is hydrogen; (ii) be chloro when R⁴ is chloro; or (iii) be methyl when R⁴ is hydrogen or methyl, and (B) when R¹ is bromo and R³ is hydrogen, R² cannot be methyl or chloro when R⁴ is hydrogen. A compound as claimed in claim 4 having the structure: wherein R₁, R₃, and R₄ are as defined in claim 1. N-([(4-Chlorophenyl)amino]carbonyl)-3-methylbenzenesulfonamide 4-Methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide. 4-Methoxy-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide. A process for preparing a compound of formula (I) as claimed in any one of claims 4 to 8 which comprises reacting a compound of formula: with a compound of formula: where X and Y are different and can each represent -NH₂ or -NCO. Claims for the following Contracting State : AT A process for preparing a compound of the formula (I): wherein: R₁ and R₃ are independently hydrogen, C₁-C₃ alkyl, halo, trifluoromethyl, or C₁-C₃ alkoxy; R₂ is halo, methyl, or trifluoromethyl; and R₄ is hydrogen, halo, methyl, or trifluoromethyl; provided that: (A) when R¹ is chloro, hydrogen or methyl and R³ is hydrogen; R² cannot (i) be halo when R⁴ is hydrogen; (ii) be chloro when R⁴ is chloro; or (iii) be methyl when R⁴ is hydrogen or methyl, and (B) when R¹ is bromo and R³ is hydrogen, R² cannot be methyl or chloro when R⁴ is hydrogen; which comprises reacting a compound of the formula: with a compound of formula: where X and Y are different and can each represent -NH₂ or -NCO. A process according to claim 1 for preparing a compound of formula (I) wherein R₂ is CF₃. A process according to claim 1 for preparing N-([(4-Chlorophenyl)amino]carbonyl)-3-methylbenzenesulfonamide. A process according to claim 1 for preparing 4-methyl-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide. A process according to claim 1 for preparing 4-methoxy-N-([(4-trifluoromethylphenyl)amino]carbonyl)benzenesulfonamide.

Inventors: HARPER, RICHARD WALTZ, POORE, GERALD AUSTON, RIEDER, BRENT JEFFERY
Applicants: ELI LILLY AND COMPANY
Application year: 1985
Main classification: A61K31
IPC codes: A61K31, C07C301, A61P35, C07C311, C07C303, C07C67