IE900716A1 - Novel sulfonamides as radiosensitizers - Google Patents

Abstract

There are described novel sulfonamides which are useful as radiosensitizers and/or chemosensitizers, pharmaceutical composition containing these compounds, methods of using them to treat a tumor in a mammal and processes for the preparation of the compounds,

Description

Novel Sulfonamides as. Radlos.ansitizers Background of the.-Invent! OP Field. of invention: This invention relates to sulfonamides,· their preparation, pharmaceutical compositions containing them and methods of using them in the treatment of tumors as radiosensitizers and chemosensitizers. aaaksEQund: The currently known radiosensitizers that are in clinical trials, such as nitroimidazoles, are hypoxic cell sensitizers and exert their radiation sensitising effect only when given before the irradiation of tumors (G. E. Adams and I. J. Stratford, Hypoxia-Dependent Radiation Sensitizers, Molecular Actions and Targets for Cancer Chemotherapeutic Agents, 1981, Page 401, Academic Press). However, it is believed that the repair of radiation damage to DNA may be an important factor in the radiocurability of human tumors (X. K. Fu, Biological Basis for the Internation of Chemotherapeutic Agents and Radiation Therapy”, Cancer, May 1 Suppl., V. 55, 2123, 1985; S. Nakatsugawa and T. Sugahara, Effects of inhibitors of Radiation-induced Potentially Lethal Damage Repair on Chemotherapy in Murine Tumors, Int. J. Radiation Oncology Biol. Phys. V.8, 1555, 1982). Therefore, efforts in this field have recently been directed toward searching for agents that can sensitize tumors after radiation by interfering with 0 the repair process. However, only a few agents have thus far been found r.o have such an effect. Agents which have been found to have this activity, such as lonidamine also have antitumor activity. It remains unclear as to whether the postradiation activity of compounds such as lonidamine, is only an additive effect 1* t of cytotoxicity. (J. H. Kim et al.,. Potentiation of Radiation Effects on Two Murine Tumors by Lonidamine, Cancer Research. AS., 1120, 1986).

U.S. Patent 4,603,133 discloses amides and esters 5 of 2-[N-(morpholinoalkyl)aminosulfonyl]-6-nitrobenzoic acids and compositions as useful adjuncts to radiation therapy.

These compounds have the formula: 0 wherein: r2- is hydroxy-(lower alkoxy), lower alkoxy, allyloxy, amino, monoa Ikylamino, dialky lamir.o, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, or ailylamino; R^ is hydrogen, lower alkyl from 1-4 carbon atoms, hydroxy-(lower alkyl), allyl; r3 is a morpholino radical of the formula 2 0 C(CH2CH2)2N(CH2)n; and n is 2 cr 3.

U.S. Patent 4,731,369 discloses amides and esters of 2-[N-(hydroxypiperidinoalkyl) and (hydroxypyrrolidinoalkyl)-aminosulfonyl]-6-nitrobenzoic acids as useful adjuncts to radiation therapy.

These compounds have the formula: J E 90716 wherein : R1 is hydroxy-(lower alkoxy), lower alkoxy, allyloxy, amino, alkylamino, di(lower alkyl)-alkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, or allylamino; R2 is hydrogen, lower alkyl from 1-4 carbon atoms, hydroxy-(lower alkyl), allyl; n is 2 or 3; m is 0, 1, or 2; and p is 1 or 2.

U.S. Patent 4,694,020 discloses amides and esters of 2-(substituted sulfamyl)-6-nitrobenroic acids and pharmaceutical composirions useful for increasing the sensitivity of hypoxic rumor cells to therapeutic radiation.

These compounds have the formula: wherein: R1 is hydroxy-(lower alkoxy), lower alkoxy, alkoxydower alkoxy), allyloxy, amino, monoalkylamino, .J IE 90716 dialkylamino, {hydroxyalkyl)amino, di(hydroxyalkyl)amino, or allylsmino; R2 and R3 are each separately hydrogen, lower alkyl from 1-4 carbon atoms, hydroxy-(lower alkyl), allyl, amino-(iower alkyl), (lower alkyl)-amino-(lower alkyl), di(lower alkyl)-amino-(lower alkyl), (nydroxyaikyl)-amino(lower alkyl), (hydroxyalkyl)alkylamino{lower alkyl), or di{hydroxyalkyl) amino(iower alkyl) or when taken together along with the nitrogen to which they are attached represent a heterocyclic ring selected from morpholino, aziridinyl, azetidinyl, pyrrolidyl, piperidyl, or R4-substituted-3-oxopiperazin-l-yl wherein R4 is hydrogen, lower alkyl from 1-4 carbon atoms, or hydroxyalkyl of from 2-4 carbon atoms.

Published European Patent Application 0270292 discloses 2-(substituted sulfamyl) derivatives of 4nitrobenzamide as agents that increase the sensitivity of hypoxic cancer cells to x-rays and γ-radiation. 0 These agents have the formula: °2Ν\^Χ. ^zSO2NR3R4 CONR1R2 wherein : R1 is hydrogen or loweralkyl of 1-4 carbons; R2and r4 are the same or different and are each hydrogen, loweralkyl of 1-4 carbons, or hydroxyloweralkyl; R3 is loweralkyl of 1-4 carbons substituted with 0 nqI-q2 wherein is the some or different from Q2 and both Q1 and Q2 are hydrogen, loweralkyl of 1-4 carbons, or hydroxyloweralkyl, or and IE 90716 q2 taken together with the nitrogen atom in NqIq2 form a heterocyclic ring such as aziridinvl, azetidinyl, pyrrolidinyl, or piperidinyl.

A broad class of sulfonamides have been described in the patent art and literature as pharmaceuticals and as agricultural agents. The closest ones are the following: Published Japanese Patent Appln. 61/257,960 shows fungicidal sulfonamides of the formula: SO2NHjT\ where Z is CH or N; and Y is Cl, CF3 or CN.

Published Japanese Patent Appln. 61/233660 shows a fungicidal sulfonamide of the formula: Cl sq2nh- cf3 Published Japanese Patent Appln. 61/200,958 shows antibacterial and fungicidal sulfonamides of the formula: where X is H or Cl.

IE 90716 Summary of the Invention Unlike many of the known radiation sensitizing agents, the compounds of the present invention are believed to exert their effect by inhibiting the repair of DNA strand breaks caused by radiation, thus the compounds are classified as postradiation sensitizers. This postradiation sensitizer terminology is descriptive of the mechanism of action of these compounds but should not be a temporal limitation for administration of the compounds. In order for the compounds to be effective they must be present after, the radiation therapy. Therefore they can be administered before, during or after the radiation therapy.

Further, since these compounds are believed to inhibit the repair of DNA strand breaks, they will be effective chemosensitizer agents when given in combination with chemotherapeutic agents which cause DNA strand breaks. For example the compounds of the present invention may enhance or sensitize the activity of intercalators, alkylating agents, DNA cross-linker agents and any other agents which exert Lheir anticancer activity by interacting with DNA, causing strand breaks.

According to the present invention, there are provided compounds having the formula: or a pharmaceutically acceptable salt thereof wherein: R-, R2, R^, r4 and R5 independently are H, alkyl, alkenyl, alkynvl of 1-10 carbon atoms, phenyl, substituted phenyl, F, Cl, Br, I, NO2, CN, CF3, (CH2)mNR6R7 (rrv=O-lO> , CO2R9, OR10, COR11, or IE 90716 S(O)yiR12 (η=Ό-3), or R1 and R2, R2 and R3, R3 and R4, or R4 and R3 when taken together may form -CONHCO- or -CONMCO- wherein M is Na+, K+' or Li+; R6 and R7 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R6 and R7 taken together can form (CH2)pNR8(CH2)q (p and q independently are 2-6); R8 and R9 independently are H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; R10 is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl or substituted phenyl; R11 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NRl3R14; R12 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, 15 phenyl, substituted phenyl or NR18R17; R13 and R14 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-Ϊ0 carbon atoms, phenyl, substituted phenyl or CF3, or R13 and R14 taken together can form (CH2)rNR15(CH2)s and s 0 independently are 2-6); R13 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; P.1-8 and rA7 independently are Π, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, '2 5 substituted phenyl, CF3 or R16 and R17 taken together can form (CH2)tNRl®(CH2)u (t and u independently are 2-6) ; R18 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; 0 Y is N or CR3; each X independently is H, F, Cl, Br, I, NO2r CN, CF3, alkyl, alkenyl, alkynyl of 1-4 carbon atoms, phenyl, substituted phenyl, (CH2) cNRl-^R2^ (c is 0-10), CO2R22, OR23, COR24, or S(O)dR25 is 0-3); b is 1 or 2; IE 90716 ΙΟ Z is N or CR; Ri9 and R20 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R19 and R20 taken together can form (CH2)eNR21(CH2)f (e and f independently are 2-6); R21 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; R22 is H, alkyl, alkenyl or alkynyl of 1-10 carbon atoms; R22 is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl or substituted phenyl; R24 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR26R27; r25 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR29R20; R2$ and R27 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R26 and R27 taken · together can form (CH2)gNR28(CH2)h and h independently are 2-6); R2® is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; R29 and R28 independently are R, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R29 and R20 taken together can form {CH2)jNR21(CH2)k (j and k independently are 2-6); R21 is H, alkyl, alkenyl or alkynyl Of 1-10 carbon atoms; A is NR22 or NR22QNR22; 0 is fCH2)„, (CH2)aCO or w is 2-10; X is 0-10; IE 90716 R32 and R33 independently are R, Na+, K+, Li+, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, benzyl or substituted benzyl; with the following provisos: (a) when X, R1, R3 and R4 are H, R2 is H, methyl, OH or Cl and Y is CH, then A cannot be NH; and (b) when X, R1, R2 and R4 are H, R3 is OH and Y is CH, then A cannot be NH.

Also provided are pharmaceutical compositions containing compounds of Formula (I).

Further provided are methods of treating a tumor in a mammal comprising administering to the mammal a compound of Formula (I) in combination with radiation and/or chemotherapy.

Additionally provided are processes for preparing the compounds of Formula (I), as more fully described hereinafter.

Preferred compounds of the present invention are those compounds of Formula (I) wherein: -SOjA is at the 1 or ? position; and/or Z is CH; and/or X is 2-halogen, provided that when X is 2-halogen, -SO2A is at the 1 position.

Specifically preferred compounds of the present invention are: (a) N-(3-Amidophenyl)-2-chloro-l-naphthalene3 0 sulfonamide (b) N-(3-Amidophenyl)-5-chloro-lnaphthalenesulfonamide (c) N-(2-Amidophenyl)-4-chloro-lnaphthalenesulfonamide IE 90716 (d) N-(3-Amidophenyl)-4-chloro-lnaphthalenesuIfonamide (e) N-(2-Amidophenyl)-2-chloro-lnaphthalenesuIfonamide (f) Benzoic acid, 3-[[(4-chloro-lnaphthalenyl)sulfonylJ amino]-, ethyl ester (g) Benzoic acid, 3-[[2-chloro-lnaphthalenyl)sulfonyl]amino] (h) N-[(3-Dimethylamino)phenyl]-2-chloro-lnaphthalenesulfonamide (i) N-(3-Acetylphenyl)-2-chloro-lnaphthalenesulfonamide (j) N-[3-(Aminosulfonvl)phenyl]-2-chloro-lnaphthalenesulfonamide (k) 3-[(2-Chloro-l-naphthalenyl)sulfonylamino]-4 methoxybenzamide (l) N-(2,3-Dihydro-l,3-dioxo-lH-isoindol-4-yl)-2 chloro-l-naphthalenesulfonamide (m) N-(3-Methylphenyl)-1-naphthalenesulfonamide (η) N-(3-Acetylphenyl)-1-naphthalenesulfonamide (ο) N-(3-Hydroxyphenyl)-1-naphthalenesulfonamide (p) N-(4-Hydroxyphenvl)-1-naphthalenesulfonsmide (q) N-(3-Chlorophenyl)-1-naphthalenesulfonamide (r) N-[3-(Aminosulfonyl)phenyl]“1naphthalenesulfonamide (s) N-(3-Iodophenyl)-1-naphthalenesulfonamide (t) N-[3-(1-Methylethoxy)phenyl]-lnaphthalenesulfonamide (u) N-[3-(1,1-Dimethyl)phenyl]-1naphthalenesu1fonamide (v) N-[3-Aminosulfonyl)phenyl]-2-chloro-lnaphthalenesulfonamide, or “he 3odium salt thereof (w) 3-[(2-Chloro-l-naphthalenyl)sulfonylamino]benzamide, or the sodium sale thereof IE 90716 (X) (γ) (z) (aa) (bb) 0 (cc) (dd) (ee) (ff) 3-[(2-Chloro-l-naphthalenyl)sulfonylamino]benzamide, or the sodium salt thereof 3-[(2-Chloro-l-naphthalenyl)sulfonylamino)benzoic acid, or the sodium salt thereof N-(4-Acetylphenyl)-2-chloro-lnaphthalenesulfonamide N~ <4-Hydroxyphenyl)-2-chloro-lnaphthalenesuIfonamide N-(4-Chlorophenyl)-2-chloro-lnaphthalenesulfonamide N—[4-Am±nosulfonyl)phenyl]-2-chloro-lnaphthalenesulfonamide 3-[(4-Chloro-l-naphthalenyl)sulfonylamino) benzamide, or the sodium salt thereof 3-[(5-Chloro-i-naphthalenyl)sulfonylamino] benzamide, or the sodium salt thereof 3-[(2-Chloro-l-naphthalenyl)sulfonylaminio]-N [2-(dimethylamino)]ethyl benzamide 3[[6-[ (2-Chloro-l-naphthalenyl)sulfonylamino] l-oxohexyl]amino] benzamide N-(3-Amidophenvl)-2-naphthalenesulfonamide 3-ί(8-Quinolinylsulfonyl)amino)benzamide.

Detailed Description of the Invention Chemistry The compounds of the present invention can be prepared according to Scheme I. The compounds of Formula (I) can be prepared by the reaction of the sulfonyl chlorides of Formula (2) with the amines of 0 Formula (3) in a suitable solvent such as pyridine, acetone or methylene chloride, with or without the addition of a suitable base, at a temperature from room temperature to the reflux temperature of the solvent. Alternatively, the compounds of Formula (I) can be prepared by the simultaneous addition of a solution of IE 90716 an amine of Formula (3) in a suitable solvent, such as tetrahydrofuran (THF), and a solution of a suitable base, such as potassium carbonate, in a suitable solvent, such as water, to a solution of an, appropriate sulfonyl chloride of Formula (2) in a suitable solvent, such as THF at a temperature from room temperature to the reflux temperature of the solvent. The reaction of a sulfonyl chloride with an amine to produce a sulfonamide is well-known in the literature. The products of these reactions may be purified by techniques well-known to those skilled in the art of organic synthesis, including but not limited to recrystallization, trituration, chromatography, and/or acid base extraction procedures.

Preparation of pharmaceutically acceptable salts of the compounds of Formula (I) can be in accordance with well-known techniques of forming salts. Physiologically acceptable salts include but are not limited to acid addition salts such as hydrochloric, sulfuric, acetic, succinic, citric, and benzene sulfonic acid salts of the compounds of Formula (I) which contain one or more basic functional groups, and the lithium, sodium or potassium salts which may be derived by the addition of a suitable base such as a metal hydroxide or metal hydride.

Materials of increased water solubility can be prepared by the addition of one or two equivalents of an aqueous sodium hydroxide solution to a suspension of a sulfonamide of the present invention in an appropriate solvent such as water, methanol or ethanol, followed by evaporation to dryness . When a compound which contains 0 only one highly acidic proton is treated with two equivalents of sodium hydroxide, a compound with the emperical formula of a disodium salt is produced. •Ε 90716 R4 (I) The compounds of this invention and their preparation can be better understood by the following examples, which do not constitute a limitation of the invention.

Examp1e 1 N-(3-Amidophenyl)-2-chloro-l-naphthalenesulfonamide To a solution of 3-aminobenzamide (6 g, 50 mmole) in THF (150 ml) was added dropwise simultaneously a solution of 2-chloro-l-naphthalenesulfonyl chloride (13 g, 50 mmole) in THF (100 ml) and a solution of K2CO3 (6.9 g, 50 mmole) in water (50 ml) at O^C over a period of 1 hour. The reaction mixture was stirred for 20 hrs at 25°C and the organic layer was separated and dried over Na2SC>4. After the evaporation of solvent, the residual oil was purified by flash chromatography on silica gel with methylene chloride/methanol (19/1) as IE 90716 the eluent to give the title product (7.9 g, 43%), mp 202-205°C.

The title compound was also prepared by adding dropwise for 30 minutes, a solution of 2-chloro5 naphthalenesulfonyl chloride (9.7 g, 37 mmole) in acetonitrile (30 ml) into a mixture of 3-aminobenzamide (4.8 g, 35 mmole) and 3-dimethylaminopyridine (0,78 g, 6.5 mmole) in pyridine (40 ml) at 25°C under nitrogen. Then the reaction mixture was stirred at 25°C for 30 minutes and water (250 ml) was added dropwise and then poured into another 250 ml of water. The resultant suspension was filtered, and the solid was washed with water and dried in vacuo to give the crude product (11.8 g) as a red solid. Recrystallization of various batches of crude product so made with hot methanol afforded the title compound in about. 70% yield as a white solid.

Example 2 w-(?-a7n-idcphenyl) -5-chloro-l-riaphthaieresul f.on£mj_dg A solution of 3-aminobenzamide (5.5 g, 40 mmole) in acetone (75 ml) was added dropwise at 25°C into a solution of 5-chloro-l-naphthaiene sulfonyl chloride (10 g, 40 mmole) in acetone (50 ml) over a period of 45 min. The reaction mixture was stirred for 20 hours and filtered to give a yellowish solid which was washed in sequence with acetone (25 ml), water (25 ml), and hot methanol (25 ml), and yielded the title compound (5.7 g, 40%) after drying in vacuo at 50°C for 2 hours, m.p. 257-259*0.

Example 3 N-<2-Amidophenyl>-4’-chloro-l-naphthalenesulfonamida A solution of 4-chloronaphthalenesulfonyl chloride (5.00 g, 19.15 mmole) and anthranilamide (2.61 g, 19.17 mmole) in pyridine (25 ml) was heated at reflux for 3 IE 90716 hours, cooled to 25°C, and concentrated in vacua. The tan pasty residue was triturated repeatedly with hot methanol to afford the title compound (5.07 g, 73%) as an off-white powder, m.p. 238-23SQC.

The compounds or this invention which were prepared or can be prepared according to the above procedures are listed in Tables I, II and III. •Ε 90716 Table I R4 :x. X R1 R2 R3 R4 Y A mp (6C> 1 2-Cl H CONH2 H H CH NH 202-205 2 5-Cl H CONH2 H H CH NH 257-259 3 4-Cl CONH2 H H H CH NH 238-239 4 H H CONH2 H H CH NH 182-185 5 3-Cl H CONH2 H H CH NH 6 4-Cl H CONH2 H H CH NH 185-190 7 6-Cl H CONH2 H H CH NH 8 7-Cl H C0NH2 H H CH NH 9 a CONH2 H H H CH NH 255-256 10 2-Cl C0NH2 H H H CH NH 235-239 11 5-Cl C0NH2 H H H CH NH 12 H H H CONH2 H CH NH 13 2-Cl H H C0NH2 H CH NH 267-271 14 4-Cl H H C0NH2 H CH NH >355 15 5-Cl H H CONH2 H CH NH 16 2-Cl H H H H CH NH 134-137 17 4-Cl H H H H CH NH 18 5-Cl H H H H CH NH 149-153 19 w H CN H H CH NH 20 2-C1 H CN H H CH NH 21 4-Cl H CN H H CH NH 209-210 22 5-C1 H CN H H CH NH 23 H H C02Et H H CH NH 24 2-C1. H C02Et H H CH NH 116-119 25 4-C1 H C02Et H H CH NH 110-111 26 5-Cl H C02Et H H CH NH Table T (continued) X εΞ r£ 5i Y A mp (°C) H H CF3 H H CH NH 2-C1 H CF? H H CH NH 4-Cl H CF3 H H CH NH 154-159 5-Cl H CF3 H H CH NH 2-Cl N02 H H H CH NH 2-C1 H N02 H H CH NH 177.5-179 2-Cl H H NO2 H CH NH 2-Cl H CO2H H H CH NH 221-226 2-Cl H CO2Me H H CH NH 2-C1 H NH2 H H CH NH 191-193 2-Cl H NM®2 H H CH NH 186-188 2-Cl H CONHMe H H CH NH 2-C1 H CONMe2 H H CH NH 2-Cl H OH H H CH NH 181-182 2-Cl H OMe H H CH NH 2-Cl H C6HS H H CH NH 173-175 3,7-di-nSu H OMe OMe OMe CH NH 4,5-di-OH H CONH2 H H CH NH 3-OH4NH2 H CONH2 H H CH NH 2-Cl H COMe H H CH NH 134-136 2-Cl H Me H H CH NH 187-188 2-Cl H OEt H H CH NH 2-Cl H SO2NH2 H H CH NH 281-286 2-Cl H Cl H H CH NH 180-182 2-Cl H I H H CH NH 207-209.5 4-Br H CONH2 H H CH NH 4-1 H CONH2 H H CH NH 4-NO2 H CONH2 H H CH NH 4-CN H CONH2 H H CH NH 4-Me H CONH2 H H CH NH 2-Pr H CONH? H H CH NH 2-CF3 H CONH2 H H CH NH Table I (continued) x Ri R2 R3 R4 Y A 2-CfH5 H CONH? H H CH NH 2-Br H NMe2 H H CH NH 5-ΝΜΘ2 H ΝΜβ2 H H CH NH 5-Cl H NMe2 H H CH NH 4-NH2 H CONH 2 H H CH NH 4-NHMe H CONH2 H H CH NH 4-NM62 H CONH2 H H CH NH 4-CO2H H CONH2 H H CH NH 4-CO2Me H CONH2 H H CH NH 4-CONH2 H CONH2 H H CH NH 4-OH H CONH2 H H CH NH 4-OMe H CONH2 H H CH NH 4-COMe H CONH2 H H CH NH 4-SH H CONH2 H H CH NH 4-SMe H CONH2 H H CH NH 4-SOMe H CONH2 H H CH NH 4-S02M<3 H CONH2 H H CH NH H H CONH2 H H N NH 2-Cl H CONH2 H H N NH 4-Cl H CONH2 H H N NH 5-OH H CONH2 H H N NH 6-NH2 H CONH2 H H N NH 4-OMe H CONH2 H H N NH 5-NMe2 H CONH2 H H N NH 6-NO2 H CONH2 H H N NH H Me CONH2 V H CH NH 2-Cl H CONH2 K Me CH NH 2-Cl H CONH2 H H CHMe NH 5-Cl ' H CONH 2 we H CH NH H H CONH2 H OMe CH NH 2-Cl H CONH2 H H CHOMe NH 4-Cl H CONH2 OMe H CH NH mp (°C) 237-240 208-210 IE 90716 Table I (continued) Ex. X r£ R^ R3 R4 V A mp <eC) 91 5-C1 OMe CONH2 H H CH NH 5 92 2-Cl H CONH2 H H CH NH(CH2)2NH 93 2-Cl H CONH2 H H CH NH(CH2)3NH 94 2-Cl H CONH2 H H CH NH(CH2)4nH 95 2-C1 -CONHCO- H H CH NH 221-227 96 2-Cl H -CONNaCO- H H CH NNa >275 10 97 2-Cl H CONH2 H H CH NH(CH2)1ONH 98 3,6-di-tBu H CONH2 H H CH NH 99 H H H H H CH NH 15:7-158 100 H H Me H H CH NH 133 101 H H COMe H H CH NH 163-164 1 5 102 H H OH H H CH NH 142-144 103 H H H OH H CH NH 192-194 104 H H Cl H H CH NH 136-137 105 U H NMe2 H H CH NH 159-160 106 H H CgH5 H H CH NH 189-191. 20 107 H H SO2NH2 H H CH NH 209-212 108 H H I H H CH NH 146-147 109 H H OiPr H H CH NH 135-149 110 H H tBu H H CH NH 158-160 111 2-C1 H OiPr H H CH NH 134-137 25 112 2-C1 H tBu H H CH NH 169-172 113 2-Cl H SO2NHNa H H CH NNa >300 114 2-C1 H CONH2'NaOH H H CH NNa >300* 115 2-C1 H CONH2 H H CH NNa >300 116 2-Cl H CO2Na H H CH NNa >300 30 117 4-NHAc H H Me H CH NH 118 2-Cl H H COMe H CH NH 253-255 119 2-Cl H H OH H CH NH 180-182 120 2-Cl H H Cl H CH NH 164-166 121 4-NHAC H H NMe2 H CH NH 35 122 2-Br H H NMe2 H CH NNa IE 90716 Table T_fcontinued) Ex. X R1 R2 R3 R4 Y A mp <’C> —— 123 2-Cl H H SO2NH2 H CH NH 251-254 5 124 2-Cl H H I H ca NH 183-185.5 125 4-NHAc H Ά tBu H CH NH 126 4-Cl CONH2*NaOH Ά H H CH NNa 287-288* 127 4-Cl H CONH2«NaOH H H CH NNa >300* 128 4-Cl H H CONH2*NaOH H CH NNa >300* 1 0 129 4-Cl NH2 H H H CH NH 172-178 130 4-Cl C02H H H H CH NH 131 4-Cl H H NH2 H CH NH >30:0 132 5-Cl H CONH2*NaOH H H CH NNa >300* 133 5-ΝΜβ2 H H H H CH NH 128-131 1 5 134 2-Cl H CON- H H CH NH 145-182 (CH2CH2)2NMe 135 2-Cl H CH2N- H H CH NH (CK2CH2)2NMe 136 2-Cl H CONH- H H CH NH 231-233 20 CH2CH2NM®2 137 2-Cl H CH2NH- H H CH NH CH2CH2NMe2 138 2-Cl H CONH2 H H CH NH(CH2)6~ 109-114 CONH 25 139 2-Cl H H CO2H H N NH 259-261 140 H OMe H OMe H CH NH 134-136 141 2-Cl OMe H OMe H CH NH 106.-108 140 H OMe H H OM© CH NH 138-140 141 2-Cl * OMe H H OMe CH NH 143-144 30 142 y H OMe OMe OMe CH NH 138-139 143 2-Cl H OMe OMe OMe CH NH 144-145 144 2-Cl H CONH2 H H CH NNa >300 145 H H H K. H CH NH 152-153 146 2-C1 H OMe H H CH NH 35 147 2-Sr C1QH21 H H CH NH Ί IE 90716 Table I (continued) Ex. X rA r£ R3 r£ Y A mp (°C) 5 148 8-Cl H (CH2)8- CHCH2 H H CH NH 149 7-NH2 H H 2)8CCH H CH NH 150 5-NM©2 H H ’ H C6H5 CH NH 151 2-C1 H H P-CSH4NO2 H CH NH 152 5-NMe2 H CO2Me H H CH NH 10 153 5-ΝΜΘ2 H CO2C10H21 H H CH NH 154 2-C1 H CO2COMe H H CH NH 155 2-C1 H O2CMe H H CH NH 156 2-Cl H O2CC10H21 H H CH NH 157 2-Cl H H H CH NH 1 5 158 2-Cl H SO3H H H CH NH 159 4-Cl H SO2Me H H CH NH 160 5-Cl H H SOMe H CH NH 161 2-Cl H SMe H H CH NH 162 4-NH25- •OH H SMe H H CH NH 20 163 NHC6H5 H H SMe H CH NH 164 2-Cl H H H CH NLi 165 2-Br H CO2K H H N NK 166 5-ΝΜΘ2 H CO2Me H H N NH 25 167 2-Cl H CONH2 H H CH NHCONH 168 6-NO2 H H H H CH NHCH2CONH 169 5-OH H H H H CH NH(CH2)5SO2NH 170 4-NHAC one ί OMe H H CH NH(CH2> 6nh 30 * Compounds which are listed in Table I < as disodium salts were prepared by the addition Of two equivalents of sodium hydroxide to the parent compound as explained in the detailed description of the invention IE 90716 Ex. X r£ Y A mp <”C) 5 171 H H CONH2 H H CH NH 218-221 172 5-Cl H H H H CH NH 180-183 173 •5-Cl H CONH2 H H CH NH 206-208 174 H CONH2 H H H CH NH 175 H H H CONH2 H CH NH 10 176 H H H H H CH NH 177 H H Me H H CH NH 178 H H COCH3 H H CH NH 179 H H OH H H CH NH 180 H H Cl H H CH NH 1 5 181 H H NMe2 H H CH NH 182 H H NMe2 H H CH NNa 183 H H SO2NH2 H H CH NH 184 H H I H H CH NH 185 H H OiPr H H CH NH 20 186 H H tSu H H CH NH 187 H H OMe H H CH NH 188 H H OMe OMe OMe CH NH 189 H H OMe H OMe CH NH 190 H H CF3 H H CH NH 25 191 H H NO2 H H CH NH 4-Pl H MA μ w CH NH 193 5-Cl H COMe H H CH NH 194 5-Cl H OH H H CH NH 195 5-Cl· H Cl H H CH NH 30 196 5-Cl H ΝΜΘ2 H H CH NH 197 5-Cl H NMe2 H H CH NNa 198 5-Cl H SO2NH2 H H CH NH 90716 Table TT (continued) EX, X R1 R2 r£ r£ Y A mo (°C 199 5-Cl H I H H CH NH 200 5-C1 H OiPr H H CH NH 5 201 5-C1 H tBu H H CH •NH 202 5-Cl H OMe ,H H CH NH 203 5-C1 H OMe OMe OMe CH NH 204 5-C1 H OMe H OMe CH NH 205 5-Cl H CF3 H H CH NH 10 205 5-Cl H NO2 H H CH NH 207 5-Cl Cl 0^21 H H H CH NH 208 5-Cl H 2)8- H H CH NH CHCH2 209 5-Cl H H (CH2)8CCH H CH NH 15 210 5-Cl H H H C6H5 CH NH 211 5-C1 H H P-C6H4NO2 H CH NH 212 5-Cl H CO2Me H K CH NH Z10 3-Cl M OO2C1Um21 II 11 cu uu 214 S-Cl H CO2COMe H H CH NH 20 215 5-Cl H O2CMe H H CH NH 216 5-C1 H O2CC10H21 H H CH NH 217 5-Cl H (CH2)5NMe2 H H CH NH 218 5-Cl H SO3H H H CH NH 219 5-Cl H SO2Me H ti CH NH 25 220 5-Cl H H soMe H CH NH 221 H H SMe H H CH NH 222 H H SMe H H CH NH 223 H H H SMe H CH NH 224 H H H (CH2> 5NMeCOMe K CH NLi 30 225 H H CO2K H H N NK 226 H H C02Me H H N NH. 227 H H CONH2 H H CH NHCONH 228 H H H H H CH NHCH2CONH 229 H H H H H CH NH2)5SO2NH 35 230 H OMe OMe OMe H CH NLi IE 90716 R4 Table ill R3 Ex. R1 R2 R^_ R4 Y A 5 231 H H H H CH NH 2 32 COMH2 H H H CH Ma 233 H CONH2 H H CH NH 234 H H CONH2 H CH NH 235 H H H H CH NH 1 0 236 H Me H H CH NH 237 H COMe H H CH NH 238 H OH H H CH NH 239 H Cl H H CH NH 240 H NMe2 H H CH NH 1 5 241 H NMe2 H H CH NNa 242 H SO2NH2 H H CH NH 243 H I H H CH NH 244 H QiPr H H CH NH 245 H tBu H H CH NH 20 246 H OMe H H CH NH 247 H OMe OMe OMe CH NH 248 H OMe H OMe CH NH 249 H CP3 H H CH NH 250 H no2 H H CH NH 25 251 H H (CH2)8CCH H CH NH 252 H H H CgHS CH NH 253 H CO2C10H21 H H CH NH 254 H CO2COMe H H CH NH 255 H O2CMe H H CH NH 30 256 H O2CC10H2I H H CH NH 257 H (CH2)5NMe2 H H CH NH mp (°C) 205-207 IE 90716 Taais iii (eonr.A»u«d) Ex. R1 R2 R3 r4 Y A mp (*C) 258 H SO3H H H CH NH 5 259 H SO2Me H H CH NH 260 H H SOMe H CH NH 261 H SMe H H CH NH 262 H SMe H H CH NH 263 H H SMe H CH NH 1 0 264 H H (CH2)SNMeCOMe H CH NLi 265 H CO2K H H N NK 266 H C02Me H H N NH 267 H CONH2 H H CH NHCONH 268 H H H H CH NHCH2CONH 15 269 H H H H CH NH(CH2)5SO2NH 270 OMe OMe OMe H CH NLi RADIOBIOLOGICAL ASSAYS Tumor Cell Survival Assav (In Vivo ~ In Vitro Assay) 20 For this assay, EMT6 tumors in female BALB/c mice are used. These mice are bred in the Stanford Radiobiology colony under specific pathogen-free conditions and are 3 to 4 months old at the beginning of each experiment. The ΞΜΤ6 tumor is grown intradermally in the flank from an inoculation of 2x10^ tumor cells taken from the 2nd to 8th in vitro passage of tumor cells since removed from a previous tumor in BALB/c mice. Two tumors per mouse are implanted. These are used at a volume of approximately 100 mm3. At this point, the tumors contain approximately 20% hypoxic cells.

The first in vivo radiosensitization experiment is done with a fixed dose of intraperitoneally (ip) injected drug (usually 2 mmole/kg or 2/3 LDjq, whichever is lower), a fixed radiation dose (20 Gy), and a IE 90716 variable interval between irradiation and injection, or between injection and irradiation. If tumor drug concentrations are required, one of the two tumors in · each mouse is cut in half, and one half is immediately frozen for subsequent analysis of drug levels by high pressure liquid chromatography (HPLC). irradiation of the emts tumors is dune by irradiating nonanesthetized, tumor-bearing mice in a Plexiglas® box. Irradiation conditions are low LET 25010 kVp X-rays, 15 mA, FSD 33 cm, added filtration of 0.35 mm Cu, half value layer 1.3 mm Cu, and a dose rate of 130 rad/min.

To assay for cell survival, the tumor-bearing mice are killed immediately after irradiation. The tumors are dissected from the skin, cut into several pieces, and made into a fine brei by high-speed chopping with a razor blade attached to a jigsaw. The brei is then added to 30 ml of Hank's Balanced Salt Solution (HBSS) containing the following enzyme concentrations: 0.02% DNase, 0.05% pronase, and 0.02% collagenase. The suspension is stirred for 30 min at 37eC and. centrifuged. The cell pellet is resuspended in complete Waymouth's medium plus 15% Fetal Calf Serum (FCS), and an aliquot is mixed with trypan blue and the cells are counted with the use of a hemacytometer. Suitabledilutions of this single-cell suspension are then made in complete Waymouth's medium plus serum and plated into 60- or 100-mm polystyrene Petri dishes (Lux Scientific Corp.) in 5 or 15 ml of medium. After incubation for 13 days, the colonies are fixed and stained, and those containing 50 cells or more are counted. The dilution yielding an average count of 25 to 100 colonies in a 60mm dish is used in the calculation of results. Results are determined as the ratio of cells killed with IE 90716 radiation versus cells killed with radiation plus sensitizer (Table IV).

Table IV Tumor Cell Survival Assay Results1 Example Dose (mg/kg) SER2 1 400 1.80 2 400 1.25 6 400 1.55 16 400 1.19 1 EMt 6 tumors in mice were treated with 20 Gy. 2 Sensitizer Enhancement Ratio (SER) is the ratio of the plate efficiency of cells taken from tumors treated with radiation and drug versus tumors from animals treated with radiation alone. An SER of >1.0 is considered active.

BsgxgM&l· Peley Assay This assay is performed with the SCCVII carcinoma transplanted in C3H mice. It is an excellent tumor for regrowth delay studies because it has a low spontaneous metastasis rate, it is relatively nonimmunogenic in its syngeneic host, and grows to a large volume without compromising the health of its host.

For tumor inoculation, cells are taken from the 2nd to the 5th in vitro passage of a SCCVII tumor previously removed from a C3H mouse. Between 1 and 2xl03 cells are inoculated in a volume of 0.05 ml HBSS intradermally in the dorsum approximately 1 cm proximal to the base of the tail.

IE 90716 The assays for each test sensitizer result in two growth delay curves (one for vehicle controls and one for the test drug), in which the mean number of days delay for the tumor to reach 4X its volume at the time of radiation is plotted as function of time. The test sensitizer was given at a dose selected in the tumor cell survival assay experiment and at its optimal time interval (also determined in the tumor cell survival assay). Mice are irradiated in a specially designed lead shield, with only the tumor and lower part of the dorsum exposed. The mice are retained by taping the tail to the side of the shield. Four mice are irradiated simultaneously with 250-KVp X-rays, FSD 31 cm, dose rate of 167 rad/min. Each growth delay curve is produced from five groups (four radiation doses + unirradiated control) of 6 mice each. Radiation dose used was 20 Gy.

Tumor diameter is measured daily in three dimensions with a vernier caliper and tumor volume calculated. At treatment tumors were about 300 mm3 to 500 mm3. After treatment tumors were measured three times per week until each tumor reaches four-fold its initial volume. The mean number of days after treatment for tumors in each group to reach four times their treatment volume is calculated. This growth delay to four times initial tumor volume which is the difference between the mean in irradiated and unirradiated controls, or between irradiated pulse drug versus unirradiated control, is shown in Table V.

IE 90716 Table V Tumor Regrowth Delay Results1 Example Growth Delay (day) Radiation alone 14.2 Ex. 1 + radiation 30.0 1 SCC-VII tumors in mice were treated with 20 Gy.

Clonogenic Survival Assay Human colon cancer clone A cells (1 x 10®) were plated in 60-mm tissue culture dishes in RPMI-C medium on day 0. The cells were incubated in a humidified atmosphere of 5%CO2~95% air at 37°C for 24 hrs. The culture medium was then removed and replaced with 4 ml of fresh RPMI-C medium. The cells were irradiated with or without 5.7 Gy of radiation. Test analogs (1 ml, 5X concentration) were added to two similar plates (+/20 radiation) immediately after radiation. The cultures were incubated at 37°C for 2 hrs and then the cells were harvested with trypsin (0.033%) and centrifuged. The cells were resuspended in RPMI-C and the cell concentrations were adjusted for appropriate seeding density (depending on concentrations of testing analogs and whether the cells were treated with radiation).

After seeding, cultures were maintained for 10 days and then the cells were washed with 0.9% NaCl and stained with crystal violet (0.5% in absolute alcohol) and the number of colonies with more than 50 cells/colony were counted. The plating efficiency (PE) was defined as the percentage of colonies formed from the total number of cells seeded. The radiosensitizing effect was defined by the survival ratio (SR) calculated from the following equation.

IE 90716 PE (rad) PE (analog) Sr = -xPE (rad+analog) PE control where PE (rad) » plating efficiency of cells treated with radiation alone PE (rad+analog) = plating efficiency of cells treated . 1 0 with radiation and test analog PE (analog) - plating efficiency of cells treated with test analog alone PE (control) = plating efficiency of control (no treatment) cells Any test analog with a SR > 1.5 is considered positive in this clonogenic survival assay. Data are shown in Table vi.

Inhibition of Repair of DNA Double Strand Breaks Induced 0 by Radiation L1210 Cells (3 x 10$ cells/ml) were incubated with 0.02 μξί/ιηΐ of [2-14C]thymidine (sp. act. 54.0 Ci/mmol) in a humidified atmosphere of 5% CO2~95% air at 37°C for 24 hrs. The cells were then harvested and centrifuged.

The cells were resuspended and adjusted to a concentration of 1 x 106 cells/ml. The cells were irradiated on ice for 1 hour in a Gamma cell 40 irradiator at a flux rate of 1.14 Gy/min. The cell suspensions were then incubated with or without test 0 analogs for 2 hr at 37°C. The DNA double-strand breaks in each sample were measured by neutral elution procedures (Kohn X-ray Induced DNA Double Strand Break Production and Repair in Mammalian Cells as Measured by Neutral Filter Elution, Nucleic Acids Research. 7., p. 793-804 (1979)). The cells were diluted with cold PAGE .004 IE 90716 FEB~28 ’90 7:53 phosphate buffered saline (PBS) and loaded onto a Smokestack funnel fitted with a 2 JX polycarbonate filter. After washing the cells three times with cold PBS, the cells were lysed with 5 ml of SDS-EDTA lysis solution. After draining the lysis solution into scintillation vials, the cell lysates were deproteinized with SDS-EDTA lysis solution containing 0.5 mg/ml proteinase K. The DNA retained on the filter was eluted with 30 ml of 0.02 M tetrapropyl ammonium hydroxide 10 EDTA solution (pH = 9.6) at a flow rate of 0.035 ml/min. The amount of radioactive DNA retained on the filter after 10 hr elution was determined. The inhibition of DNA repair by test analog is calculated by the following formula : DNAa-DNAo % Inhibition = 100 - { (---) x 100] DNAb-DNAo 0 where DNAa is %DNA retained when cells were incubated at 37°C in the presence of test analog DNAij is %DNA retained when cells were incubated at 37°c in the absence of test analog (designated as 100% repair) DNAq is %DNA retained when cells remained on ice for 2 XXX _ XXX. XXxX. XX -X------...X, ,. J. x.. J A . i -J J). I. I (designated as 0% repair) If a testing analog produced a >50% inhibition of DNA repair, the analog was considered active and a + sign was assigned in Table VI.

IE 90716 PAGE 003 FEB 23 ’90 7:53 Aerobic Cell Ex. Sensitization^·'3 + 2 + + 1.6 24 2.5 + 34 + + + 46 + + 86 + + 100 + 0 ιοί + 102 + 103 + Tdklfi Vl· Inhibition of DNA Double Strand Break'Repair2»2 + + + + nt + + nt + + + nt nt + nt + + nt + + + nt + + + nt + + IE 90716 PAGE .002 FEB 28 ’90 7:52 Table VI (continued! Aerobic Cell Ex. Sensitization^'3 104 106 107 108 109 110 111 112 113 114 115 116 118 119 120 123 124 126 127 128 129 132 133 134 136 136 171 172 173 233 + + + + + + + + + + + + 4.

Iiihibition of DNA Double Strand Break· Repair2'3 + + nt + + + + + nt + nt nt nt + + nt + nt nt + + + + + + nt nt + + nt IE 90716 FEB 29 ’90 7:59 .............---· ........................ PAGE. 014 .34 Table. Vl_ tcon.tinuscLL 1) In this test, compounds with a SR of >1.5 are ”+·’ and compounds with a SR of <1.5 are . 2) In this test, compounds which inhibit DNA double strand break repair >50% are +·’ and compounds which inhibit DNA double strand break repair <50% are 3) The nt” indicates that the test was not performed on this compound. 0 P.gsaga-forma The postradiation and/or chemotherapeutic sensitizing compounds (active ingredients) of this invention can be administered to enhance radiation or chemotherapy treatment by any means that produces contact of the active ingredient with the agent’s site of action in the body of a mammal after such radiation or chemotherapy treatment. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual active ingredients or in a combination of active ingredients. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will be a radiation or chemotherapy enhancing amount of active ingredient and will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular active ingredient, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a dosage of active ingredient can be about 5 to 1000 milligrams per kilogram of body IE 90716 PAGE .015 weight administered after radiation. A typical dose is about 400 mg/kg.

Dosage forms (compositions) suitable for internal administration contain from about 5 milligrams' to about 1000 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in 10 solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions, it can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and 15 powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.

Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if PAGE .016 co co 'aa 8:00 IE 90716 necessary/ buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. i r.aJ. carriers are described in Remington '.s- Pharmaceutical..Sciences, A. Osoi, a reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: C£££iil££ A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 175 milligrams of lactose, 24 milligrams of talc, and 6 milligrams magnesium stearate.

A mixture Of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried. laklStS A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

PAGE .017 rco £b ’90 g.gj IE 90716 Ifl3£.cfcateXa A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

Su&psnaisa An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.

’’Consisting essentially of in the present disclosure is intended to have its customary meaning: namely, that all specified material and conditions are very important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

Claims (86)

1. A compound having the formula: or a pharmaceutically acceptable salt thereof wherein: r1, R 2 , r 2 , R 4 and R 5 independently are H, alkyl,· alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl, F, Cl, Br, I, N02, CN, CF3, 10 (CH2)mNR 6 R 7 (m«0-l0), CO2R 9 , OR 10 , COR 11 or S(O) n R 12 (n-0-3), or R 1 and R 2 , R 2 and R 2 , R 2 and R 4 , or R 4 and R 2 when taken together may form -CONHCO- or -CONMCO- wherein M is Na + , K + or Li + ; R® and R 7 independently are H, alkyl, alkenyl, alkynyl, 15 acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R® and R 7 taken together can form (CH2)pNR®(CH2)q (P and q independently are 2-6); R® and R 9 independently are H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; 20 R 1 ® is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl or substituted phenyl; Rll is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 12 R 14 ; r 12 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms,

2. 5 phenyl, substituted phenyl or NR 18 R 17 ; R^ 2 and R^ 4 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl or CF3, or R 12 and R^· 4 taken together can form (CH2) rNRl® (CH2) s ( r and s

3. 0 independently are 2-6; i S aixyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; .....- ...... —----- PAGE, aig IE 90716 R- 5 and R 17 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 16 and R 17 taken together on fnrm f^H^^NR 18 (CH2)u (t and u independently are 5 2-6) ; R 18 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; Y is N or CR 3 ; each X independently is H, F, Cl, Br, I, NO2, CN, CF3, 10 alkyl, alkenyl, alkynyl of 1-4 carbon atoms, phenyl, substituted phenyl, (CH2)cNR 18 R 28 (c is 0-10), CO2R 22 , OR 23 , COR 24 or S(O)dR 25 (d is 0-3); b is 1-2; Z 13 N or CH; 15 R 18 and R 2 ^ independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 19 and R 2 Q taken together can form (CH2)eNR 21 (CH2)f (e and f independently are 2-6); 20 R 21 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; r22 is H, alkyl, alkenyl or alkynyl of 1-10 carbon atoms; R 23 is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon 25 atoms, phenyl or substituted phenyl; R 24 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 28 R 27 ; r 25 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 29 R 38 ; 3 0 R 28 and R 27 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 28 and R 27 taken together can form (CH2)gNR 28 PAGE .020 EEB 28 ’80 S;02 IE 90716 r 28 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; r29 an 3 r30 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl', substituted phenyl, CF3 or R 2 ^ and r 30 taken together can form (CH2)jNR 3 ^·(CH2)k (j and k independently are 2-6) ; R 31 is H, alkyl, alkenyl or alkynyl of 1-10 carbon atoms; A is NR 32 or NR 32 QNR 33 ; Q is w , X SO 2 ; w is 2-10; x is 0-10; R 32 and R 33 independently are H, Na + , K + , Li + , alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, benzyl or substituted benzyl; with the following provisos: (a) when X, R 1 , R 3 and R 4 are H, R 2 is H, methyl, OH or Cl and Y is CH, then A cannot be NH; and (b) when X, R 3 , R 2 and R 4 are H, R 3 is OH and Y is CH, then A cannot be NH.

2. A compound of Claim 1 wherein -SO2A is attached at the 1 or 2 position.

3. A compound of Claim 1 wherein Z is CH.

4. A compound of Claim 1 wherein X is 2-halogen, provided that -SO2A is at the 1 position.

5. A compound of Claim 1 wherein: -SO2A is attached at the 1 or 2 position; Z is CH; and λ is 2 provided that, if X is 2halogen, then -SO2A is at the 1 position .

6. The compound of Claim 1 which is N-(3-amidophenyl)-2-chloro-l-naphthalene-sulfonamide. •J fcj a: 03 IE 90716 PAGE.021

7. The compound of Claim 1 which is N-(3-amidophenyl)-5-chloro-l-naphthalenesulfonamide.

8. The compound of Claim 1 which is N-(2-amidophenyl)-4-chloro-l-naphthalenesulfonamide. 5

9. The compound of Claim 1 which is N-(3-amidophenyl)-4-chloro-l-naphthalenesulfonamide.

10. The compound of Claim 1 which is N-(2-amidophenyl)-2-chloro-l-naphthalenesulfonamide.

11. The compound of Claim 1 which is 10 benzoic acid, 3-[[(4-chloro-l-naphthalenyl) sulfonyl]amino]-, ethyl ester.

12. The compound of Claim 1 which is benzoic acid, 3-[[2-chloro-l-naphthalenyl) sulfonyl]amino]. 15

13. The compound of Claim 1 which is N-[(3-dimethylamino)phenyl]-2-chloro-l-naphthalenesulfonamide.

14. The compound of Claim 1 which is N-(3-acetylphenyl)-2-chloro-l-naphthalenesulfonamide. 20

15. The compound of Claim 1 which is N-[3-(aminosulfonyl)phenyl]-2-chloro-l-naphthalenesulf onamide.

16. The compound of Claim 1 which is 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-4-methoxy25 benzamide.

17. The compound of Claim 1 which is N-(2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl)-2-chloro-lnaphthalenesulf onamide .

13. The compound of Claim 1 which is 3 0 N-(3-methylphenyl)-1-naphthalenesulfonamide.

19. The compound of Claim 1 which is N-(3-acetylphenyl)-1-naphthalenesulfonamide. rco dd ’90 8:04 PAGE .022 IE 90716

20. The compound of Claim 1 which is N-(3-hydroxyphenyl)-1-naphthalenesulfonamide.

21. The compound of Claim 1 which is N-(4-hydroxyphenyl) -l-naphtnaieneou*^v.—,i 5

22. The compound of Claim 1 which is N-{3-chlorophenyl)-1-naphthalenesulfonamide.

23. The compound of Claim 1 which is N-[3-(aminosulfonyl)phenyl]-1-naphthalenesulfonamide.

24. The compound of Claim 1 which is 10 N- (3-iodophenyl) -1-naphthalenesulfonamide.

25. The compound of Claim 1 which is N-[3-(1-methylethoxy)phenyl 3-1-naphthalenesulfonamide.

26. The compound of Claim 1 which is N-[3-{1,1-dimethy1) phenyl]-1-naphthalenesulfonamide.

14. 15 27. The compound of Claim 1 which is N-(3-aminosulfonyl)phenyl]-2-chloro-lnaphthalenesulf onamide, or the sodium salt thereof.

28. The compound of Claim 1 which is 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-benzamide, or 20 the sodium salt thereof.

29. The compound of Claim 1 which is 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-benzamide, or the sodium salt thereof.

30. The compound of Claim 1 which is 25 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-benzoic acid, or the sodium salt thereof.

31. The compound of Claim 1 which is N-(4-acetylphenyl)-2-chloro-l-naphthalenesulfonamide.

32. The compound of Claim 1 which is 3 0 N-(4-hydroxyphenyl)-2-chloro-l-naphthalenesulfonamide.

33. The compound of Claim 1 which is N-(4-chlorophenyl)-2-chloro-l-naphthalenesulfonamide.

34. The compound of Claim 1 which is N-[4-aminosulfonyl)phenyl]-2-chloro-l3 5 naphthalenesulfonamide . IE 90716 FEB 28 ’90 8:04 .......----------—.......... PAGE. 023

35. The compound of Claim 1 which is 3-[(4-chloro-l-naphthalenyl)sulfonylamino] benzamide, or the sodium salt thereof.

36. The compound of Claim 1 which is 5 3-[(5-chloro-l-naphthalenyl)sulfonylamino] benzamide, or the sodium salt thereof.

37. The compound of Claim 1 which is 3-((2-chloro-l-naphthalenyl)sulfonylaminio]-N-[2(dimethylamino)]ethyl benzamide. 10

38. The compound of Claim 1 which is 3[[6-[(2-chloro-l-naphthalenyl)sulfonylamino]-1o'xohexy 1 ] amino ] benzamide.

39. The compound of Claim 1 which is N-(3-amidophenyl)-2-naphthalenesulfonamide. 1 5

40. The compound of Claim 1 which is 3-[(8-guinolinylsulfonyl)amino]benzamide.

41. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of any of the compounds of Claims 1 through 40.

15. 20 42. In a method of treating a tumor in a mammal by radiation or chemotherapy, the improvement comprising administering in conjunction with such radiation or chemotherapy, a compound of the formula: or a pharmaceutically acceptable salt thereof wherein: R 1 , 8.2, R^ f R 4 and R 3 independently are H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, 3 0 substituted phenyl, F, Cl, Br, I, NO2, CN, CF3, (CH2>mNR 6 R 7 (πυ=0-10) , CO2H 9 , OR 10 , COR 11 or S(O) n R 12 (n-0-3), or R 1 and R 3 , r2 and R 3 , R 3 and R 4 , or R 4 IE 90716 _ ΓΧ - β — 28 —> g0 gT05 .. —· — .............. PAGE. 024 and R 3 when taken together may form -CONHCO- or -CONMCO- wherein M is Na + , K + or Li + ; R 6 and R 7 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted 5 phenyl, CF3 or R® and R 7 taken together can form (CH2)pNR®(CH2>q (P and q independently are 2-6); R® and R 9 independently are H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; RiO is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon 10 atoms, phenyl or substituted phenyl; RU is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR^ 3 R^· 4 ; R 12 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or ΝρΑθίΑ 7 ; 1 5 Ri 3 and lA 4 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl or CF3, or Ri 3 and R i4 taken together can form {CH2) r NR 13 (CH2) s (f and 3 independently are 2-6; 20 R 15 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; R 1 ® and R i7 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 16 and R 17 taken together 2 5 can form (CH2) t NR ^ (CH2) u and u independently are 2-6) ; Ri® is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; Y is N or CR 3 ; 3 0 each X independently is H, F, Cl, Br, I, NO2, CN, CF3, alkyl, alkenyl, alkynyl of 1-4 carbon atoms, phenyl, substituted phenyl, (CH2>cNR 19 ^ 20 (c is 0-10), CO2R 22 , OR 23 , COR 24 or S(O)dR 25 (d is 0-3); b is 1-2; 3 5 Z is N or CH; IE 90716 F'E’B — 2'0~’~9Γ0 S':-0'5 PAGE . 025 R^· 9 and R 2 ® independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R^· 9 and R 2 ® taken together can form (CH2) eNR 2 ^-(CH2) f (e and f 5 independently are 2-6) ; R21 is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; R 22 is H, alkyl, alkenyl or alkynyl of 1-10 carbon atoms; 10 R 22 is H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl or substituted phenyl; R 24 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, phenyl, substituted phenyl or NR 2 ®R 27 ; R25 is H, alkyl, alkenyl, alkynyl of 1-10 carbon atoms, 15 phenyl, substituted phenyl or NR 29 R 2 ®; R 2 ® and R 27 independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, CF3 or R 2 ® and R 27 taken together can form (CH2)gNR 2 ®(CH2)h (9 and h 2 0 independently are 2-6); R 2 ® is H, alkyl, alkenyl, alkynyl or acyl of 1-10 carbon atoms; R 29 and R 2 ® independently are H, alkyl, alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, 2 5 substituted phenyl, CF3 or R 29 and R 2 ® taken together can form (CH2)jNR 2 ^(CH2)k (j and k independently are 2-6); R 21 is H, alkyl, alkenyl or alkynyl of 1-10 carbon atoms; 3 0 A is NR 22 or NR 22 QNR 22 ; Q is (CK2) W , (CH2) X CO or X SO 2 ; w is 2-10; x is 0-10; FEB 28 ’80 8:06 PAGE.026 R 32 and R 33 independently are H, Na + , X + , Li + , alkenyl, alkynyl, acyl of 1-10 carbon atoms, phenyl, substituted phenyl, benzyl or substituted benzyl; with the following provisos: 5 (a) when X is H, R 1 is CONH2 and R 2 is H or R 1 is H and R 2 is NMe, R 3 and R 4 are H and Y is CH, then A cannot be NH; (b) when X is 2-C1, R 1 , R 3 and R 4 are H, R 2 io CONNaCO and Y is CH, then A cannot be NNa; and 10 (c) when X is 4-C1, R 1 , R 2 and R 4 are II, ft 3 is CONH2 and Y is CH, then A cannot be NH2.

43. A method of Claim 42 wherein -SO2A is attached ir rrtr 1 nr ϋ ϊ»ϊϋί? η ·

44. A method of Claim 42 wherein Z is CH. 15

45. A method of Claim 42 wherein X is 2-halogen, provided that -SO 2 A is at the 42 position.

46. A method of Claim 42 wherein: -SO2A is attached at the 1 or 2 position; Z is CH; and 20 X is 2-halogen, provided that if X is 2halogen, then -SO2A is at the 1 position.

47. The method of Claim 42 wherein the compound is N-(3-amidophenyl)-2-chloro-l-naphthalene-sulfonamide.

16. 25 48. The method of Claim 42 wherein the compound is N-(3-amidophenyl)-5-chloro-l-naphthalenesulfonamide.

49. The method of Claim 42 wherein the compound is N-(2-amidophenyl)-4-chloro-l-naphthalenesulfonamide.

50. The method of Claim 42 wherein the compound is

17. 30 N-(3-amidophenyl)-4-chlcro-l-naphthalenesulfonamide.

51. The method of Claim 42 wherein the compound is N-(2-amidophenyl)-2-chloro-l-naphthalenesulfonamide.

52. The method of Claim 42 wherein the compound is benzoic acid, 3-[[ (4-chloro-l-naphthalenyl)sulfonyl]3 5 amino]-, ethyl ester. FEB 28 ’80 8:07 PAGE .027 90716

53. The method of Claim 42 wherein the compound is benzoic acid, 3-[[2-chloro-l-naphthalenyl)sulfonyl]amino].

54. The method of Claim 42 wherein the compound is 5 N-[(3-dimethylamino)phenyl]-2-chloro-l-naphthalenesulf onamide .

55. The method of Claim 42 wherein the compound is N-(3-acetylphenyl)-2-chloro-l-naphthalenesulfonamide.

56. The method of Claim 42 wherein the compound is 10 N—[3-(aminosulfonyl)phenyl]-2-chloro-lnaphthalenesulfonamide.

57. The method of Claim 42 wherein the compound is 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-4methoxybenzamide. 15

58. The method of Claim 42 wherein the compound is N-(2,3-dihydro-l,3-dioxo-lH-isoindol-4-yl)-2-chloro-lnaphthalenesulfonamide.

59. The method of Claim 42 wherein the compound is N-(3-methylphenyl)-1-naphthalenesulfonamide. 2 0 bU. me method of Claim 42 wherein the compound ic N-(3-acetylphenyl)-1-naphthalenesulfonamide.

PAGE .028 IE 90716 τ-χτυ—ta ~=iu errer?

61. The method of Claim 42 wherein the compound is N-(3-hydroxyphenyl)-1-naphthalenesuifonamide.

62. The method of Claim 42 wherein the compound is N-(4-hydroxyphenyl)-1-naphthalenesulfonamide. 5

63. The method of Claim 42 wherein the compound is N-(3-chlorophenyl)-1-naphthalenesulfonamide.

64. The method of Claim 42 wherein the compound is N-[3-(aminosulfonyl)phenyl]-1-naphthalenesulfonamide.

65. The method of Claim 42 wherein the compound is 10 N-(3-iodophenyl)-1-naphthalenesulfonamide.

66. The method of Claim 42 wherein the compound is N-[3-(1-methylethoxy)phenyl]-1-naphthalenesulfonamide.

67. The method of Claim 42 wherein the compound is N-[3-(1,1-dimethyl)phenyl]-1-naphthalenesulfonamide. 15

68. The method of Claim 42 wherein the compound is N-(3-aminosulfonyl)phenyl]-2-chloro-lnaphthalenesulf onamide, or the sodium salt thereof.

69. The method of Claim 42 wherein the compound is 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-benzamide, or 2 0 the sodium salt thereof.

70. The method of Claim 42 wherein the compound is 3-[(2-chloro-l-naphthalenyl)sulfonylamino]-benzamide, or the sodium salt thereof.

71. The method of Claim 42 wherein the compound is 25 3-((2-chloro-l-naphthalenyl)sulfonylamino]-benzoic acid, or the sodium salt thereof.

72. The method of Claim 42 wherein the compound is N-(4-acetylphenyl)-2-chloro-l-naphthalenesulfonamide.

73. The method of Claim 42 wherein the compound is 30 N-(4-hydroxyphenyl)-2-chloro-l-naphthalenesulfonamide.

74. The method of Claim 42 wherein the compound is N-(4-chlorophenyl)-2-chloro-l-naphthalenesulfonamide.

75. The method of Claim 42 wherein the compound is N-(4-aminosulfonyl)phenyl]-2-chloro-l-naphthalene3 5 sulfonamide . PAGE .029 IE 90716 FEB 29 ’90 8:08

76. The method of Claim 42 wherein the compound is 3-[(4-chloro-l-naphthalenyl)sulfonylamino] benzamide, or the sodium salt thereof.

77. The method of Claim 42 wherein the compound is 5 3-[(5-chloro-l-naphthalenyl)sulfonylamino] benzamide, or the sodium salt thereof.

78. The method of Claim 42 wherein the compound is 3-[(2-chloro-l-naphthalenyl)sulfonylaminio]-N-[2(dimethylamino)]ethyl benzamide . 10

79. The method of Claim 42 wherein the compound is 3[[6-[(2-chloro-l-naphthalenyl)sulfonylamino]-1oxohexy1]amino] benzamide.

80. The method of Claim 42 wherein the compound is N-(3-amidophenyl)-2-naphthalenesulfonamide. 15

81. The method of Claim 42 wherein the compound is 3-[(8-quinolinylsulfonyl)amino]benzamide.

82. A process for preparing a compound of Claim 1 comprising: (a) reacting in the presence of an inert 2 0 solvent such as pyridine, acetone or methylene chloride a naphthalenesulfonyl chloride of the formula where X is defined in Claim 1, with (i) an aryl or heteroaryl amine of the formula: PAGE .030 IE 90716 FEB 28 ’90 8:09 where R 1 and R 2 are defined in Claim 1; or (b) adding simultaneously into a .'solution of a compound of formula (2) in tetrahydrofuran, a compound of formula (3) in tetrahydrofuran and a solution of aqueous potassium carbonate.

83. A compound substantially as hereinbefore described with reference to the Examples.

84. A composition substantially as hereinbefore described with reference to the Examples.

85. A method substantially as hereinbefore described with reference to the Examples.

86. A process substantially as hereinbefore described with reference to the Examples.