JPH04503672A - Novel naphthalene sulfonamides as radiosensitizers - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Novel radiosensitizer naphthalene sulfonamide The present invention relates to a sulfonamide, a method for producing the same, a pharmaceutical composition containing the same, and a method for producing the same. for its use in the treatment of tumors as a radiosensitizer and chemotherapeutic enhancer.

background: Currently known radiosensitizers in clinical trials, such as nitroimidazoles, The drugs are hypoxic cell sensitizers and are radiosensitizers that can only be used if administered before irradiation of the tumor. exerts a sensitizing effect (G, E, Adams & 1. J, 5tratfor d, -Hypoxia-Dependent Radiation 5ens itizers-, Mo1ecular Actionsand Target s for Cancer Chemotherapeutic Agents .

1981, 401 pages, Academic Press). However, The repair of radiation damage to DNA is important for the possibility of radiotherapy for cancerous tumors. It is considered to be an important factor (K, Ni, Fu, -Biological Ba5is for the International of Chemothe rapeutic Agents and Radiation + Thera py”.

Cancer, May 1st Supplement, Volume 55, 2123.1985: S, Naka -Tsugawa & T, Sugahara, +Effects of Inhibitors of Radiation (induced Potent ially Lethal Da+mage Repairon Chemot therapy in 1lurine Tumors-, Int, J, Ra Dia-tion Oncology Biol, Phys, Volume 8, 1555 ．． 19g2). Therefore, recent efforts in this field have been The search for drugs that can interfere with radiation therapy and sensitize tumors after irradiation has been directed. but However, there are several drugs that have been found to have this effect. Only. Drugs such as lonidamine, which were found to have this activity, are antitumor agents. Has tumor activity. Postirradiation activity of compounds like lonidamine leads to additive cytotoxic effects It remains unclear whether the n-tiation of Radiation Effects on Tw o l1urine Tumorsby Lonidamine”, Canc er　Re5earch,　46.1120.1986).

U.S. Pat. No. 4,603,133 describes 2- [N-(morpholinoalkyl)aminosulfonyl]-6-nitrobenzoic acid amide and esters and compositions are disclosed.

These compounds have the formula has. During the ceremony, RI is hydroxy (lower alkoxy), lower alkokene, allyloxy, amino Monoalkylamino, dialkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino or allylamino, R2 is hydrogen, carbon lower alkyl, hydroxy-(lower alkyl), allyl having 1 to 4 atoms; , R3 is a morpholino group of formula 0 (CLCHdJ(CH2)n, where n is 2 or or 3.

U.S. Pat. No. 4,731,369 describes 2- (N-(hydroxypiperidinoalkyl) and (hydroxypyrrolidinoalgyl) Amides and esters of (l)-aminosulfonyl]-6-nitrobenzoic acid are disclosed. has been done. These compounds have the formula: During the ceremony, R1 is hydroxy (lower alkoxy), lower alkoxy, allyloxy, amino -, alkylamino, di(lower alkyl)-alkylamino, (hydroxyalkyl) (kyl)amino, di(hydroxyalkyl)amino, or allylamino, R2 is hydrogen, lower alkyl having 1 to 4 carbon atoms, hydroxy-(lower alkyl) kill), allyl, n is 2 or 3, m is 0.1 or 2, p is 1 or 2.

U.S. Patent No. 4.694.020 describes the treatment of hypoxic tumor cells with therapeutic radiation 2-(1!-transformed sulfamyl)-6-nitrobenzoin useful for increasing sensitivity Amides and esters of acids and pharmaceutical compositions are disclosed. These compounds things are expressions has. During the ceremony, R1 is hydroxy (lower alkoxy), lower alkoxy, alkoxy (lower alkoxy), allyloxy, amino, monoalkylamino, dialkylamino , (hydroxyalkyl)amino, di(hydroxyalkyl)amino, or a It is lylamino, R2 and R3 are each independently hydrogen, lower alkyl having 1 to 4 carbon atoms; , hydroxy-(lower alkyl), allyl, amino-(lower alkyl), (lower alkyl)-amino-(lower alkyl), di(lower alkyl)-amino-(lower alkyl), (hydroxyalkyl)-amino(lower alkyl), (hydroxy alkyl)-alkylamino (lower alkyl), or di(hydroxyalkyl) ) amino (lower alkyl) or with the nitrogen atom to which they are attached. morpholino, aziridinyl, azetidinyl, pyrrolidyl, piperidyl or is R4-substituted-3-year-old xopiperazin-1-yl (R4 is hydrogen, 1 to 4 carbon atoms or hydroxyalkyl having 2 to 4 carbon atoms represents a heterocycle selected from

Published European Patent Application No. 0270292 describes the X-ray and gamma - 2 of 4-nitrobenzamide as an agent that increases sensitivity to radiation; -(!i!-substituted sulfamyl) derivatives are disclosed. These drugs have the formula has. During the ceremony, R1 is hydrogen or lower alkyl having 1 to 4 carbon atoms; R2 and R4 are the same or different, each containing hydrogen and 1 to 4 carbon atoms. lower alkyl, or hydroxy lower alkyl, R3 is NQ'Q" (wherein, Ql is the same or different from O2, Q, and O Both of 2 are hydrogen, lower alkyl having 1 to 4 carbon atoms or hydroxy lower or Ql and O2, together with the nitrogen atom in NQIQ2, are Heterogeneous compounds such as diridinyl, azetidinyl, pyrrolidinyl, or piperidinyl lower alkyl having 1 to 4 carbon atoms, substituted with

A wide range of sulfonamides have been used as pharmaceutical or agricultural agents through patented technology. and are described in literature. The most similar compounds are:

Published Japanese Patent Application No. 61/257.960 contains the formula (where Z is CB or N, Y is C1%CF3 or CN) antifungal sulfonamides are indicated. It is.

Published Japanese Patent Application No. 61/233660 describes the antifungal sulfone of the formula Amides are shown.

The antibacterial and antifungal sulfonamides (wherein X is H or CI) has been done.

Summary of the invention Unlike many known radiosensitizers, the compounds of the present invention are capable of reducing the D It is thought that these effects are exerted by inhibiting the repair of breaks in the NA sequence. and is therefore classified as a post-irradiation sensitizer. This post-irradiation sensitizer term is describes the mechanism of action of the compound and also limits the timing of administration of the compound. It's not. For these compounds to be effective, they must be present after radiation therapy. Must be. Therefore, their administration is recommended either before, during or after radiotherapy. This may be the case.

Furthermore, since these compounds are thought to inhibit the repair of DNA strand breaks, , is an effective chemotherapy when administered in combination with a chemotherapeutic agent that causes DNA strand breaks. Acts as a law enhancer. For example, the compounds of the invention may be used as intercalators, alkaline Its anti-cancer properties by interacting with killing agents, DNA cross-linking agents and DNA, and strand scission. Enhances or sensitizes the activity of other agents that exert their activity.

The present invention is based on the formula or a pharmaceutically acceptable salt thereof. During the ceremony, R1, R2, R3, R4 and R5 independently have 1 to 10 H1 carbon atoms Alkyl, alkenyl, alkynyl: phenyl, substituted phenyl, F SCL Br, I, NO2, CN, CF,, (CH2)mNR'R' (m=0~1 0), CO, R’, ORI O, COR or 5(0)nR’” (n = 0 to 3) or R1 and R2, R2 Oyohi l? s, R3o Yohi R4, *Taha R4 Oyohi R'ha both -CONHCO- or -CONM forming CO- (M is Na″″, R4 or Li″), R6 and R7 are independently alkyl or alkenyl having 1 to 10 H1 carbon atoms; R, alkynyl, acyl; phenyl, substituted phenyl, CF3, or R 6 and Rf are both (CH2)pNR'(CHz)q (+) and q are independent 2 to 6), R8 and R9 are independently alkyl, alkenyl, aryl having 1 to 10 H1 carbon atoms; ruquinyl or acyl, RIG is I], alkyl having 1 to 10 carbon atoms; Kyl, alkenyl, alkynyl, acyl; phenyl or substituted phenyl; R11 is H1 alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR”R, R12 is H1 alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms: phenyl, substituted phenyl or NRI @RI7, RI3 and R14 are independently alkyl or alkyl having 1 to 10 H1 carbon atoms; Kenyl, alkynyl, acyl; phenyl, substituted phenyl or CF? , or R+3 and )714 are both (Cut)rNR''(Cut)s (r and S are independently 2 to 6), R is alkyl, alkenyl, alkynyl, or H1 having 1 to 10 carbon atoms. or acyl, and Rts and R17 independently have 1 to 10 H1 carbon atoms. Alkyl, alkenyl, alkynyl, acyl: phenyl, substituted phenyl, C F, or R16 and RI7 are both (CHdtNR”(Ct12 ) u (t and U are independently 2 to 6), RIB is ■], alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms or acyl, Y is N or CR', X is each independently HSF, Cl5BrSI, NO2, and CN.

CF5, alkyl, alkenyl, alkynyl having 1 to 4 carbon atoms: phenyl ru, substituted phenyl, (c112). )i)llJ211 (C is 0-10) ,CO,i? ”, ORri3, COR24 or 5(0), R2S (d is 0 to 3), b is 1 or 2, Z is N or CI’l; Rts and R2° independently represent an alkyl or alkyl group having 1 to 10 H1 carbon atoms; Nyl, alkynyl, acyl: phenyl, substituted phenyl, CF, or 2 mouth and R2° are both (CL)eNR”(CJ)r (e and f are independently 2 to 6), R21 is alkyl, alkenyl, alkynyl or H1 having 1 to 10 carbon atoms; or acyl, and R22 is 14, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl or alkynyl, R21 is H1 alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms, Acyl: phenyl or substituted phenyl; R24 is H1 alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms: phenyl, substituted phenyl or HRZ@R11, R15 is H1 alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms: phenyl, substituted phenyl or NR29R8°, R211 and)72? are independently H1 alkyl having 1 to 10 carbon atoms, Alkenyl, alkynyl, acyl: phenyl, substituted phenyl, CF3, or R26 and R2?1; i both ftl' (Cat), gNR" (CHz) h (g oyohi h c independent Lr 2-6) is formed, Rts is alkyl, alkenyl, alkynyl or H1 having 1 to 10 carbon atoms. or acyl, and R21 and R2O independently have 1 to 4 carbon atoms on the H1 carbon. Alkyl, alkenyl, arginyl, acyl: phenyl, substituted phenyl, C F, or R29 and R311 are both (CB or JNR” (CH I) form yo (j and k are independently 2 to 6); R3+ is H1 alkyl, alkenyl or alkynyl having 1 to 4 carbon atoms; and A is NH31 or NR"QNR", Q is CCHt)-((JJz)+c CO or (CL)xsOz, W is 2 to 10, X is 0 to 10, Ro and R33 are independently H, Na''', R4, Li', 1 to IO carbon atoms alkenyl, alkynyl, acyl; phenyl, substituted phenyl, benzyl or substituted benzyl, but However, (a) X, R', R" and R4 are H, and R" is H.

methyl, 011 or CI, and when Y is CH, A is not NH. (b) XSR', R2 and R4 are H, R3 is OH, and Y is If it is CH, A cannot be NH.

The present invention also provides pharmaceutical compositions containing compounds of formula (I).

The present invention further provides compounds of formula (I) in combination with radiotherapy and/or chemotherapy. Provided is a method of treating a tumor in a mammal comprising administering to the mammal an agent. .

The invention further provides a process for the preparation of compounds of formula (I) as described in more detail below. provide

A preferred compound of the present invention is a compound of formula (1) in which -So, A is at the 1st or 2nd position. and/or compounds in which Z is CH; and/or compounds in which X is Compounds that are 2-halogen (provided that when X is 2-halogen, -SO , ^ exists in the 1st place).

Particularly preferred compounds of the present invention are: (a) N-(3-amidophenyl)-2-chloro-1-naphthalenesulfonamide de (b) N-(3-amidophenyl)-5-chloro-1-naphthalenesulfonamide de (c) N-(2-amidophenyl)-4-chloro-1-naphthalenesulfonamide de (d) N-(3-amidophenyl)-4-chloro-1-naphthalenesulfonamide de (e) N-(2-amidophenyl)-2-chloro-1-naphthalenesulfonamide de (f) 3-([(4-chloro-1-naphthalenyl)sulfonyl]amino]- Benzoic acid ethyl ester (g) 3-[[(2-chloro-1-naphthalenyl) Sulfonyl]amino]-benzoic acid (h) N-((3-dimethylamino)phenyl]-2-chloro-1-naphthalene Sulfonamide (i) N-(3-acetylphenyl)-2-chloro-1-naphtha Rensulfonamide (ON-C3-(aminosulfonyl)phenyl]-2-chloro-1-naphthalene Sulfonamide (k) 3-[(2-chloro-1-naphthalenyl)sulfonyl amide Noco-4-methoxybenzamide (1) N-(2,3-dihydro-1,3-di Oxo-1-isoindol-4-yl)-2-chloro-I-naphthalenesul Honamide (■) N-(3-methylphenyl)-1-naphthalenesulfonamide (n) N-(3-acetylphenyl)-1-naphthalenesulfonamide (o) N-(3-hydroxyphenyl)-1-naphthalenesulfonamide (p)N-(4-hydroxyphenyl)-1-naphthalenesulfonamide (q) N-(3-chlorophenyl)-1-naphthalenesulfonamide Cr)N-(3-(aminosulfonyl)phenyl)-1-naphthalenesulfona Mido (s)N-(3-iodophenyl)-1-naphthalenesulfonamide (t)N-[3-(1-methylethoxy)phenyl]-1-naphthalenesulfone Amide (u)N-(3-(1,1-dimethyl)phenyl]-1-naphthalenesulfona Mido (v) N-((3-aminosulfonyl)phenyl-2-chloro-1-naphthalene sulfonamide or its salt (w) 3-[(2-chloro-1-naphthalenyl)sulfonylaminocoben Zuamide, or its sodium salt (x) 3-((2-chloro-1-naphtha Renyl) sulfonylamino co-benzamide or its sodium salt (y) 3-[(2-chloro-1-naphthalenyl)sulfonylaminoco-benzoic acid, or its sodium salt (z)N-(4-acetylphenyl)-2-chloro-1- naphthalene sulfonamide (aa) N-(4-hydroxyphenyl)-2-chloro-1-naphthalenesul Honamide (bb) N-(4-chlorophenyl)-2-chloro-1-naphthalenesulfone Amide (cc) N-((4-aminosulfonyl)phenyl-2-chloro-1-naphtha Rensulfonamide (dd) 3-[(4-chloro-1-naphthalenyl)sul Honylaminocobenzamide or its sodium salt (ee) 3-[(5 -chloro-1-naphthalenyl) sulfonylaminocobenzamide or sodium thereof Thorium salt Cff) 3-[(2-chloro-1-naphthalenyl)sulfonylua [mino]-N-[2-(dimethylamino)]ethylbenzamide (gg) 3-’[[6-[(2-chloro-1-naphthalenyl)sulfonyla Minococ-1-oxohexyl]amino]benzamide (hh) N-(3-amidophenyl)-2-naphthalenesulfonamide (ii) 3-((8-quinolinylsulfonyl)aminocobenzamide Compounds of the invention can be prepared according to Scheme I. The compound of formula (I) has the formula (2) sulfonyl chloride in a suitable solvent such as pyridine, acetone or methylene. from room temperature to the reflux temperature of the solvent with or without addition of a suitable base. can be prepared by reaction with an amine of formula (3) at a temperature of . Alternatively, the expression ( The compound of I) can be dissolved in a suitable solvent such as tetrahydrofuran (TFIF). A suitable solution is added to the solution of sulfonyl chloride at a temperature between room temperature and the reflux temperature of the solvent. A solution of the amine of formula (3) in a medium such as TITF and a suitable solvent such as in water. It can be prepared by simultaneous addition of a base such as a solution of potassium carbonate. Sur The preparation of sulfonamides by reaction of onyl chloride with amines is well known in the literature. It is. The products of these reactions are well known to those skilled in the art of organic synthesis. techniques such as recrystallization, trituration, chromatography, and/or acid-base extraction Although it can be purified by various operations, the purification method is not limited to these.

The preparation of pharmaceutically acceptable salts of compounds of formula (1) can be carried out using well-known techniques of salt formation. It can be done with Physiologically acceptable salts include, for example, one or more salts. Hydrochloric acid, sulfuric acid, acetic acid, succinic acid, quenchant of the compound of formula (1) containing the above basic functional group addition salts of acids such as benzenesulfonic acid and benzenesulfonic acid, as well as suitable base analogs. lithium, sodium, which can be derived by addition of metal hydroxides or metal hydrides. or potassium salts, but are not limited to these.

Substances with increased solubility in water can be dissolved in a suitable solvent such as water, methanol or alcohol. Adding 1 or 2 equivalents of aqueous sodium hydroxide to a suspension of the invention in ethanol , and then evaporated to dryness. Contains only one highly acidic proton When a compound with 2 equivalents of sodium hydroxide is treated with 2 equivalents of sodium hydroxide, the disodium salt A compound having the empirical formula is produced.

Reaction formula 1 % formula % (3) The compounds of the present invention and the process for their preparation are better illustrated by the following examples. However, these examples are not intended to limit the invention.

N-(3-amidophenyl)-2-chloro-1-natsuta 3-aminobenzamide 2-chloro-1 - TIIF of naphthalenesulfonyl chloride (139,50 mmol) (10 Solution of ICJ (5.9 g, 50 mmol) in water (50++/) The solutions were added dropwise simultaneously over a period of 1 hour at 0°C. The reaction mixture was heated for 20 hours, 25 Stirred at <0>C, the organic phase was separated and dried over Na2SO4. evaporated the solvent Then, transfer the remaining oil onto silica gel using methylene chloride/methanol as the eluent. When purified by flash chromatography using (19/1), The title compound (7,99,43%), melting point 202-205°C was obtained.

The title compound is also combined with 3-aminobenzamide (4,8q, 35 mmol) and 3-aminobenzamide (4,8q, 35 mmol). Dimethylaminopyridine (0.78 g, 6.5 mmol) in pyridine (40 liters) ) 2-chloro-naphthalenesulfonyl chloride ( 9,79,37 mmol) in acetonitrile (30 mA') for 30 minutes. It could also be produced by adding drops. The reaction mixture was then stirred at 25°C for 30 min and diluted with water (25°C). 0 st') was added dropwise and then poured into another 250 mA' of water. Filter the resulting suspension. After filtration, washing the solid with water and drying in vacuo, the crude product (11.8 g) was red. Obtained as a solid. For recrystallization of many batches of crude product, heat methanol When used, it gave the title compound as a white solid in about 70% yield.

Example 2 3-aminobenzamide (5.5 g, 40 mmol) in acetone (75 l) The solution was heated to 25°C and treated with 5-chloro-1-naphthalenesulfonyl chloride (10 g, 4 0 mmol) in acetone (50 μl) was added dropwise over 45 minutes. anti The reaction mixture was stirred for 20 hours and filtered to give a yellow solid, which was dissolved in acetone ( 25ml), water (25*+A') and hot methanol (25ml). , dried in vacuo at 50°C for 2 hours to produce the title compound (5,79,40%). Ta. Melting point 257~N-(2-amidophenyl)-4-chloro-1-naphthalene Ruphonamide 4-chloronaphthalenesulfonyl chloride (5,009, -19,15 mmol ) and anthranilamide (2.61 g, 19.17 mmol) in pyridine (25 (l) The Nakomizo liquid was heated under reflux for 3 hours, cooled to 25°C, and concentrated in vacuo. Yellow Repeated trituration of the pasty residue with hot methanol yielded the title compound (5,079 , 73%) was obtained as an off-white powder. Melting point 238-239°C.

The compounds of the present invention produced or can be produced by the above operations are listed in Tables ■, ■, and ■. Geru.

Table ■ 1 2-CI HωNil, II B CIl NH202-20525-CI B C0NB, 11 II CI'l Nil 257-2593 4-Q' C0NH! II II HCB Nl’l 238-2394 II HC0 NII, TI HCONll 182-1855 3-(J HC0NH, H [ I C1l NB6 4-CI HC0NII, II [I CHN11 18 5-1907 6-(J HωNil, B III C1l Ni18 7(J l’I C0NH, ■ 1icHNH911C0NH, II H[I CI Nu 255-25610 2-CI C0N1'i, II 11 It CH NU　235-23911　5(:IC0NFIt　■　flllcl’1NH 12F! 'HHC0NI'l, HCRN) 113 2-(J 11 + 1 C 0N1'12HC1I N) + 267-27114 4-CAI HHC0N H, l’l CHNH>35515 5-C1 [I It C0NHt HCH NH162-CI HHHII C1l NB134-137174-(J 1 1 II HHCtlNll.

18 5-CI HI'l l'l HCHNH149-15319tll'1 Between CNHI’1C1l 202-CI HCN HB CHNH214-G’ F! CN 11 FI CHNl 209-210225-C1 [I CN HRCFINF! 23 HB C0tEtHn Ctl NH242-(J 1 1 CO! Et Htl CFI Nil 116-11925 4-CI I I C0tEt 11 II CONu 110-111 Table I (continued) 26 5-CI HCo! Et [I HC1l N027 HII CF, HB CIINH282-CI Hci’3Hfl CHNH294-CI H CF3 HII CB NO154-159305-CI HCFI HII CHNU31 2-CI NO! HHtI Between CHs 32 2<l [I No , II HCtl NB177.5-17933 2’CI HHNo! [ I CHNH342-CA' II C01ll II [I C1l III 221-22635 2-CIl IT CO,lie II HC1l N B56 2-CI H, I'l B Ctl NB 191-19337 2-CJ HNMe, HHCI NH186-188382-CI HC0N H1leHB Ctl NH392-CI HCONMe!　■　IICHN[ I40 2i:Z [10H11B CB NH181-182412-CI HOMe　H11CHNH422’CI　HCJs　Htl　Ctl　Book 17 3-175433.7-di-nBuH01le Ole Ole CI N1 44 4.5-di-OHHC0, flllcITNH453-0H1Nil , HCON■! I’1HCtlNB46 2-CI HCOMe HHCl’ l NB 134-13647 2-CI HMe HfI CHI Dragon 18 7-18848 2-CI HOEt II RCHNH492-CI II 5otNl’l, HII C1l NTI 281-28650 2-CI B CI IT Ill CHNu 180-18251 2-CJ II I II　II　Cfl　NH2O7-209,5524-Br　B　C0NH,H HC1l NH334-I HC0NHI II II CHNH544-No □　HcoNHt　■　IICHNt155　4-CN　HωN11tII　H C0N1'12H4-Me HC0NHt H[I CHNH372-Pr [ I C0NHtll HCHNH382-CFI II C0NIIt II II C [I N'1 Table ■ (Continued) 59 2-c, n, EI C0Nth Hl’l C1l NTI60 2-B r HNMe4 1'l tl CI NH615-NMe2 HN11e, HTI CIl NH625-CI HNMeIHHCHI'1H634-NT I2 HcaNH21’l I’l CHNl’164 4-NHMe HC0 NB211 HCHN) +65 4-NMel! 'I C0NU2 HIt CHB66 4-C02Hl’I C0NHt HHCHNH674-CO2M eHC0NHt HHCHNH684-CONHz FI C0NI’l! H I CONR694-OHI'l (I)N11. 11 HCHNFI70 4-011e HC0NH,HHCHNH714-COMe HC0NH,FI HCHNH724-3Rtl CIJN'Rt HHC[i NH734-5 lle Fl cONHx HFI CHNFI74 (SOMe TI CO 1’tHz IT [I Cn NH754-84-8Oz CDNHt HI I CFJ NH76Tl 11 C0NH, I (I'l N Ni177 2 -Q' D C0NH, HHN NH784 (e HCONH2HHN Nl' 179 5-011 HC0Nr (, HHN NH806-NFI, HC0N H, HHN NH31, 4-OMe n CONH2HFIN NR825-N Me2FI C0NFlz HRN NH336-No20CONFI20II NNO84II Me C0NHt HHCONH352<l)I CON[ Iz　HMe　CONH362-cl　[I　CIJNH2HR(JIMe　N [I 237-24087 5CI HC0NHz Me RC[l NH38 HFI C0NH! HOMe CFI NH392-CIHCONHtHHC 口OMeNH20g-210904-CI HCONH2OMe fl CFI Table N8 1 (continued) Example X RI R" R3) + 4 Y A Melting point (℃) 91 5-CI O ne C0tJH, I’l [ICI NH922’CI HC0NHz HH CHNH(CJlz)2NH932-(11’I C0NB! 11 II C ONH (Cf12)sNH942-CI HC0NH! HHCHNl’1(C HI) 4NB95 2-CI -CONIICO-H11CIT NH221- 227962-C1■-CONNaαl-HHCHNNa>27597 2 'CI I CONH2[I HCHNH((+5)+oNH983,6-dL -tBuHC0NH, Hl’l CHNH99HHIf HHCFI Nfl 157-158100 [I Rlie [IHCHNH133101FIHα] jle　Bfl　CHNO163-1641,021'l　FI　O1'l　1 1　HCHIJH142-144103HHHOHHCONH192-1941 040HCIHHCDNF+136-137105 HHN11e2 1'l HCHNR159-1601061 (Fl c, u, n HC1l NH18 9-191,51,0711l’l 5OJH2 [I n CI’l NO20 9-212108II) I I 11 B CIT NTJ 146-147 109HHOiPrH日CITNl’+135-149110 HII tBu H [I CHNH158-1601112-CI H0iPr HTa CH N’H134-1371122-CI +1 tBu 111’l CHN1f l 169-172113 2-CI H5O2NHNa [I HCONNa >300114 2-CI HCONI12/NaOHHHC1l NNa >300 pieces 115 2-CI HC0NH, HHCtl NNa >30011 6 2’CI lIC02Na RHCHNNa >300117 4-Nl’ l^cHHMen　C0NB118　2-CI　HFl　α1lle　HCHN l? 253-255119 2-CI FI HOHHC1l NR180-1 821202-CIlHHC/11 CHNH164-1661214-IJ H^cal HN11e! HCHNH1222-Br　HHNMetHCI　N Na table 1 (continued) 123 2-CI HHSo, Nl’1. [I CB NH251-2541 242-Ct IT Hr II C) I sn 11113-185.512 5 4-NHAc HHtBu HCD N11151 4-CICONHrN aOHHHHCB NNa 287-288”127 4-CIHC0NTl, ・Na0HHHCHNNa>300 wealth 128 4-CI B B CON [1 l-NaO [IHCTI NNa>300 end 1.29 4-CINH,nH HCll Nl (172-178130 4-Q+ Co, HB B 11 C tl　NH1314’C1■　HNHl　Ro　C1’l　NH>300132　 5-CJ　HC0NT+2・Na01’l　Rfl　Ctl　NNa　＞300 "133 5-NMe, HHHHCHNTI 128-1311.34 2-C IHC0N-[IRCB Nl(145-182(C0NI’l!)2NM e 135 2-CIHCB2N-H[ICINO(CH12(+12)zNM e 1.36 2-CI HC0NIi-HHCIT Nl’+ 231-233C H2C[I,NMe! 1.37 2-(J 11 cR2Nn-II l1ctl NHCH, CH2 NMe2 138 2-CI I'I C0NL HI Cl'INH (CL) s-109 -1140NH 1392-CI　Hl(Co□日　[IN　NTI　259-261140　 H01le RHOMeCHNH’138-140141 2-CI 0g1e H11011eCHNH143-144142H110g1e 01le 0 11eCTI NH138-1391432-CI H01le 0)le 0 1leCHNH144-1451442-CI HCONH2HHCHNNa >300145 HHHl (If CIl NH152-1531462-CI H01le HHCI NH1472-Br C+ellt+ HHC1l N8 table I (continued) 148 8-CI [+ (CJ) s-H [I CHNtlcncn].

149 7-NH2[IH(CEIt)sccflHCtl N0150 5 -NMe, II HII CJs Ctl N11151 2-C1 [I Hp -C, [1, No, lI CHN11151 5-NMe, 11 co, Me HHCHNH1535-N11c4 HC02C+oH+ HHCD NH15 42-CI HCo, COMe HHCHNOl, 55 2-CI [102( Je II FI CHNH1562-CI TI 0zff-+oHt+ R IT Ctl NO+57 2-CI H(Cut)sNMe=II IC I NH1582-C1115o3n If HCI NHl, 59 4-CI FI SO2Me HHCHtfF1160 5-CI HH5O1le H CHNB161 2-CI HSMe FI HCfl Ni1162 (NH z5-011 HSMe II II C [l NH163Ni162. Fi Fi SMe HCHNH1642-CI H■ (CHt)s-11CI NLiN Me 165 2-Br HCo, K HHN NK166 5-NMe4 +1 C O211e HHN N0167 2-C1tT C0NHt FI HCI NFICONI'11686-NO, 11n fl HC1'I NIICH, C0NH1695-OHFI　HI(HCHNH(CHJsSO2NI1170 4-NIT^c 01le HHC1'l NH (CH2)sNIT 8 Compounds listed as disodium salts in Table 1 are listed in the Detailed Description of the Invention section. Manufactured by adding 2 equivalents of sodium hydroxide to the parent compound as described. It was done.

Table ■ 171 11 B C0NBt H11Cfl Ni1 218-221172 5-(J II HII HC1I Nl'+ 180-183173 5- CI　B　C0IITI! 11 HC1l N! 'l　206-208174 IT C0NH, HII I’l CHNB175 HH11C0)jH2H C1’l NB176 [I HHI’l HCONH1177HHMe HHC HN0 178HHα)CHs HHCON0 17911 HOHHHC1'1NR 180tl HCI HI (CIINF! 1811T HNMe, lT11C HNFi182 HHNMe2H [I CHNNa183 HFI SQ, Fj H, Hfl　CHNR184HHI　RII　CONH 185RH0iPr HHCHN71 186 H[1tBu TI HCD N11203 14 1+ 0)le HHCHNl’1188■口OMeOMeOMeCHNH189H110g1e H0kle Ctl N) 119011 HCF, HHCHNF119+, HHNo, 1+RC1l NTl1925-CIBMeHHCFIN■ 193 5-CI HCOMe B I’I CI NH1O45-CJ HO HIT)I CIT Ni+195 5-CA' IT CI HHCONB 196 5-cA’ HN11et HHCI NB197 5-CI HNM e2HHC1l NNa198 5-clIt SO, NHxHHCHN8 table ■(continued) 1995<J HI HHCHN11 2005<IHOiPrHBCH)JH201,5-C111tBu HHC1 'l N0202 5-CI 11 0g1e HHCHN11203 5-C I H0g1e OMe OMe CHNH2O45-CI[T 0ile H OMe CONH2O55-C7! HCF, HHCB NH2O65-CI HNo, nn cHNH2075-CI C+. H□ I’1llflC HNI1208 5-CI H (CHz)s-CIICBzHHCTI NH2 O95-cl　Hl’i　(CH 5CCHHC[i　NTl210　5-CI Fl l’l II C6HsC1l NB211 5-CI HHp-C, H,NO,HCHNt12+2 5-CI 11 C02Me II II C FI N11203 5(:/H0JxC+oHxr HHCHNB214 5-CIHC02CO) le II HCHN0215 5-CI Tl O, CMe 11 11 CI NB216 5-cl [10zCC+oHn R HCTI, NB217 5-CI H(CHx)sNIIe2HIT Cn NB218 5’C1II SO3[I Htl CB NR2195-(1 Ni a! H3O2le HHCHNB220 5-CI H)I 5O1le H CHNTl221 ■ HSMe HHCHNB 222 HHSMe TI HCI NB223TI HT (SMeHCONH 224HHH(Clb)s-11CI NLiNllNLiN1 1eCOHC02Kll II N NK226 11 HCO, 11eH11 N NB227 1’l HC0NH, HFI CHNHCIJNH22811 [! HIt HC1l IIECII, CONH229IT HHH11CH NH(CH2)ssOzNR230HOMe OMe OMe TI CFI NLi table m 231　11　HH[I　CONH 232C0NTl, I'l B IT CIl NB233 HC0N) I, 11 HCONil 205-207234 11 I C0NHt 11 C IT NB235 RHl’l HCONH 229TI Me HHCHN11 239 HCOMe HTI CHNB238 H01111HC1l N11 239 HCI II HCFI NTl240 HNMet HHCl’l NR241II NMt4 1’l ■ CHNNa242 H5O2NHz TI HCHNB243 Fl r HHCONH 229H03Pr HHCONB 245 HtBu HHC1l NB 246　H01le　HHC1’l　N0247　B　OMe　OMe　OMe CHNB248 HOMe’ IT OMe CHN11203 HCF, Hl’l CHN11203 n No21’l I’l CB NB251 11 Fl　(CH,)sccHf! C1l N) I252 Hl’l)l c, n, co NB253■■tC+. II,, HI’l CFI N B254■ ω, C0IIe HHCI NB255 HOzCMe I’l fl CI NB256 B 02CC+5lln tl HCHNH table ■( Continued) 258n 5o3HH11CIl N0259 H3O2le HHCB N B260 HH8OMe 11 CB N11203 HSMe HB CHN 0 262 HSMe HHCONB 263 B HSMe II C1’l NB264 HH(CTlz)s-E I CI NLiNMeCOlle 265　HCo□KTII’1NNK 266 HCo2Me II HN NB267 II C0NH, l’l I I CRNFICON11268 FI FI H[I CI'I NllCl , CONH269RHH[I CHNFI(CFIJsSO2NB270OM e01le OMe HCHNLi Physiological Assay This assay uses EIIT6 cells in female BAL B/c mice. use These mice were treated with 5tan-ford Rad under SPF conditions. Breed in iobiology Colony and start each experiment at 3-4 months of age. . Since removal from the pre-tumor of BALB/c mice, tumor cells from 2nd to 8th in. On the inoculated side of 2 x 10' tumor cells harvested after vitro passage, MT5 tumor is grown sarcastically. Two tumors are implanted per mouse.

These are used in a capacity of about 100 mm3. At this point, the tumor is approximately 20% hypoxic. Contains cells.

The first in vivo radiosensitization experiments were performed using a fixed dose of intraperitoneal (ip) injected drug ( Usually 2 mmol/&q or 2/3 LD. lower dose) and solid A constant radiation dose (20 Gy) was used, and the interval between irradiation and injection or between injection and irradiation was varied. I will do it.

If tumor drug concentration is required, cut one of the two tumors in each mouse in half. , half was immediately frozen and used for subsequent high-pressure liquid chromatography (IPLC). The drug level will be analyzed by

Irradiation of EMT 6 tumors was performed by irradiating unanesthetized tumor-bearing mice in a Plexigl’as@box. This is done by shooting. Irradiation conditions are low LET 250kVp X-rays, 15mA, FSD 33cm, additional shielding Q, 35t++ Cu, half value layer 1.3mm Cu, The irradiation speed is L30 rad/min.

For assay of cell viability, tumor-bearing mice are sacrificed immediately after irradiation. Cut the tumor through the skin cut into several pieces, and finely chopped by high-speed shredding with a leather blade attached to a jigsaw. Make it braai. Then add the following concentration of enzyme + 0.02% DNase, 0 ．． Hank's Balanced Salts containing 0.05% pronase and 0.02% collagenase Add to 30ysl of similar solution (HBSS). The suspension was stirred at 37°C for 30 minutes, Centrifuge. Cell pellets, complete mouse medium plus 15% bovine blood resuspended in FCS, a portion of which was mixed with trivan blue, and added to the hemacytometer. Count the cells using a micrometer.

Appropriately dilute this single cell suspension in complete Wei mouse medium plus serum, and Or 100-recommendation Boristyrene veterinary dish (1, ux 5 scientific Corp.), plate with medium 5 or 15 s+/teprate. 13 days After incubation, colonies were fixed and stained to contain 50 or more cells. Count the colonies. Add an average number of colonies of 25 to 100 in a 5Q-mmm vet dish. The resulting dilution is used to calculate the results. The results show that cells killed by irradiation and 1,400 1,80 by injection plus sensitizer 2 400 1.25 6 400 1, 55 16 400 1, 19 ! EMT 6 tumors in mice were treated with 2ocy.

2 sensitization index enhancement ratio (SEI?) for tumors treated with irradiation and drug versus animals treated with irradiation alone is the ratio of plating efficiency of harvested cells in tumors from .

SER>1.0 is considered active.

Regrowth delay assay This assay is performed using SCC ■ carcinomas transplanted into C3fl mice. This tumor is autologous. low metastatic rate (relatively non-immunogenic in its syngeneic hosts; It is an excellent tumor for regrowth delay tests because it grows in large volumes without damaging the tumor. be.

For tumor inoculation, C31 (second to second part of the SCC tumor previously excised from the mouse) was used. 5. Harvest cells from in vitro subcultured tumors. 1~2X1. O' cell Inoculate the dorsal skin approximately 1 cm proximal to the base of the tail in HBSS O.05 shoulder volume. do.

Two growth retardation curves are obtained for each test sensitizer assay (one vehicle control, one one test drug). These are the delays until the tumor reaches four times its volume at the time of irradiation. The average number of days is plotted as a function of time. The test sensitizer is At the dose chosen for the tumor cell survival assay experiment, its optimal time (also for the tumor cell survival assay) (determined). The mice are irradiated only to the tumor and the lower part of the back. Mau The tail is held in place by taping it to the side of the shield. 4 mice at the same time 2 Irradiation with 50-KVp X-ray, FSD 31cm, irradiation rate 167rad/min do. 6 mice in each group, each increased from 5 groups of mice (4 different irradiation doses and non-irradiated control). Create a reproductive delay curve. The irradiation dose used was 20 Gy.

Tumor diameter is measured daily with calipers in three directions and tumor volume is calculated. During treatment , the tumor was approximately 300 mm3 to 500 mm3. After treatment, each tumor Measurements were taken three times a week until four times its initial capacity was reached. Tumors in each group have their treatment Calculate the average number of days after treatment to reach 4x capacity. Irradiated and non-irradiated controls 4 times the initial tumor volume, which is the difference between the average or irradiated plus drug versus non-irradiated controls. This growth retardation up to the point in time is shown in Table V.

Irradiation alone 14.2 Example 1 + irradiation 30.0 1. 5CC-■ tumor of mouse was treated with 20 Gy.

Clonogen survival assay Human colon cancer clone A cells (I P) Blated on day 0 in II-C medium.

Cells were incubated for 24 hours at 37°C in a humidified atmosphere of 5% CO2-95% air. I did it. The culture medium was then removed and replaced with 4 ml of fresh RPMI-C medium. . Cells were irradiated with 5.7 GV of irradiation or were not irradiated. Tested relatives body (1 ml, 5× concentration) onto two homogeneous plates (+/− irradiation) immediately after irradiation. Added. Cultures were incubated for 2 hours at 37°C, then cells were treated with trypsin. (33%) and centrifuged. Cells? Resuspend in pHI-C and concentrate the cells. The concentration was adjusted to the appropriate inoculum concentration (concentration of test analog and cells treated with radiation). depending on the situation). After inoculation, the culture was maintained for 10 days, and then the cells were treated with 0.9% Na. Washed with C1 and stained with crystal violet (0.5% in absolute alcohol). , the number of colonies exceeding 50 cells/colony was counted. Plate efficiency (PE) is inoculated It was defined as the percentage of colonies formed from the total number of cells. Radiosensitizing effect was determined by the survival rate (SR) calculated from the following formula:

PE (rad) is the plating efficiency of cells treated with radiation alone, PE (rad + a nalog) is the plating efficiency of cells treated with radiation and the tested analog; PE (analog) is the plating efficiency of cells treated with the test analog alone; PE (control) is the plating efficiency of control (untreated) cells.

Test analogs with SR>1.5 are considered positive for this clonogen survival assay. day The data are shown in Table ■.

Inhibition of repair of radiation-induced DNA double-strand breaks L12], 0 cells (3X10' 0.02 μC1/11 [2-14 (:) thymidine (specific activity 54 ．． OCi/mgol) and 5% CO2-95% air at 37°C for 24 hours. Incubated for hours. Cells were then harvested and centrifuged. resuspend the cells , adjusted to a concentration of 1X10' cells/*l. Place cells on ice for 1 hour with Gamma Cell Irradiation was performed using a 40 irradiator at an irradiation rate of 1.14 Gy/min. each sample DNA double-strand breaks in the medium are performed using a neutral elution procedure (Kohn: -X-ray duced DNA dou-ble 5trand break produ ction and repair in IIamIlali-an cell ls as measured by neutral filter elu tion-.

Nucl, Ac1ds Res, Uni 793~804.1979) It was measured using Cells were diluted with cold phosphate-buffered saline (PBS) and Loaded into a Sokestack funnel fitted with a bonate filter. Cold P the cells After washing three times with BS, cells were lysed with 5DS-EDTA lysis solution 5/5.

After draining the lysis solution into a scintillation vial, the cell lysate was diluted with 0.5* Deproteinization was performed with a 5DS-EDTA lysis solution containing q/ml proteinase K.

Transfer the DNA remaining on the funnel to 30 μl of 0.02M tetrapropylammonium hydroxide. Elute with U-EDT^ solution (pH = 9.6) at a flow rate of 0.035 ml/min. did. The amount of radioactive DNA remaining on the funnel after 10 hours of elution was determined. Tested relatives The inhibition of DNA repair by the body is calculated using the following formula.

DNA, is maintained when cells are incubated at 37°C in the presence of the test analogue. %DN^ DNAt, when cells are incubated at 37°C in the absence of the test analogue. Maintained %DN^ (referred to as 100% repair) DNA0 exposed cells to 68.4 Gy %DNA (referred to as 0% repair) when kept on ice for 2 hours after irradiation with radiation. be.

A test analog is considered active if it causes >50% DNA repair inhibition. The results are shown in Table ■ with a +'' mark.

109 + + Table ■ (continued) 1) In this test, compounds with SR>1.5 are marked "+", and compounds with SR<1.5 are marked "+". “-”.

The compound is “-”.

3) "nt" indicates that the compound was not tested.

Dosage form The post-irradiation and/or chemotherapeutic sensitizing compounds (active ingredients) of the present invention Site of action and activity of these agents in mammals after radiotherapy or chemotherapy administered to augment irradiation or chemotherapy treatment by any means of contacting the components. can be given. These are available for any medicinal use. Administered by conventional means as individual active ingredients or in the form of mixtures of active ingredients. can be done. These may be administered alone, but generally the selected administration It is administered with a pharmaceutical carrier selected on the basis of route and standard pharmaceutical practice.

The amount administered is that amount of active ingredient that can enhance radiation or chemotherapy, and of course However, known factors such as the pharmacodynamic properties of the particular active ingredient, its mode of administration and route, age, health status and weight of the recipient, nature and severity of symptoms, concurrent treatment. It will vary depending on the type, frequency of treatment, and desired effect. usually The dosage of the active ingredient is approximately 5 to 1.5 mg/hg of body weight when administered after irradiation. ．． 000 -9. A typical dose is about 9 in 400 doses.

Dosage forms (compositions) suitable for internal administration contain from about 5 parts to about 1 part active ingredient per unit. OO Contains Omy. In these pharmaceutical compositions, the active ingredient usually accounts for the total weight of the composition. The content is about 0.5 to 95% by weight.

The active ingredient may be present in solid dosage forms such as capsules, tablets and powders or in liquid dosage form. For example, they can be administered orally as elixirs, syrups and suspensions. Also, sterile It can also be administered parenterally as a liquid dosage form.

Gelatin capsules contain the active ingredient and a powdered carrier such as lactose, sucrose, mannitol, Contains starch, cellulose derivatives, magnesium stearate, stearic acid, etc. have

Similar diluents can be used to make compressed tablets. Both tablets and capsules Can be manufactured as sustained-release products to release medication continuously over many hours. can.

Compressed tablets may be used to mask unpleasant tastes or to protect tablets from the atmosphere. Can be sugar-coated or film-coated, and can be selectively disintegrated in the gastrointestinal tract. Enteric coatings can be applied to prevent damage.

Liquid dosage forms for oral administration include colorants and flavors to increase patient acceptance. can be added.

“Generally, water, suitable oil, saline, dextran (glucose) aqueous solution, and similar solutions of sugars, and glycols such as propylene glycol or Polyethylene glycol is a suitable carrier for solutions for parenteral administration. Parenteral administration Solutions for use preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, Add buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite um or ascorbic acid, alone or in mixtures, are suitable stabilizers. quest Also used are phosphoric acid and its salts and sodium EDT^. In addition, parenteral Dosing solutions may contain preservatives such as benzalkonium chloride, methyl or propyl Parabens and chlorobutanol can be added.

Suitable pharmaceutical carriers are described in Remington's standard reference book in this field. Described in s Pharmaceutical 5 sciences, ^, 0sol has been done.

Illustrated below are a number of unit capsules useful for administering the compounds of this invention. Each semi-hard gelatin capsule contains 100 m9 of powdered active ingredient and 175 m of lactose. 89, filled with 24 talc 9 and magnesium stearate 6 9 Therefore, it is manufactured.

Prepare a mixture of active ingredients in soybean oil and inject into gelatin using a positive pressure displacement pump to form soft gelatin capsules containing 100 grams of active ingredient. capsule Wash and dry.

tablet A number of tablets are prepared in dosage units containing 100 mv of active ingredient and 0.0 mv of colloidal silicon dioxide. 2 mq, magnesium stearate 5 shoulders 9, microcrystalline cellulose 275 mv, tow Manufactured using conventional procedures to produce 11 weight sorghum starch and 98.8 q lactose. Ru.

Appropriate coatings may also be applied to improve mouthfeel or delay absorption. Ru.

Injectable drug A parenteral composition suitable for administration by injection contains 10% by volume of the active ingredient. It is prepared by stirring a 1.5% by weight solution in aqueous lene glycol solution. solution with salt Make isotonic and sterilize.

suspending agent Aqueous suspensions for oral administration contain 100 carbonates of micronized active ingredient, 9 carboxylic acids in each 5 ml. Dimethylcellulose sodium sodium benzoate 5 irises 9, sorbitol solution ( US Bureau) 1.09 and Vanirin 0. Manufactured to contain 025+ig.

In the specification, the term "consisting essentially of" is intended to have its conventional meaning. i.e., all specified materials and conditions are critical to the practice of the invention. Of particular importance, unspecified substances and conditions may also contribute to the benefit of the present invention. This means that it cannot be excluded unless it prevents its realization.

international search report PCT/US90101054 Ca7O303/30: C07C311/15, 16, 18. Engineering 9, 21, 29, 39, 44.4B, 51.5B.

60, 62: Ca2O31 104. Yu6; C07C317/Yu4.　 22. 24. 26. 44. 46. 48. 507CO7C323/6 77 C07D 213/61. 62. 6 pieces, 64. 643. 65.　 66, 69. 70. 71. 7 B 75.76.79,80,803,84,85j C07D 215/20,2 2,227,233,24,26°28.30,32,36,38,40,42 , 44.4B, 50, 52, 54, 5U C07D 241104; C07D 243108+ C07D 2451024 C07D 295/185+ C 07D 401104/ 06/ 10/ 14e (:07D 40310n, 10.141 C07D 4'1104/) 4+ C07D 487104゜514/313,314,344,345,346 ,347,348,349,352,411,417,510゜562.592 ,593,602,603+540/1,575;544/357,360 , 361, 362, 363° 372, 373. 386. 389. 393 ．． 394. 395. 398. 399. 400. 4o1+546/ 82.　P12゜ 153, 155. 156. 157. 159. 160. 168. 1 70. 171. 172. :104.　307.308K 309, :110. 311. )12+548/433/430+558 7412. 4X3F 560/10. 12. 13:562/427. 4 Ko O: 564/39. 40. 84. 85. 86. 117. 88. 89゜Continuation from ForIll 210. Pa rt　工x-rxgLX：J　gzλRC! IIIJ393.394. 395 ．． 348,399,400,4011 546/82. 112. Yu53. 155. 156. 157°159, 160. 168. 170. 1 71. 172. 304. 307. 308. 309. 310. 31 1.　312G 548/433. 480: 558/412. 41 pieces 560/10.　 12. i3j 560/427. 430f 564/3X゜ 40.84, 85, 86, 87.8B, 89°1111@111j111116 1AIIll↑fI11stta欝t,, qantn+nqbtry/nqcX 1101054

Claims (82)

[Claims] (1) A compound represented by formula I or a pharmaceutically acceptable salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the above formula, R1, R2, R3, R4 and and R5 are independently H, alkyl having 1 to 10 carbon atoms, alkenyl, Alkynyl; phenyl, substituted phenyl, F, Cl, Br, I, NO2, CN, C F3, (CH2)mNR6R7 (m=0-10), CO2R9, OR10, CO R11 or S(O)nR12 (n=0-3), or R1 and R 2, R2 and R3, R3 and R4, or R4 and R5 are both -CON HCO- or -CONMCO- (M is Na+, K+ or Li+) and R6 and R7 are independently H, alkyl having 1 to 10 carbon atoms, Alkenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3; Or R6 and R7 are both (CH2)pNR8(CH2)q (p and q are are independently 2 to 6), R8 and R9 are independently H, alkyl having 1 to 10 carbon atoms, alkenyl, aryl; ruquinyl or acyl, R10 is H, alkyl having 1 to 10 carbon atoms; phenyl or substituted phenyl, R11 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR13R14, R12 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR16R17; R13 and R14 are independently H, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl, alkynyl, acyl; phenyl, substituted phenyl or CF3 , or R13 and R14 are both (CH2)rNR15(CH2)5(r and and s are independently 2 to 6), R15 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or acyl, R16 and R17 are independently H, 1 to 10 carbon atoms; Alkyl, alkenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3 or R16 and R17 are both (CH2)tNR18(C H2) form u (t and u are independently 2-6), R18 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or or acyl, Y is N or CR5, X is each independently H, F, Cl, Br, I, NO2, CN, CF3, carbon Alkyl, alkenyl, alkynyl having 1 to 4 atoms; phenyl, substituted phenyl Nyl, (CH2)cNR19R20 (c is 0-10), CO2R22, O R23, COR24 or S(O)dR25 (d is 0-3), and b is 1 or 2, Z is N or CH, R19 and R20 are independently H, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3, or R19 and R20 are both (CH2)eNR21(CH2)f(e and f are independently 2 to 6), R21 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or or acyl, and R22 is H, alkyl or alkyl having 1 to 10 carbon atoms. nyl or alkynyl; R23 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, Acyl; phenyl or substituted phenyl; R24 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR26R27, R25 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR29R30, R26 and R27 are independently H, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3, or R26 and R27 are both (CH2)gNR28(CH2)h(g and h are independently 2 to 6), R28 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or or acyl, and R29 and R30 are independently H, having 1 to 10 carbon atoms; alkyl, alkenyl, alkynyl, acyl; phenyl, substituted phenyl, C F3, or R29 and R30 are both (CH2)jNR31(CH 2) form k (j and k are independently 2 to 6); R31 is H, alkyl having 1 to 10 carbon atoms, alkenyl or alkynyl; and A is NR32 or NR32QNR33, Q is (CH2)w, (CH2) xCO or (CH2)xSO2, w is 2 to 10, x is 0 to 10, R32 and R33 are independently H, Na+, K+, Li+, 1 to 10 carbon atoms alkenyl, alkynyl, acyl; phenyl, substituted phenyl, benzyl or substituted benzyl, but However, (a) X, R1, R3 and R4 are H, and R2 is H, methyl, OH or Cl, and if Y is CH, then A cannot be NH, and (b) , R1, R2 and R4 are H, R3 is OH and Y is CH , A cannot be NH. (2) The compound according to claim 1, wherein -SO2A is bonded to the 1 or 2 position. (3) The compound according to claim 1, wherein Z is CH. (4) Claim 1 in which X is 2-halogen with the proviso that -SO2A is in the 1st position. Compounds described. (5) -SO2A is bonded to the 1 or 2 position, Z is CH, and If it is a halogen, then the claim is that it is a 2-halogen, provided that SO2A is in the first place. The compound according to item 1. (6) N-(3-amidophenyl)-2-chloro-1-naphthalenesulfonamide 2. The compound according to claim 1, which is (7) N-(3-amidophenyl)-5-chloro-1-naphthalenesulfonamide 2. The compound according to claim 1, which is (8) N-(2-amidophenyl)-4-chloro-1-naphthalenesulfonamide 2. The compound according to claim 1, which is (9) N-(3-amidophenyl)-4-chloro-1-naphthalenesulfonamide 2. The compound according to claim 1, which is (10) N-(2-amidophenyl)-2-chloro-1-naphthalenesulfona 2. The compound according to claim 1, which is a mido. (11) Benzoic acid, 3-[[(4-chloro-1-naphthalenyl)sulfonyl]a 2. The compound according to claim 1, which is a [mino]-, ethyl ester. (12) Benzoic acid, 3-[[(2-chloro-1-naphthalenyl)sulfonyl]a 2. The compound according to claim 1, which is [Mino]. (13) N-[(3-dimethylamino)phenyl]-2-chloro-1-naphthalene 2. A compound according to claim 1, which is a sulfonamide. (14) N-(3-acetylphenyl)-2-chloro-1-naphthalenesulfone 2. The compound according to claim 1, which is an amide. (15) N-[3-(aminosulfonyl)phenyl]-2-chloro-1-naphtha 2. A compound according to claim 1, which is a rensulfonamide. (16) 3-[(2-chloro-1-naphthalenyl)sulfonylamino]-4-methane 2. A compound according to claim 1, which is a toxybenzamide. (17) N-(2,3-dihydro-1,3-dioxo-1H-isoindole- 4-yl)-2-chloro-1-naphthalenesulfonamide. Compound. (18) N-(3-methylphenyl)-1-naphthalenesulfonamide A compound according to claim 1. (19) N-(3-acetylphenyl)-1-naphthalenesulfonamide A compound according to claim 1. (20) N-(3-hydroxyphenyl)-1-naphthalenesulfonamide 2. The compound according to claim 1. (21) N-(4-hydroxyphenyl)-1-naphthalenesulfonamide 2. The compound according to claim 1. (22) N-(3-chlorophenyl)-1-naphthalenesulfonamide A compound according to claim 1. (23) N-[3-(aminosulfonyl)phenyl]-1-naphthalenesulfone 2. The compound according to claim 1, which is an amide. (24) N-(3-iodophenyl)-1-naphthalenesulfonamide A compound according to claim 1. (25) N-[3-(1-methylethoxy)phenyl]-1-naphthalenesulfo 2. The compound according to claim 1, which is an amide. (26) N-[3-(1,1-dimethyl)phenyl]-1-naphthalenesulfone 2. The compound according to claim 1, which is an amide. (27) N-[(3-aminosulfonyl)phenyl]-2-chloro-1-naphtha 2. The compound according to claim 1, which is renesulfonamide or its sodium salt. (28) 3-[(2-chloro-1-naphthalenyl)sulfonylamino]-benz 2. The compound according to claim 1, which is an amide or a sodium salt thereof. (29) 3-[(2-chloro-1-naphthalenyl)sulfonylamino]-benz 2. The compound according to claim 1, which is an amide or a sodium salt thereof. (30) 3-[(2-chloro-1-naphthalel)sulfonylamino]-benzoin 2. The compound according to claim 1, which is an acid or a sodium salt thereof. (31) N-(4-acetylphenyl)-2-chloro-1-naphthalenesulfone 2. The compound according to claim 1, which is an amide. (32) N-(4-hydroxyphenyl)-2-chloro-1-naphthalenesulfo 2. The compound according to claim 1, which is an amide. (33) N-(4-chlorophenyl)-2-chloro-1-naphthalenesulfona 2. The compound according to claim 1, which is a mido. (34) N-[(4-aminosulfonyl)phenyl]-2-chloro-1-naphtha 2. A compound according to claim 1, which is a rensulfonamide. (35) 3-[(4-chloro-1-naphthalenyl)sulfonylamino]benza 2. The compound according to claim 1, which is amide or its sodium salt. (36) 3-[(5-chloro-1-naphthalenyl)sulfonylamino]benza 2. The compound according to claim 1, which is amide or its sodium salt. (37) 3-[(2-chloro-1-naphthalenyl)sulfonylamino]-N-[ 2. The compound according to claim 1, which is 2-(dimethylamino)]ethylbenzamide. (38) 3-[[6-[(2-chloro-1-naphthalenyl)sulfonylamino] 2. The compound according to claim 1, which is -1-oxohexyl]amino]benzamide. (39) N-(3-amidophenyl)-2-naphthalenesulfonamide A compound according to claim 1. (40) 3-[(8-quinolinylsulfonyl)amino]benzamide The compound according to item 1. (41) Any of the pharmaceutically acceptable carrier and the compound of claims 1 to 40 A pharmaceutical composition comprising an effective amount of. (42) A method for treating a mammalian tumor by radiation irradiation or chemotherapy, In conjunction with this radiation or chemotherapy, the formula ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ Compounds with (I) or their pharmaceutically acceptable An improved method comprising administering a salt that is tolerated. In the above formula, R1, R2, R3, R4 and R5 are independently H, 1 to 1 carbon atoms Alkyl, alkenyl, alkynyl having 0; phenyl, substituted phenyl, F , Cl, Br, I, NO2, CN, CF3, (CH2)mNR6R7 (m=0~ 10), CO2R9, OR10, COR11 or S(O)nR12 (n=0 ~3), or R1 and R2, R2 and R3, R3 and R4, or or R4 and R5 are both -CONHCO- or -CONMCO- (M is Na+, K+ or Li+), and R6 and R7 are independently H, carbon Alkyl, alkenyl, alkynyl, acyl having 1 to 10 atoms; phenyl substituted phenyl, CF3, or R6 and R7 are both (CH2) forming pNR8(CH2)q (p and q are independently 2-6); R8 and R9 are independently H, alkyl having 1 to 10 carbon atoms, alkenyl, aryl; ruquinyl or acyl, R10 is H, alkyl having 1 to 10 carbon atoms; phenyl or substituted phenyl, R11 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR13R14, R12 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR16R17; R13 and R14 are independently H, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl, alkynyl, acyl; phenyl, substituted phenyl or CF3 , or R13 and R14 are both (CH2)rNR15(CH2)5(r and and s are independently 2 to 6), R15 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or acyl, R16 and R17 are independently H, 1 to 10 carbon atoms; Alkyl, alkenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3 or R16 and R17 are both (CH2)tNR18(C H2) form u (t and u are independently 2-6), R18 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or or acyl, Y is N or CR5, X is each independently H, F, Cl, Br, I, NO2, CN, CF3, carbon Alkyl, alkenyl, alkynyl having 1 to 4 atoms; phenyl, substituted phenyl Nyl, (CH2)cNR19R20 (c is 0-10), CO2R22, O R23, COR24 or S(O)dR25 (d is 0-3), and b is 1 or 2, Z is N or CH, R19 and R20 are independently H, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3, or R19 and R20 are both (CH2)eNR21(CH2)f(e and f are independently 2 to 6), R21 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or or acyl, and R22 is H, alkyl or alkyl having 1 to 10 carbon atoms. nyl or alkynyl; R23 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, Acyl; phenyl or substituted phenyl; R2 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR26R27, R25 is H, alkyl, alkenyl, alkynyl having 1 to 10 carbon atoms; phenyl, substituted phenyl or NR29R30, R26 and R27 are independently H, alkyl having 1 to 10 carbon atoms, alkyl; Kenyl, alkynyl, acyl; phenyl, substituted phenyl, CF3, or R28 and R27 are both (CH2)gNR28(CH2)h(g and h are independently 2 to 6), R28 is H, alkyl having 1 to 10 carbon atoms, alkenyl, alkynyl, or or acyl, and R29 and R30 are independently H, having 1 to 10 carbon atoms; alkyl, alkenyl, alkynyl, acyl; phenyl, substituted phenyl, C F3, or R29 and R30 are both (CH2)jNR31(CH 2) form k (j and k are independently 2 to 6); R31 is H, alkyl having 1 to 10 carbon atoms, alkenyl or alkynyl; is le, A is NR32 or NR32ONR33, Q is (CH2)w, (CH2) xCO or (CH2)xSO2, w is 2 to 10, x is 0 to 10, R32 and R33 are independently H, Na+, K+, Li+, 1 to 10 carbon atoms alkenyl, alkynyl, acyl; phenyl, substituted phenyl, benzyl or substituted benzyl, but However, (a) X is H, R1 is CONH2 and R2 is H, or R1 is When R2 is NMe in H, R3 and R4 are H, and Y is CH, A cannot be NH, and (b) X is 2-Cl and R1, R3 and R4 are H. , if R2 is CONNaCO and Y is CH, then A cannot be NNa. and (c) X is 4-Cl, R1, R2 and R4 are H, and R3 is CO If NH2 and Y is CH, A cannot be NH2. 43. The method according to claim 42, wherein (43)-SO2A is bonded to the 1 or 2 position. (44) The method according to claim 42, wherein Z is CH. (45) -Claim that X is 2-halogen, provided that SO2A is at position 42 The method according to item 42. (46)-SO2A is bonded to the 1 or 2 position, Z is CH, and In the case of halogen, 2-halogen must be present on the condition that -SO2A is present at the 1st position. 43. The method of claim 42. (47) The compound is N-(3-amidophenyl)-2-chloro-1-naphthalene 43. The method of claim 42, wherein the method is a sulfonamide. (48) The compound is N-(3-amidophenyl)-5-chloro-1-naphthalene 43. The method of claim 42, wherein the method is a sulfonamide. (49) The compound is N-(2-amidophenyl)-4-chloro-1-naphthalene 43. The method of claim 42, wherein the method is a sulfonamide. (50) The compound is N-(3-amidophenyl)-4-chloro-1-naphthalene 43. The method of claim 42, wherein the method is a sulfonamide. (51) The compound is N-(2-amidophenyl)-2-chloro-1-naphthalene 43. The method of claim 42, wherein the method is a sulfonamide. (52) The compound is benzoic acid, 3-[[(4-chloro-1-naphthalenyl)sulfonate] 43. The method according to claim 42, wherein the ester is a nyl]amino]-, ethyl ester. (53) The compound is benzoic acid, 3-[[(2-chloro-1-naphthalenyl)sulfonate] 43. The method according to claim 42, wherein the amino acid is [nyl]amino]-. (54) The compound is N-[(3-dimethylamino)phenyl]-2-chloro-1- 43. The method of claim 42, wherein the naphthalene sulfonamide is naphthalene sulfonamide. (55) The compound is N-(3-acetylphenyl)-2-chloro-1-naphthalene 43. The method of claim 42, wherein the sulfonamide is a sulfonamide. (56) The compound is N-[3-(aminosulfonyl)phenyl]-2-chloro-1 - naphthalene sulfonamide. (57) The compound is 3-[(2-chloro-1-naphthalenyl)sulfonylamino] -4-methoxybenzamide. 43. The method according to claim 42. (58) The compound is N-(2,3-dihydro-1,3-dioxo-1H-isoin A claim that the compound is dol-4-yl)-2-chloro-1-naphthalenesulfonamide. 42. The method described in 42. (59) The compound is N-(3-methylphenyl)-1-naphthalenesulfonamide 43. The method of claim 42. (60) The compound is N-(3-acetylphenyl)-1-naphthalenesulfonamide 43. The method of claim 42. (61) The compound is N-(3-hydroxyphenyl)-1-naphthalenesulfona 43. The method according to claim 42, wherein the method is mido. (62) The compound is N-(4-hydroxyphenyl)-1-naphthalenesulfonate 43. The method according to claim 42, wherein the method is mido. (63) The compound is N-(3-chlorophenyl)-1-naphthalenesulfonamide 43. The method of claim 42. (64) The compound is N-[3-(aminosulfonyl)phenyl]-1-naphthalene 43. The method of claim 42, wherein the sulfonamide is a sulfonamide. (65) The compound is N-(3-iodophenyl)-1-naphthalenesulfonamide 43. The method of claim 42. (66) The compound is N-[3-(1-methylethoxy)phenyl]-1-naphthalene. 43. The method of claim 42, wherein the compound is a sulfonamide. (67) The compound is N-[3-(1,1-dimethyl)phenyl]-1-naphthalene 43. The method of claim 42, wherein the sulfonamide is a sulfonamide. (68) The compound is N-[(3-aminosulfonyl)phenyl]-2-chloro-1 -naphthalenesulfonamide or its sodium salt according to claim 42. Method. (69) The compound is 3-[(2-chloro-1-naphthalenyl)sulfonylamino] 43. The method according to claim 42, which is benzamide or a sodium salt thereof. (70) The compound is 3-[(2-chloro-1-naphthalenyl)sulfonylamino] - benzamide, or its sodium salt. (71) The compound is 3-[(2-chloro-1-naphthalenyl)sulfonylamino] 43. The method according to claim 42, which is benzoic acid or its sodium salt. (72) The compound is N-(4-acetylphenyl)-2-chloro-1-naphthalene 43. The method of claim 42, wherein the sulfonamide is a sulfonamide. (73) The compound is N-(4-hydroxyphenyl)-2-chloro-1-naphthalene. 43. The method of claim 42, wherein the compound is a sulfonamide. (74) The compound is N-(4-chlorophenyl)-2-chloro-1-naphthalene 43. The method of claim 42, wherein the method is a sulfonamide. (75) The compound is N-[(4-aminosulfonyl)phenyl]-2-chloro-1 - naphthalene sulfonamide. (76) The compound is 3-[(4-chloro-1-naphthalenyl)sulfonylamino] 43. The method according to claim 42, which is benzamide or a sodium salt thereof. (77) The compound is 3-[(5-chloro-1-naphthalenyl)sulfonylamino] 43. The method according to claim 42, which is benzamide or a sodium salt thereof. (78) The compound is 3-[(2-chloro-1-naphthalenyl)sulfonylamino] -N-[2-(dimethylamino)]ethylbenzamide according to claim 42. Method. (79) The compound is 3-[[6-[(2-chloro-1-naphthalenyl)sulfonyl] 43. The compound according to claim 42, which is amino]-1-oxohexyl]amino]benzamide. Method. (80) The compound is N-(3-amidophenyl)-2-naphthalenesulfonamide 43. The method of claim 42. (81) The compound is 3-[(8-quinolinylsulfonyl)amino]benzamide. 43. The method of claim 42. (82) In producing the compound according to claim 1, (a) pyridine, acetone or in the presence of an inert solvent such as methylene chloride, the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(2) (In the formula, X is as defined in claim 1 Naphthalene sulfonyl chloride of formula (i) ▼ (3) (wherein R1 and R2 are as defined in claim 1) (b) a compound of formula (2); At the same time, the compound of formula (3) in tetrahydrofuran is added to the tetrahydrofuran solution. method by adding aqueous potassium carbonate solution.