J. Med. Chem. 1982,25,441-446
44 1
A New Class of Nitrosoureas, 4.' Synthesis and Antitumor Activity of Disaccharide Derivatives of 3,3-Disubstituted l-(2-Chloroethyl)-l-nitrosoureas Kenji Tsujihara,* Masakatsu Ozeki, Tamio Morikawa, Masatoshi Kawamori, Yukio Akaike, and Yoshihisa Arai Research Laboratories, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda-shi, Saitama 335, Japan. Received August 26, 1981 A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N204Structureactivity relationships of these trisubstituted nitrosoureas were investigated by varing the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosy1 derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed. Scheme I Since the emergence of 1,3-bis(2-chloroethyl)-lnitrosourea (BCNU) and l-(2-chloroethyl)-3-cyclohexyl1-nitrosourea (CCNU) as useful antitumor agents in treating a variety of human malignancies, a large number NO NOH of nitrosourea derivatives that are highly active in experimental tumor systems have been reported.2 Among A these derivatives, water-soluble 3-[ (4-amino-2-methyl-5pyrimidiny1)methyll-1-(2-chloroethy1)- 1-nitrosourea Scheme I1 (ACNU) has already been on the market, and some niR R trosourea derivatives, such as 1-(2-chloroethy1)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea (PCNU),3 2- [3 42-chloroethyl)-3-nitrosoureido]-2-deoxy-~-glucopyranose (DCNU): -CH -CH 0 + NCHzCHzCI l-(2-chloroethyl)-3-(~-~-glucopyranosyl)-l-nitrosourea \CH' (1 (GANU),5 and 1-(2-chloroethyl)-3-(methyl-a-D-glucoI NOH I pyranos-6-yl)-l-nitrosourea(MCNU)? etc., are currently B under clinical trials. These nitrosoureas (A) necessarily possess one hydrogen Scheme I11 atom a t the N-3 position, and this seems likely to be imR portant in conferring antitumor activity. They decompose R\ \N-~o-NcH,CH,C~ N-CO + NCH2CH2CI under physiological conditions to generate isocyanates and sugar' C L \ chloroethyl diazohydroxide and consequently exhibit an-OH NO titumor activity. This decomposition is considered to be C initiated by abstraction of the proton at the N-3 position as the first step' (Scheme I). Scheme IV Our interest in the antitumor activity of 3,3-disubstituted l-(2-chloroethyl)-l-nitrosoureasas masked nitrosoR-NHz CICH2CH2NCO sugar(0H)e sugar(OH17NHR urea derivatives8 has led to the synthesis of the nitrosoureas (B) having an hydroxyl group a t the p position of their substituents. This new class of nitrosoureas having CH OH sugar(OH)7NCONHCH,CHzCl % sugar(ON017NCONCH,CH2Cl no proton at their N-3 position differed from known niH+ I trosoureas in its activation mechanism and exhibited re1-32
-
- '
-
P
-
r
NO
R
I
(1) For part 3 of this series, see Morikawa, T.; Ozeki, M.; Umino,
N.; Kawamori, M.; Arai, Y.; Tsujihara, K. Chem. Pharm. Bull., in press. (2) (a) Montgomery, J. A. Cancer Treat. Rep., 1976,60,651. (b) Hansch, C.; Leo, A.; Schmidt, C.; Jow, P. Y. C. J.Med. Chem. 1980,23, 1095. (3) Phase I study of PCNU Gralla, R. J.; Young, C. W.; Tan, C. T.; Sykes, M. P. Proc. Am. Assoc. Cancer Res. 1980, 21, 71 Meet., 185. (4) Phase I1 study of DCNU: For example, see Casper E. S.; Gralla, R. J. Cancer Treat. Rep. 1979,63, 549. ( 5 ) Phase I study of GANU Kanko, T.; Saito, T. Gun To Kagaku Ryoho 1981,8, 557. (6) Sekido, S.; Ninomiya, K.; Iwasaki, M. Cancer Treat. Rep. 1979, 63, 961. (7) For example, see Brundrett, R. B.; Cowens, J. W.; Colvin, M.; Jardine, I. J. Med. Chem. 1976, 19, 958. (8) The trisubstituted nitrosoureas, such as 1-(2-~hloroethyl)-3,3dimethyl-1-nitrosourea, have been reported to be latent antitumor agents: see Brundrett, R. B.; Cowens, J. M.; Colvin, M. Proc. Am. Assoc. Cancer Res. ASCO 1976,17, 102. 0022-262318211825-0441$01.25/0
s u g a r ( 0 H I7N CONC HC , H,C I
I
NO
33-64
markable antitumor a ~ t i v i t y . ~They were activated by attack of the hydroxyl group on the carbonyl group to give oxazolidinones and chloroethyl diazohydroxide without generation of isocyanates (Scheme 11). This observation was followed by the finding that the 3,3-disubstituted nitrosoureas (C) bearing aldohexoselO and aldopentosel moieties are activated by essentially the same (9) For part 1 of this series, see Tsujihara, K.; Ozeki, M.; Morikawa, T.; Arai, Y. Chem. Pharm. Bull. 1981,29, 2509. (10) For part 2 of this series, see Tsujihara, K.; Ozeki, M.; Morikawa, T.; Taga, N.; Miyazaki, M.; Kawamori, M.; Arai, Y. Chem. Pharm. Bull., 1981,29, 3262. 0 1982 American Chemical Society
Tsujihara et al.
442 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 4
Table I. Properties of Urea Derivatives of Disaccharides
R I
sugar-N-CONHCH,CH,Cl yield, no.
R
%
IR (Nujol) urnax, cm-'
NMR (D,O),6
68 73 70 75 77 62 72 75 70 72 74 74 70 75 76 74 72 68 70
3350,1640,1535,1070,1030 3350,1640,1535,1070,1040 3350,1620,1540,1070,1040 3350,1640,1540,1070,1030 3350, 1635,1540,1080, 1030 3350,1640, 1 5 4 0 , 1 0 7 0 , 1 0 3 0 3350,1640,1540,1070 3350,1640,1540,1070,1030 3350,1630,1535,1070 3350,1645,1540,1070,1030 3350, 1640, 1530, 1070, 1030 3350,1635,1530,1070,1030 3350,1640,1535,1070,1030 3350,1630,1540,1070,1025 3340,1640,1555,1070,1025 3350, 1635, 1 5 4 0 , 1 0 7 0 , 1 0 3 0 3380,1640,1550,1070,1030 3 3 5 0 , 1 6 3 0 , 1 5 3 0 , 1 0 6 5 , 1020 3350,1630, 1540, 1 0 7 0 , 1 0 4 0
3.15 ( 3 H, s ) 0.90 ( 3 H, t), 1.4-1.9 ( 2 H, m) 1.38 ( 6 H, d ) 0.7-2.0 (7 H, m ) 0.91 ( 6 H, d), 1.8-2.3 (1H, m ) 0.91 ( 3 H, t), 1.28 ( 3 H, d), 1.5-1.9 ( 2 H, m) 0.7-1.0 ( 3 H, m), 1.0-2.0 ( 6 H, m ) 0.7-2.1 (11 H, m)
66
3350, 1630, 1540, 1070, 1030
0.7-2.15 (m, ring protons)
68
3370, 1640, 1540, 1070, 1040
1.75-2.25 (m, ring protons)
70 71 73 75
3320, 3350, 3350, 3320,
7.3-7.55 ( 4 H, m ) 7.2-7.5 ( 4 H, m ) 2.3 ( 3 H, s), 7.20 ( 4 H, 9) 3.80 ( 3 H, s), 7.20 ( 4 H, 9)
9
70
3350,1640,1530,1070,1030
6.46 ( 2 H, m ) , 7.53 (1 H, m )
77 2-39
67
3340, 1620, 1530,1070, 1020
6.9-7.2 ( 2 H, m), 7.3-7.5 (1 H, m )
sugar
1 maltoa 2 malto 3 malto 4 malto 5 malto 6 malto 7 malto 8 malto 9 malto 10 malto 11 malto 1 2 malto 13 malto 1 4 malto 15 malto 16 malto 1 7 malto 18 malto 19 malto 20 malto
CH3 CH,CH,CH, CH(CH3
12
CH,CH,CH,CH, CH2CH(CH3)2
CH(CH,)CH,CH, CH,(CH,),CH, CH,(CH,),CH, CH,(CH,),,CH, CH,CH=CH, CH,CH=CHCH, CH,CH,CH=CH, CH,C(=CH,)CH, CH,CH,OCH, CH,CH,OCH,CH, CH,CH,CH,OCH, CH,CH(CH,)OCH, CH(CH,)CH,OCH, CH,-C,H, ib
