January, 1963
HEXAHYDROAZEPINYL-BIS(AZIRIDINYL)PHOSPHINE OXIDEA N I SULFIDE 47
Synthesis of Hexahydroazepinyl-bis(aziridiny1)phosphine Oxide, Sulfide, and Related Compounds for Cancer Therapy1 I .4SllLYTICAL I)ATA (IF IIEXAalaTHYLESI.\lI.uE
-Cum~~ounii-S R, R,
No.
B . p , CC. 11.1).,
I I1 111
IV
v
VI VI1 VI11
s 8 8
0 0
IS s
x s
XI a
8
C1 c1 ... H s C l 29.5-30 HX HS 104-105 E“ E ... 11s 1.; 1.: 1; 5-0 11s I< -10 E c‘l 128-130.5
(I”
89-92 ( 0 . 3 ) 162-3 (0.15) 199-202(0.15) 65-67 ( 0 . 0 2 ) ... ... 0 6 . 8 (0.025) 135-136 ( 0 . 0 5 ) 117 (0.5) ...
...
SUBSTITUTED ( h M P O G X D S
,
i
s-.-p-= X--. All melting points and boiling points are corrected. e Calcd.: P, 1 1 . 1 1 . Found: P, 10.70. .’ Cnlcd.: CH, P, 9.07. F o u r d - P ; 9.07. 0 Cnlcd.: P, 13.35; P, 13.81. Found: P, 13.19; e, 13.86. Calcd.: H, 10.51; C1, 12.03. Fourid: P, 10.62; C1, 12.34. Calcd.: S, 8.97. Found: S, 8.95. 7 Calcd.: P, 13.51. Found: P, 13.75. k Calcd.: P, 10.85. Found: P, 10.9:3. Calcd.: S, 13.43. Found: S, 13.31. Calcd.: S, 10.64. Found: S,10.31. E is Aziridingl
EVALI:ATIOS
Conipound
IS
a
O F SOME
T-ABLE I1 HEXAHYDROAZEPISYL S U B S T I T U T E D P H O S I ~ H i S EOXIItES
1)ose ing./kg.
100 50 25 12.5 12.5 6.25 3.12 1.56 s 100.0 25.0 5 .0 I’ll I 250,o 100.0 “5, 0 10.0 5.0 I11 100 0 25.0 5.0 T/C = Tumor/Control.
Vehicle (route)
Ah’U S U L F I D E S IS
KT-Figlit change
Eiirvivors
C l I C (1.P.)
CAIC (1.P.)
Oil (S.C.)
Oil (S.C.)
Oil (S.C.)
t i d y low toxicity of compound T’IE and its good therapeutic effectiveness as compared to ThioTEPA and TEPA warrant further extensive study. The infrared spectra of the compounds prepared in this srrics provide uscfiil information leading t o the detrrmination of the structure of compounds and were used t o advantage in preparing highly purified samples for animal screening and clinical evaluation. All the ethylenimine derivatives contain a characteristic 3.25 p band. The hexamethylenimine ring is characterized by the 3 4 2 and 3 5 0 p -CH,- stretching bands. The interaction of C--S vibration bands in the 8.0 -10.0 p region is interfered with by the P=O or P-S stretching vitmtions and definite assignment. has to await more d:it:L. ,Inother useful band lies in the 1’-S region. ,111 rompounds prepared in this
O/6 O/6 0/6 3 iC 2/6 G/G 6/6 G/G 3/3 3/3 3/3 3/:3 :I /’3 3/3 3/:3 3j3 :1/3 3/3 3/3
TjC“
(g.)
-/44.0
-/44.0 - j4.1 0 22,0/14.0 -25,0/40,0 33.O/40.0 26.0/40.0 40,0/40,0 37/33 171% 21 /33 7/23 2op3
32/23 :io;2:t
2’”/”’3 19/23 28/23 24/23
DCXXISG LEUKEMIA SYSTEM Survival Time T/C (daw)
Percentagu
5.0/14,0 3.0/14.0 6 . 5/14.0 30.0/14.0 7.0/14,0 30.0/14.0 25,5/14.0 16.0/14.0 14. i / 1 4 . 3 11.0/14.3 14.7/14.3 18.0/13.i 14 , 3/ 13.7 14 .:3/’1:3 . 7 I3,7/13.7 1 6 .7/13,: 1 3 .:3/14.:I 14.3/14.3 17, 0j14.3
35 35 46 214 50 21‘1I 82 125 103 98 103 132 10.1 104 100 114 93 100 I19
series have u chnracteristic band in the 13.7;,- 14.40 p region. This has been labeled by Bellamy6 as a doubtful region for P-S stretching vibration becausc of the absence of any absorption of bis(dimethy1amino)fluorophosphine oxide in this region. The bis(hrsahydroazepiny1)chlorophosphine oxide, however, docs have an absorption band at 14.1: p. The tris-dimethylaminophosphine oxide, on the other hand, has been found b y us t o h a m a characteristic 1’-K band at 13.50 p. It therefore seems to us that thth absence of absorption in the case cited by Bellamye is due to the symmetry of the molecule and is an exception to the general rule, and this region can be iiscd safely in the characterization of X=P(
