3984
RICHARD M. PECK,ROBERTK. PRESTON AND HUGHJ. CREECH
Vol. 81
[CONTRIBUTION FROM THE INSTITUTE FOR CANCER RESEARCH]
Nitrogen Mustard Analogs of Antimalarial Drugs1 BY RICHARD M. PECK, ROBERTK. PRESTON AND HUGHJ. CREECH RECEIVED SEPTEMBER 18, 1958 The hydrochlorides of thirty nitrogen mustard derivatives in the quinoline and acridine series of antimalarial drugs have been synthesized for studies of their antitumor potentialities. Pamoates of several of the mustards have also been prepared. Some of the diol intermediates were made by independent syntheses.
Introduction The nitrogen mustard group has been incorporated into many organic molecules possessing varying types of physiological a ~ t i v i t y . ~ -We ~ decided to utilize the substituted quinoline nuclei of several antimalarial drugs as carriers of the bis-(2chloroethy1)-amino group. Pharmacologic data5 on the toxicity and tissue distribution of the antimalarials suggested that such carriers might lead to some preferential localization of the alkylating activity in certain tissues; in addition, several of the antimalarials themselves show bone marrow depressant activity.6 The majority of the antimalarial mustards have displayed pronounced antitumor activities in tests employing mouse ascites tumor^.^ Further information on this point will be reported elsewhere by Creech, et al.; pharmacologic studies are being conducted by Leon H. Schmidt and investigations of the effects of these mustards on rat leukemia and in patients are being made by Ralph Jones, Jr. Attempts were made to place the bis-(2-chloroethyl)-amino group directly into the 4- and 8-POsitions of representative quinoline nuclei. Even with the use of reactive 4-bromoquinolines, the yields were low. The diol skeleton could be introduced into the 8-position of 6-methoxyquinolineJ but subsequent chlorination led to cyclization to a pyridoquinoxalinium skeleton (I) accompanied by hydrolysis of the ether. Although it was unstable, the 8-(monochloroethyl)-amino derivative of Ginethoxyquinoline was isolated successfully.
Since the di- and monofunctional compounds obtained by direct introduction of the substituent into the quinoline nucleus were found to be ineffective against ascites t ~ m o r ssynthetic ,~ efforts were concentrated on compounds in which the mustard group was placed a t the end of an “antimalarial” (1) Supported in p a r t by a research grant, number CY-2975, from t h e National Cancer Institute, Public Health Service, and in part by a fellowship grant from t h e American Cancer Society t o K . M . P . for work a t t h e Chester Beatty Research Institute, Royal Cancer Hospital, London, England, from September, 1955, to September, 1958. (2) F. Bergel. V. C. E. Burnop and J. A. Stock, J . Chrnz. Sor., 1223 (1955). (3) B . Kellner a n d L. Nenieth, Z . Krebsfousch., 61, 165 (1956). (4) F. Bergel and G . E. Leais, J. C h e m . Sac., 181G (1957). ( 5 ) L. H. Schmidt, in “ A Survey of Antimalarial Drugs,” F. Y. b‘iselogle, ed., Edwards Rros., Ann Arbor, Mich.. IR-Lti. ( 8 ) L. H. Schmidt, h-ational Research Council Piit>. 200, 81 (1961). ( 7 ) H. J. Creech, el al., Proc. A m . Assoc. Cancer Resenvch, 2, 195 (1957); Anir. ,V. Y . A c a d . Sci., 68, 808 (1958).
side chain as in the types synthesized by Jones, Price and Sen.* Many of the compounds possible from eleven nuclei and six side-chains have been made. Two methods were employed for the synthesis of the intermediate diols. The procedure used for most of the compounds was to preform the entire side chain before incorporation into the quinoline nucleus, as exemplified by the reactions
CHI-CHI 0 ‘’
CHaCONH( CH2)&Ht
I1
HBr
CHaCONH(CHZ)~N(CHZCHIOH)~ I11 HzN( CHz)e,N( CHzCHz0H)z IV
\’I1
The diol intermediates of several of the compounds carrying the two- and six-carbon side-chains were also obtained by attaching the primary aminoalkylamino chain first and hydroxyethylating the primary amine group, as shown by VIII, IX and VI.
The general scheme of synthesis has remained fairly constant, with variations being made only in the temperatures and times of condensation and chlorination, and in the modes of isolation; data are recorded in Tables I and 11. The majority of the diol intermediates were ultimately crystallized or yielded crystalline salts; the rest were molecularly distilled. Of the several methods of chlorination used to produce the we had greatest success (8) R . Jones, C . C. Price a n d A . K . S e n , J. Org. Chent., 22, 78X (1957). (9) J. L. Everett, J. J. Roberts and W. C. J. Ross, J . CIienz. S u r 2386 (1953). (10) F. C . Copp and G. M . Timmis, ibid., 2021 (19551.
3OS5
NITROGENMUSTARD ANALOGS OF ANTIMALARIALS
-4ug. 5 , 1959
TABLE I DIOLS
-
-
Side-chains = -NH(CH~),N(CHZCHZOH)Z and - S H C H ( CHI)( CH2)3N(CH2CHzOH)z No.
Side-chain
Other substituents
Condensation Time, Temp., hr. OC.
':z:'
Yield, --Calcd.--
o/o
C
H
62 67 34 30 40 85 51 60 79 65 48 54 60 20
65.43
7.69
Analyses, %a--Found-C
N
H
N
7.71
;m: Quinolines 5
1 2-Ethyl (n = 2) 2 2-Propyl (n = 3) 3 2-Butyl ( n = 4) 4 2-Methylbutyl 5 4-Propyl 6 4-Methylbutyl 7 4-Propyl 8 4-Methylbutyl 9 4-Hexyl ( n = 6) 1 0 4-Ethyl 11 4-Propyl 12 4-Methylhutyl 13 4-Propyl 14 4-Methylbutyl 15 16 17
4-Propyl 4-Ethyl 4-Propyl 18 4-Methylbutyl 19 4-Hexyl 20 4-Ethyl 21 4-Propyl 22 4-Hexyl 23 4-Ethyl 24 4-Propyl 25 4-Butyl 26 4-Amyl (n = 5 ) 27 4-Heptyl ( n = 7) 28 4-Ethyl 29 4-Propyl 30 4-Hexyl 31 4-Ethyl 32 4-Propyl 33 4-Methylbutyl 34 4-Hexyl 35 4-Propyl
10 100 48 100 6 115 12 130 4 145 3 150 7 130 2-Methyl 2-Methyl 3 160 (4 125)' 2-Methyl 6 150 2-Phenyl 2-Phenyl 5 135 2-Phenyl 4 180 2-fi-Chlorophenyl 7 150 2-fi-Chlorophenyl (a) 4 (a) 165 (b) 1 (b) 195 3-Methyl 6 155 4 115 5-Chloro 5-Chloro 6 130 10 100 5-Chloro 2 125 5-Chloro 5 130 6-Methoxy 5 135 6-Methoxy (7 135)' 6-Methoxy 7-Chloro 4 120 7-Chloro 5 100 8 125 7-Cbloro 5 135 7-Chloro Proc. B 7-Chloro 3 140 2-Methyl-7-chloro 2- Methyl-7-chloro 2 150 2-Methyl-7-chloro Proc. B (7 128)h 3-Methyl-7-chloro 3-Methyl-7-chloro 10 135 3-Methyl-7-chloro (18 150)h 3-Methyl-7-chloro 4 120 3-Methyl-6-methoxy 14 135
1
15ob 15~5~ 150' 187-188'
250b 138-139.5 185b 207-21 I d 102-104 131.5-132.5 250b 1951 25Ob 206-208f 158.5-159.5/ 135.2-136.2 265* 110' 74-75 129-130 201-203d 136.5-138 135-136 136.5-137 155-157 129.2-130 110-113 149.5-150.5 137-138 157-158.5 97-97.8 200b 155b 164-16Sd
l8ob
8.31 18.17 66.41 7.95 68.11 8.57 67.20 8.24 P 11.75d 69.52 9.05 71.77 7.18 72.31 7.45 1 39.09j 6.50 66.00 1 37.121
15.26 14.52 13.86 10.76 14.52 13.24 13.86 7.96 12.15 11.95 11.49 6.47 10.50 6.15
66.81 8.21 CI 17.91 68.75 8.25 67.75 9.32 66.84 8.30 P 11.65d 69.60 8.67 72.11 7.30 71.96 7.35 138.34/ 66.18 6.07 137.13/
15.41 14.80 13.52 10.65 13.77 13.32 13.69 7.59 12.21 11.49 11.71 6.54 10.17 5.91
36 90 32 65 46 95 96 83 97 59 82 76 40 65 50 55 68 40 49 84 52
I 45.401 58.16 6.52 59.34 6.80 49.83 6.73 62.37 7.71 62.93 7.61 P 12.02d 66.46 8.65 58.16 6.52 59.34 6.85 60.40 7.12 61.45 7.40 63.23 7.96 59.34 6.85 60.40 7.13 63.23 7.97 59.34 6.85 60.40 7.13 62.36 7.71 P 10.75d 64.66 8.14
7.51 13.56 12.97 9.68 11.49 13.75 8.15 11.63 13.56 12.98 12.42 11.91 11.06 12.98 12.41 11.05 12.98 12.41 11.50 7.29 12.59
145.68l 58.22 6.60 59.42 6.72 49.90 6.98 62.66 7.76 63.54 7.59 P 12.04d 66.00 8.63 57.70 6.40 59.40 6.97 60.47 6.94 61.67 7.57 62.65 7.75 60.20 6.88 60.66 7.44 6 3 . 3 1 8.04 59.45 6.77 60.03 7.45 62.50 7.93 P 10. 63d 63.51 8.33
7.72 13.28 13.09 10.17 11.54 13.19 7.78 11.23 13.54 12.89 12.35 11.87 11.01 13.06 11.80 11.21 12.88 12.37 11.79 7.19 12.06
45 54
59.04 55.55
6.45 6.60
10.30 C1 20.50
58.73 54.83
6.45 6.75
10.45 CI 1 9 . 8 7
56
66.41
8.01
14.52
66.47
8.02
14.76
67.30
CI
65.16
Acridines
36 37
9-Ethyl 9-Hexyl
2-Methoxy-6-chloro 2-Methoxy-6-chloro
4 3
110 120
168-169.5' 190
Isoquinoline :
38
I-Propyl
3
150
l6ob
4
Values are either single analyses or averages of checks. Pot temperature of molecular distillation (Hickman still); Isolated as the dihydrochloride. Isolated as the diphosphate. pressure 0.01-0.1 p . Also prepared by procedure R. 9 Isolated as the dihydrochloride. l/zH20. f Isolated as the dihydriodide. Starting material 4-bromo-7-chloro-3-methylquinoline. i Monohydrate. 0
with the one involving standing for several days with a large excess of thionyl chloride. The products were all isolated as dihydrochlorides ; these ranged widely in solubility characteristics and ease of purification. It was found that the melting range was not a satisfactory index of purity; products in which the replacement of hydroxyl by chlorine was far from complete often gave melting points identical with those of analytically pure products,
The sparingly soluble salts of pamoic acid, methylene bis-(2-hydroxy-&naphthoic acid), were made of some of the mustards to take advantage of certain improved pharmacological properties, such as greater antitumor effectiveness and lower t ~ x i c i t y . ~ When these salts could be induced to separate in a crystalline form, individuals of good analytical purity were obtained; amorphous preparations tended to be much less pure.
RICHARD 11.PECK,ROBERTE;. PRESTOX AND HUGH J. CIIEECI-I TABLE I1 MUSTARDS DERIVED FROM DIOLSI N TABLE I Table I ref
Chlorination conditions Additional At heating hours hours " C . Hr.
On,
?';'.,
72 48 24 ..
..
-~-____Solvation
A t . p., OC.
Yield,
-Calcd.---------. H
x
c
N
-----_
Analyses, C/70" --Found----------. c1 C H S ~
C1
r-
143- 145 11 46 76 5 50 10 91 36.82 46.73 5 76 10.62 3 5 . 1 4 217-218 5 2 3.5 I ..... 72 48 14 5 81 10 53 3 5 . 5 3 47.91 5 94 10.31 3 5 . 5 0 218 5-220 3 a5 1 , . , . . . 82 49 41 6 10 10 17 3 4 . 3 2 49.47 6 38 10.32 33.57 4 .. .. .. . . . 208 5-209 5 42 50 60 6 37 9 84 33.17 50.40 6 53 9 . 5 8 32.82 3 .. . .... 82 48 14 5 81 10 53 3 5 . 5 3 48.26 5 90 1 1 . 1 4 34.67 .. .
