692 G. R. PETTIT, S. I(. GUPTA, AKD P. A. WHITEHOCSE \-Ill. 10

Antineoplastic Agents. XVIII. N- (2-Haloethyl) benzylamines'

A ,ei,ies of N-berizyl-N-(%-haloethyl)amiiie~ have bee11 *yiithesized for c.oriip:wisoii of pubsible aiitiueoplastic: properties with those of the corresponding S-bis(2-chloroethy1)amines. Coiiversioii of 3,4-dichlorobenzoylaziridiiie (11) with HC1 or FIBr to, respectively, amides I I I a arid I I I b followed by a diboraiie reductio11 sequence yielding nrniiiei I\-a aiid I \ % outlines the synthetic methods employed. Several S-2-iodoethylamides of the type illus- trated by strrictwe I I Ic were prepared from the correrpoiidi~ig aziridine amide employing HI or from a K-2- cahloroethylimide precursor using NaI i i i acet,one. Reaction hetweeii the N-2-iodoethylamides and diborane (in tetrahydrofuran) at approximately 60' for 2 hr or at room temperatiire (overnight j was sho~v11 to c'ause virtually complete hydrogetiolysis of the C-I bond. Presetit,ly available biological resulta indicate the N-(2-chloroethyl)- I)eiizylamiIies to be considerably less active than t,he c~)rre\poiidiiig N-hi~(2-chloroethyl)beii~ylamiiie~.

&sed 011 an earlier study4a of the aromatic sybteni oi pod(iphyl1otosiri as a carrier group for nitrogen mus- tardh, i t bec~ame necessary to prepare a number of S- tieiizyl-X-bib( %haloethyl) amines. 411-d Several of the rciulting hcnzylamines displayed potentially useful :tiitincoplast I(* propertieq 411~11 The present investiga- ti011 ~ - a \ uiidcrt:il;en t o evaluate the possibility of uii- c~)vcring uheful canccr cahemotherapeutic properties :~iiioiig the rorresponding S-benzyl-S-(2-haloethyl)- :tmiiws ( e 8.. amine Ia L S . Ib)

Sonic S-(L'-c.hloroethyl)amiiies such as l,B-(%-chloro- ct hylani~~io)-l ,fi-dideoxy-n-maiinitol dihydrochloride 1i:ir.c reached clinical trial: and others have given cvidcncae of antineoplastic3 Generally these "~i~i~~-:triiied" iiitrogen mustards have been considered le- ubeful. To determine the relative merits of ccr- tail] hcmzylamine carrier groups for S-(%haloethyl)- miiiies, 5ynthem of the wbstatices summarized in

undertalien. Scheme I illustrates the geiic~al route found most batisfactory for obtaining bclrizylamirics of this type.' Selection of the aziridiiie heiimmides a s intermediates reqided with their ready ontry l l l t ( J ring-opening reactions aiid availability of t hc correhpoudirig benzoic ac2id.i. 111 each case the aniidc wa5 prepared from the correbponding aroyl ( 8 hloride arid aziridine i n the preqence of aqueous KOH.

[ I ) l o r Part ST ' I I refer t o G . R. Petti t and 31. R . Chamberland, Can. J .

' l i This in\-estiEation mas aided by Grants pio. T-T9F and T-79G from

Ilepartment of Chemistry, Arizona d ta te University. 1-11 ( a i G R. Pett i t and J. .L Settepani. J . O r g . Chem., 27, 2962 (1962):

( I t 1 C;. I?. Petti t , hf, R, Chamberland, D. S. Dlonda, and 31. Vickers, Can. J . 42 , 1699 (1964): ( e ) G. R . Pett i t and R . L. Smith, ?bid., 42, 5 i 2

( r l i C . R. Pett i t . D. S. lilonda, and E. Harrington, ihzd.. 41, 2962

c.7) I,. 1'. Lariunuv, "Cancer Chemotherapy." PerKamon Press Inc. . S r a 1 urk, K, \.., 196;. rj 2'34.

16) R . 31. P e r k , . A . P. O'vonnell, and ti. .J. Crepcli, .J. Meil . Chem., 9, 217 i11)t i t i i : E l . %. S?inmer, C'. Sclier, S. Ilien, G. OIsen, .I. IC. Chakraharti, and 0. hl . Friedman, ibzri., 9, 81 (1966); P. Hebhorn and D. .I. Triggle, ibid.. 8 , .-,11 (l!l6.5i: R. F. Pittillo. .\. .T. h-arkates, and .J. l%urns. Cnnrer Res . , 24, 1'222 i l 9 6 4 ) ; T . P. Jolinston, G. 8. 3lcCaleh. J . .i. Rlonr-

Skipper, ? h i d , 23, 725 11963); TV. IV. Lee, and I,. Goodman, J . J l e d . Chem., 6 , ,567

( 7 ) For a recent rerien of synthetic routes to pi-(2-haloethSlfamines see: .I. S . Sinx11 and .\. Ii. L a l , $7. Inrli i in Chem. S o r . . 4 3 , 808 (1966); C-Y. \Til a r i i l ti. l?. Rohertson, Chem. I n d . (London), I95 (1966): N. .I. Leonard, 11 ) . Ninr. and I t . L. liootli, J . O r g . Chem., 30, 4357 (1965): G. F. Hennion and .\. C . Hazy, ib id . , 30, 2650 (1965): K . .J. Leonard and J. V. Paukstelis, I / , < < / . , 30 , 821 (1965): R . 11. 3loffett. .I. .Wed. Chem., 7 , 319 (1964); L. 8. ~~airiizliinskii ani1 .\. )-a, I%erlin. J . Gcn. Ciiern. L.SSR. 33, 3004 (1'368); N. I:. ( 'hapman and 1). .J. Triggle, J . Ciiern. Soc., 1885 (1963): S . J. Leonard, I<. .laon. .I. V. Paukstelis. and C. K , Steiniiardt, J . Ore . Chrm., 28, l4YY l1'36:i): bee also ref 6.

('he'fn., 44, 81:1 (1968).

(lie .\merican Cancer Society.

1:. 31. ,Sctialiel. .T

hcirm. Bull. (Tokyo), 10, 390 (1962).

SCHEME I R

C1

Ia, R = Rt = OCHJ; Nz = CHzCHzCl I1 b, R=Ri=OCHs; Rz=H C, R=Rl=Cl ; Rz=CHzCHaCl d ,R=Ri=Cl ; Rz=H

C I ~ C O N H C H ~ C H ~ X - BHJ

e 1

IIIa, X = C1 b,X=Br c , X = I

c1-f-J- C H ~ N H C H ~ C H ~ X

C1

IVa, X = C1 b ,X=Br c ,X-H

Treating, for example, amide I1 in CHCld with HC1 readily opened the aziridine ring8 to afford a quanti- t ative yield of S-(%-chloroethyl)-3,4-dichlorobenzamide (IIIa). Several of the S-(2-chloroethyl)amides wcre also prepared using concentrated HCl to open the aziri- dine ring or by eliminating aqueous MOH from the ini- tial aroyl chloride-aziridine cwndensation reaction. However, the latter procedure was considered lehh satisfactory than the hydrogen chloride technique. Siniilar reaction between amide I1 (Table I ) and hy- drogen bromide provided the corresponding bromo derivative IIIb. In several cases, the S-(%-bromo- ethy1)amides were obtained by displacing chloride from a S-(2-chloroethyl)amide precursor using LiBr

( 8 ) For a reviea of N-suhstituted aziridines consult: G. .illen, I). . I . Oldfield, N. L. Paddock. F. Rallo, J . Serregi, and S. 31. Todd. Chem. I n d . (London), 1032 (1965): D. Rosenthal, G . Brandrup, K. If . Davis, ,I.-., and R I . E. Wall, J . Org. Chem., S O , 3689 (1965); A , T. 13ottini and R. I,. Van Et ten , ih id . , 30, 575 (1965): G. K. Ilelmkamp. R. D. Clark, and J . It. KOP- kinen, i h i d . , 30, 666 (1965); C. TV, Woods, :L. 13. I3orkovec. and F. M. Ifart . J . M e n ' . Chem., 7, 371 (3984): C . Harder, E. Pfeil. and I<-F. Zenner, Be r . . 97, 510 (1964): Vi. Ijeroaa and A. H. Uorkovec. J . X e d . Cliem., 7 , 44 (1964): -1. Hassner and C. Heathcock, Tetmhedron, 20, 1037 (1U61); 11, M.. Heine. J . .4m. Chem. SOC., 86, 2743 (1963): 11. \V. Heine. A n y e x . Chem., 74, 772 (19621.

July 1967 ANTINEOPLASTIC AGENTS. XVIII 693

TABLE I

Rt

R Yield,* Sol- h IpSd Carbon, % Hydroaen. R Nitrogen, Yo

R R I RI Yo ventC O C Formula Calrd Found Calcd Found Calcd Found

CH30 85.5 1 76.5 CicHiiN09 67.79 67.99 6.26 6.24 7.90 8.02 CHIO CHI0 72 1 86 CIIHI~NO~ 63.76 63.56 6.32 6.46 6.76 6.90 -0CH20- 75 1 62.5 CiuHgN03 62.82 62.67 4.74 4.72 7.33 7.66

CHI0 CHI0 CH80 90 2 61-62 CirHi~N0.i~ 60.75 60.87 6.32 6.42 5.90 5.84 CHI0 CFT:{O CH30' 75 2 70.5-71 CI~HIINO,~ 62.15 62.36 6.82 6.95

F 35 3 42.5-43 CgHSFNO 65.44 65.00 4.72 5.25 CI c1 80 2 97.5-98 CsHiClSOj 50.00 50.03 3.24 3.45 6.48 6.33 C H I CHS 60 . . 0iP CIIHI~SO 75.40 75.35 7.48 7.63 7.99 7.93 Represents 3,4,5-trimethoxyphenethyI. * Over-dl yield from the corresponding acid and based on recrystallized amide. c The

amide was recrystallized from ( 1 ) benzene-hexane, ( 2 ) henzene-petroleum ether, (3) petroleum ether. d .\Ielting point of the colorless analyt,ical sample. e Anal. Calcd: 0, 27.00. Found: 0, 27.20. f .4naZ. Calcd: C1, 32.87. Found: C1, 32.67. 0 Purified by chromatography (eluted with benzene) on silica gel, nZ9D 1.5464.

11 acetone. Again, the HBr technique was considered superior. The N-(2-iodoethyl)amides such as IIIc were easily obtained from the N-(2-chloroethyl)amides using KaI in acetone solution or by treating the cor- responding aziridine amide with hydriodic acid.

The N-(2-haloethyl)amides summarized in Table I1 did not display the great sensitivity to moisture exhibited by the corresponding N-bis(2-haloethyl)- amides prepared earlier.4c In fact, the amide +- ester rearrangement reaction generally observed with K- bis(2-haloethy1)amides was not encountered in the present study. Although t'his point was not pursued, prolonged heating in H20 might cause rearrangement of these S-(2-haloet~hyl)amides, since Fryg has report'ed rearrangement of a-benzoylamino-p-chloropropionic acid to 0-benzoylserine in hot H20.

The previously reportedlo successful reduction of various amides to amine derivatives by diborane com- bined with our own experience (e .g . , ref 11) with this mild and versat'ile reagent clearly indicated that di- borane should be the reagent of choice for converting the N-(2-haloethyl) amides to the corresponding benzyl- amines (111 +- IV). The chloro- and bromoet'hyl- amide reduction to the respective benzylamines was easily achieved using commercially available 1 M diborane in T H F solution at room temperature. Under the same conditions, the N-(2-iodoethyl)amides (e.g., IIIc) underwent, hydrogenolysis of the carbon-iodine bond. When t,he reduct'ion react'ion was repeated at approximately 60" for 2 hr, hydrogenolysis again con- stituted the major reaction pathway. By this means amide IIIc was converted in nearly quantitative yield to N-ethylamine IVc. As the N-(2-iodoethyl)benzyl- amines were considered of much less interest than the chloro and bromo derivatives, further effort in this direction mas discontinued.12 All but one of the sub- stances summarized in each of Tables I1 and I11 have nitrogen one carbon removed from the aromatic system. For comparison purposes, synthesis of N-

(9) E. hl . F ry , J. O r p . Chem., 14, 887 (1949). (10) H. C. Brown and P. Heim, J . A m . Chem. Soc., 86, 3566 (1964): Z.

13. Papanastassiou and R. J . Bruni. J . O r @ . Chen., 29, 2870 (1964): and W. V. Curran and R. B. Angier, ibid. , 91, 3867 (1966).

( 1 1 ) G. R. Pet t i t and W. J. Evers, Cnn. J . Chem., 44, 1293 (1966). (12) T h e 2-iodoethylamines should be easily obtainable by treating the

N-2-chloroethylamines with NaI-acetone (c f . ref 4d).

(2-(*hloroethyl)-3,4,5-trimethoxyphenethylamine hy- drochloride, a two-carbon system characteristic of mescaline,4d was included.

Structures assigned each of the amides (Table 11) and the amine hydrohalides (Table 111) were supported by results of infrared spectral analysis and nmr studies. The pmr survey of these substances was carried out as part of another study and experimental results will be reported in a future communication.13 The number of similar compounds available for infrared spectral study led to some observations which can now be recorded. A summary of these results appears in Table IV.

Biological evaluations are being performed under guidance of the Cancer Chemotherapy Kational Service Center, National Institutes of Health, U. S. Public Health Service, and results available at present indi- cate that, in general, the N-(2-haloethyl)benzylamines will be less active than the N-bis(2-haloethy1)benzyl- amines against Walker 256 (subcutaneous) in randomly bred albino rats. Comparison of two of the more promising N-bis(2-chloroethy1)benzylamines prepared in our laboratory, namely, Ia4b and Ic , I4 with the re- spective one-armed derivatives Ib and Id reported here provide support (at present) for such a conclusion. A t a dose of 4.8 mg/kg tertiary amine I a completely inhibited tumor growth while the corresponding second- ary amine I b a t 50 mg/kg led to only about 10% inhibition of tumor growth. Similarly, tertiary amine Ic.HC1 at 50 mg/kg gave approximately 96% inhibi- tion of growth, whereas secondary amine Id.HC1 at the same dose level was ineffectual; raising the dose of amine Id hydrochloride to 100 mg/kg afforded only 15:!& inhibition of growth. Doubling the dose to 200 mg/kg resulted in approximately 17% mortality and, in the survivors, 52y0 inhibition of tumor growth. In each case, the substance was given intraperitoneally in saline solution on the first day of tumor transplant and continued for 5 days. Evaluation of tumor growth was made on the tenth day.

( 1 3 ) The mass spectrum of earh substance was also found consistent with the assigned structurp and for the reason j u s t noted, the rpectra will be dis- cussed in a future contribution.

(14) The chemistry of this substance will be described in a subsequent paper by G. R. Pettit. P. A. Whitehouse. and M. A. Sciaraffa. in preparation.

G. R . PETTIT, S. I<. GUPTA, AXD P. A. WHITKHVI*KE

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July 1967 ANTINEOPLASTIC AGENTS. XVIII 693

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