Alkylating Agents Derived from Indole. Synthesis of ... - ACS Publications

In a previous communication2 the preparation of the j-nitrogen mustard of DL-tryptophan was described. The interesting antitumor activity of this comp...
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ALKYLATING AGEXTSDERIVED FROM INDOLE. 1V

March, 1964

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Alkylating Agents Derived from Indole. IV. Synthesis of the 5-Nitrogen Mustard of Indole-3-carboxylic Acid'" JOSEPH DEGRAWA N D LEOXGOOD&fAX'h Life Sciences Research, Stanford Research Institute, X e n l o Park, Calzfornia Received October 4, 1963 The preparation of 5-[bis(2-chloroethyl)amino]indole-3-carboxylicacid (XIII) is described. A comparison of the antitumor activity of XIII with some related 5-bis( 2-chloroethy1)amino derivatives of indole is also presented.

I n a previous communication2 the preparation of the j-nitrogen mustard of DL-tryptophan was described. The interesting antitumor activity of this compound stimulated the synthesis of the 5-nitrogen mustards of indole-3-acetic and propionic acids. As a continuation of this series, the preparation of the 5-nitrogen mustard of indole-3-carboxylic acid (XIII) is described in this manuscript. For the synthesis of XIII, utilization of the general method for preparing the indolealkanoic acid mustards3 required a practical preparation of 5-nitroindolecarboxylic acid (V). Treatment of 5-nitroindole (I) with phosphoryl chloride in IT,?;-dimethylformamide afforded the 3-aldehyde (11) in 97y0 yielde4 Efforts to oxidize I1 directly to the acid (V) were unsuccessful and a three-step process was employed for the conversion of I1 to V. The aldehyde (11) was converted to the oxime (111) which was dehydrated with thionyl chloride to afford the nitrile (IV). Hydrolysis of IV with strong alkali gave the acid (V) .5 The ketone (TI), prepared by stannic chloride mediated acetylation of I, 5-OzNR

+5-02NRCHO +5-0zNRCH=NOH +

I

I1

5-0zNRCX

V

+

VI1

5-HzNRCOzCzHs +~ - ( H O C H ~ C H ~ ) Z N R C O+ ~C~H~

IX

I

17111

TABLEI ACTIVITYO F INDOLE 5-SITROCEN 51lJSTARDS"**

( C I C H , C K ~ ; K ~ ~ R H R

COzH COzCzHs

LDio (mg./kg./dayY

13 . O 25 0

MED (rng./kg./dayId

T. 1.8

3 4.3 6 CH~CO~H' i.1 1.5 5 CH~CH~CO~H~ 3.8 0.15 25 CHzCH(NH2)COzHg 1.2 0 31 4 a The observations are for the Walker 256 (subcutaneous) tumor in rats. The drugs were administered intraperitoneally following the standard Cancer Chemotherapy Sational Service Center protocol, Cancer Chemotherapy Rept., 25, 11 (1962). We are indebted to Miss Ann Morris Smith, Southern Research Institute, Birmingham, Alabama for many of these testing results. The LD,, is that dose that kills more than 10% of the The minimum animals and is the maximum tolerated dose. effective dose ( M E D ) is that dose which gives a ratio of tumor weight in treated animals to tumor weight in control animals of 0.10. e The therapeutic index (T. I.) is defined as LD,,/MED. 'See ref. 3. 0 See ref. 2. 4 i

I11

+5-02SRC02H -5-02NRCOzCzHs

IV

hTITUMOR

[ I

5 4 H O C H $ ~ H & ~ R C O Z C H ~ C ,-+H~ X

.1

5-( ClCHzCHz),SRCO&HzC,H,

XI1

.1

5-( ClCHjCH,) 2NRCO?C2Hr

XT

5-NOzRCOCHa

5-( ClCHzCH2)zNRCOzH

571

XI11

K=

mH

was considered as an alternative source of V, but hypochlorite oxidation of VI was unsuccessful. The acid (1) (a) This work was carried o u t under t h e auspices of t h e Cancer Cheniotherapy National Service Center, National Cancer Institute, National Institutes of Health, Public Health Service. Contract N o . SA-43-ph1892. T h e opinions expressed in this paper are those of t h e authors a n d not necessarily those of t h e Cancer Chemotherapy National Service Center. (b) Reprint requests should be addressed t o this a u t h o r . (2) J. DeGraw a n d L. Goodman, J. O r g . Chem.. 27, 1395 (1962). (3) J. DeGraw a n d L. Goodman, ibid., 27, 1728 (1962). (4) J. DeGraw and L. Goodman, J . .Wed. Chem., In press. ( 5 ) Subsequent t o this work a much niore efficient preparation of V from I was described: hl. hlelzer, J. Oro. Chem.. 27, 496 (1962).

(V) was readily decarboxylated by boiling hydrochloric acid yielding, apparently, a polymeric form of 5-nitroindole. The ester (VII) was prepared from V with ethanol under acid catalysis and was converted to the amino ester (VIII) by catalytic hydrogenation. The reaction of VI11 with ethylene oxide in ethanol gave the bis(Zhydroxyethy1)amine (IX) as a crystalline solid that, with methanesulfonyl chloride in afforded the mustard ester (XI). All attempts to convert XI to XI11 with hot, concentrated hydrochloric acid led to decarboxylation. An alternative, and successful, route to XI11 was available by first transesterifying IX with sodium benzyloxide in benzyl alcohol to give a rather low yield of the ester (X). Chlorination using methanesulfonyl chloride converted X to XII, and hydrogenolysis of the benzyl ester over platinum oxide in acidic tetrahydrofuran afforded the desired mustard acid (XIII). A comparison of the antitumor activity of XI11 with a number of related indole mustards is presented in Table I. These data indicate the superiority of the propionic acid mustard in this series. It would be of interest to prepare and test 5- [bis(2-chloroethyl)amino]indole-3-butyric acid, since in an analogous series of p - [bis(2-~hloroethyl)amino]phenylalkanoic acids tested against the Walker tumor, the

1Iarch. 1064

FLUORINATED POTESTIAL AXTICASCER AGEKTS. I1

was recrystallized from 5 nil. of benzene to give 1.14 g. (27%) of product, m.p. 131-136". An analytical sample, m.p. 137-138.5", was obtained similarly. -4naZ. Calcd. for C20H20C12X202: C, 61.5; H, 5.17; N, 7.17; C1, 18.2. Found: C, 61.8; H, 5.40; N,6.95; C1,17.8. 5- [Bis(2-chloroethyl)amino]indole-3-carboxylic Acid (XIII).To a solution of 300 mg. of the benzyl ester (XII) in 10 ml. of tetrahydrofuran was added 0.1 ml. of concentrated hydrochloric acid and 50 mg. of platinum oxide. The mixture was stirred under an atmosphere of hydrogen a t room temperature, consuming the theoretical amount of gas during 35 min. The product, n hich had crystallized from solution as its hydrochloride, u as collected along with the catalyst. The mixture was stirred in a solution of 5 nil. of water and 5 ml. of ethyl acetate, followed by

215

removal of the catalyst by filtration. The ethyl acetate extract was evaporated to dryness in vacuo to leave 200 mg. (87%) of a sirup which crystallized when stirred with 2 ml. of water. The white crystals were collected, washed with water, and dried. Recrystallization of this material from 507, ethyl acetate-Skellysolve B afforded 93 mg. (40%), m.p. 180-152". Another recrystallization gave an analytical sample, m.p. 151.5-152.5". AnaE. Calcd. for C13H14C12NL@2: CI, 51.8; H, 4.68; S , 9.30; C1, 23.55. Found: C, 51.9; H, 5.21; N, 9.07; CI, 23.16.

Acknowledgments.-The authors wish to thank Dr. Peter Lim for interpretatioii of the infrared spectra and hlr. 0. P. C r e w and staff for the large-scale preparation of certain intermediates.

Fluorine-Containing Potential Anticancer Agents. 11.'" Syntheses of Some Trifluoromethylpurines and Trifluoromethyltliiazolopyrimidines'b HIDEOSAGANO, SHOJIINOUE, AXDREWJ. SAGGIOMO, AXD EDWARD -4.SOD IFF'^ The Research Institute of Temple Cniversit,y, Phzladelphia, Pennsylaania 19144 Received October 4, 1962 As part of a search for improved cancer chemotherapeutic agents, various trifluoromethylpyrimidines were prepared and cyclized by standard techniques to the corresponding trifluoromethyl analogs of purine and thiazolopyrimidine. The compounds were evaluated in the routine three-tumor mouse screen of the Cancer Chemotherapy Xational Service Center. All were ineffective as tumor inhibitors.

Paper 1'" of this series described the synthesis of varautoclave with ethanolic ammonia. The 2-chloroious trifluoromethylpyrimidiiies as the first stage in a purines (XV-XT'II) were converted with potassium program for the preparation of potential antimetabhydrogen sulfide in methanol to the 2-mercapto derivatives (XXI). These were difficult to purify. They olites. This program has now been extended to include were therefore treated with ethyl bromide and ethanolic trifluoromethyl analogs of purines and thiazolopyrimipotassium hydroxide, and isolated as the ethyl derivadines. The syntheses of 5-amino-4,6-dichloro-2-trifluorotives (XXII-XXIT') . methylpyrimidine (XXV) and 5-amino-2,4-dichloro-6The reaction of ethanolic ammonia with XXI' and trifluoromethylpyrimidine (XXVI) were reported preXXT'I gave the corresponding 4,5-diaminopyrimidines viously. These intermediates have been converted to (XXXI and XXT'II). I n Scheme B, cyclization of various purines in the standard preparative sequence XXVlI and XXXI, using method A, produced 2shown in Schemes A and B. chloro-6-trifluoromethylpurine (XXVIII) and 6-chloroRefluxing XXV and XXT'I in methanol with var2-trifluoromethylpurine (XXXIV), respectively. When ious alkylamines provided the corresponding 4-alkylcyclization of XXTTI was carried out with trifluoroaminopyriniidines (I-IT' and XI-XIT') . Ring closure acetic anhydride in trifluoroacetic acid the product was of the 4-alkylaminopyrimidines to the 2- and 6-tri2-chloro-6,8-bis(trifluorometliyl)purine(XXIX). and XV-XT'II) was fluoromethylpuriiies (T'-T?I Thiourea and the chloropurine (XXXIT') provided effected by heating either with a mixture of ethyl ortho6-mercapto-2-trifluoromethylpurine (XXXI') . Conformate and acetic anhydride (method A), with 97% densation of XXXIV with ethylamine, butylamine, formic acid (method B), or with pure ethyl orthoaniline, and benzylamine gave the corresponding alkylformate (method C). amino derivatives (XXXT'I-XXXIX) . Method A, applied to the 2-trifluoromethyl series Various trifluoromethyl[5,4-d]thiazolopyrimidines gave the .~-acetamido-6-chloro-4-alkylamino-2-trifluorowere prepared as outlined in Scheme C. methylpyrimidines as side products. With method B, 2,4-Dichloro->-nitro-6-trifluoromethylpyrimidin e the side products were the corresponding >-formamidowas converted via XXT'I to 5-aniino-2-chloro(XL) pyrimidines. KO side product was isolated when using 4-mercapto-6-trifluoroniethylpyrimidine (XLI) as method C 011 the 2-trifluoroniethyl compounds or when described previously.'" Ring closure of X L I to using any of the methods on the 6-trifluoromethyl series. form 5-chloro-7-trifluoromethylthiazolo [5,4-d]pyrimiX o attempt was made to cyclize the butylamino pydine (XLII) was brought about by heating with ethyl rimidines (111and XIII). orthoformate. The conversion of b-amino-6-chlor0-4The 2- and 6-aminopurines (VIII-X and XI'IIImercapto-2-trifluoromethylpyriniidiiie (XLVI)" to 7XX) were obtained b y heating the chloropurines in an chloro-5-trifluoromethyl t h i a z o lo [ ci,4-d ] p y r i m i d i n e (XLVII) was carried out in the same fashion. Reac( 1 ) (a) Paper I of this series: S. Inoue, 1.J. Saggiomo, a n d E. A . Nodiff, tion of X L with 1 mole of potassium thiocyanate in J . O r g . Chsm., 2 6 , 4504 (1961): (b) this investigation was supported by Kesearch ( ; r a n t CP-4270, from the National Cancer Institute, National Inacetic acid afforded the 4-thiocyano derivative (XLIII). stitutes of Health, L-. P. Public Health Service; ( c ) to a h o i n inquiries Treatment of XLIII with aniline then gave the 2should be addressed.