Journal of Medicinal Chemistry, 1971, Vol. 14, S o . 9 887
NOTES upon attempted recrystn of the salt from ?vleOH. The gum afforded 8.8 g (40%) of 2.2HC1.21IeOH as cryst from CHC13E t 2 0 ;mp 183-185'; nmr (D20) 6 6.85 (symm 6 line m, 2 H, C&), 4.0-2.5 (m, 18 H, PhCH2CH2, PhCH, CH2NCH2, NCH,, 2CH30), and 2.5-1.3 ppm (m, 7 H, CH&H(CHt)CHs). Anal. (CzoH3dXN,O,) C, H, N.
TABLE I 4- { ~-[L~,~V-BIS(~-HYDROXYETHYL)AMINO] PHEXYL) THIAZOLES I-\
NO.
Potential A.nticancer Agents. Nitrogen Mustards of Aminophenylthiazoles J. D. 1 1 0 ~ 1 , l SS. . S a u ~ r s A, N D C. V. DELIWALL* Department of Chemotherapy, Haffkine Institute, Bombay 12, India Received March 5, 1971
R e have already reported the synthesis of a variety of Schiff bases (I) from substituted benzaldehyde Nmustards and 4-(p-aminophenyl)thiazolesz~3 many of which have shown interesting activity against experimental tumor systems. (CICH~CH,~+J-CH=N-(+-~
R1
R2
R
R
Y ~ e l d , " ' ~ M p , "C 5% (uncor)
FormulaC
CH3 55 132-134 CiaHiJV201Sd C6HjCH2 48127-128 C>oHxN?OiS CsHjOCH, 57 138-139 C2oH22N203S p-CHsCeHaOCH2 53 128-129 C2iH2aNiOaS O - C H ~ C G H ~ O C H32 ~ 158-160 CiiH24N203S CsHj 50 8,;-87 CiiH2oN202S p-CHsC& 52 129-130 C2aH22N202Sd p-CHaOCsHa 50 120-122 C~OHZZN~O~S p-ClCsHa 55 151-133 CiqHisClN202S a The yields reported are the results of single experiment and are based on w-chloro-4-[,\~,.~-bis(2-hydroxyethyl)amino]acetophenone. Recrystd from EtOH-H20. All compds were anal. for K,S and were within 0.47, of theor values. Anal. C, H. 1 2 3 4 3 6 7 8 9
The identity of compds prepared by both the methods was established by mmp and ir spectra. The corresponding N-mustards (11,X = C1) were obtained by the use of Poc134in 30-35% yields (Table 11). TABLE I1 4-p- { [~\~,S-BIS(2-CHLOROF,THYL).~RIINO]PHENYL } THI.IZOLI:S
I
OlpR
( X CH2CH2),N
With R = CHgOPh, R1 = H, and RP = OCH,. the Schiff base I was active against Dunning leukemia (solid) (6/6 cures a t 11 mg/lig per day), L 1210 lymphoid leukemia ( T I C = 146% a t 15 mg/kg per day), and Walker 256 intramuscular ( T / C = 4% a t 32 mg/kg per day).3 With R = CHPPh, R 1 = CH3, and RP = OCH3, I had good activity against L 1210 lymphoid leukemia and Walker carcinosarcoma 256 (im) The most active in this series (I) against L 1210 lymphoid leukemia ( 2 out of 6 cures at 25 mg/lig per day and T / C = 129% a t 3 mg/kg per day) had R = R1 = CH3 and R,= OCH,. The structure-activity study of these compounds having shown the importance of aminophenylthiazoles for the anticancer activity, we decided to synthesize a series of N-mustards (11, X = C1) from these active aminophenylthiazoles. Chemistry.-4- { p- [N,N-bis(2-hydroxyethy1)aminolphenyl {-2-substituted thiazoles (11, X = OH) were prepared by suspending the requisite aminophenylthiazole in aq AcOH and treating with ethylene oxide (yields 45-35Yc). But we could not isolate the desired product when the substituent in position 2 of the thiazole was Ph. Accordingly, another method was tried wherein a suspension of w-chloro-p-aminoacetophenone in aq AcOH was treated nith (CH2)PO to furnish the corresponding bis(2-hydroxyethyl) compd in 55yo yield which on condensation with the appropriate thioamide in dry E t O H afforded all the bis(2-hydroxyethy1)thiazoles (11, X = OH) as cryst solids (Table I).
.,
(1) Government of I n d i a Research Scholar. (2) S S Sahnis, I n d i a n J . Chem , 6 , 619 (1967) (3) J D. Modi, S S.Sahnis, and C V Delimala, J M e d Ckem (1970).
R Mp, o c a Formulab CHI 72-74 CirHd&N2Sc 110-112 C2oHIoC12KS C6HjCH2 CsH,OCHz 123-123 CloH2oC12S2OS p-CH3C6HaOCHz 112-114 CiiH22Cl&iOS t5 O - C H ~ C ~ H ~ O C H ~107-109 C2iH22CLN2OS 6 CgHj 68-69 CigHi,CI2S2S 7 p-CHsC6Ha 108-110 CioHioCIiN2S 8 p-CHaOCsH, 105-107 C2oHioClaN2OS 9 p-ClCGH, 138-139 C~OH,,CI,NIS a Recrystd from EtOH-H20 except 6 which was recrystd from hexane. All compounds were anal. for S and S and were within 0.4% of theor values. e Anal. C, H. NO.
I1
, 13, 935
1 2 3 4
Biological Activity.-Four representative compds were screened by C.C.N.S.C. and their data are summarized in Table 111. All these showed a low order of toxicity compared to our earlier Schiff bases from aminophenylthiazoles. Only 1 exhibited significant activity against Dunning leukemia (solid) and also showed high tumor inhibition in Jl'allier carcinosarcoma 256 (im). Experimental Section586 2-Methyl-4- { p - [S,AY;-bis(2-hydroxyethyl)amino] phenyl}thiazole.-Ethylene oxide (20 g ) was bubbled in a suspension of 2-methyl-4-(p-aminopheiiyl)thiazole (1.9 g, 0.01 mole) in AcOH (50 ml of 4 LY) at 0'. The mixt was stirred in ice bath for 7 hr and then left at ca. 10' for 4 days. I t was neutralized (NaHCO3) t o pH 7 and cooled (ice). The granular solid was filtered off, washed (H*O),and recrystd (EtOH-H20). 2-Phenyl-4- ( p - [S,S-bis(2-hydroxyethyl)amino]phenyl ) thiazole.-w-Chloro-4- [S,.V-bis(2-hydroxyethyl) amino] acetophenone was obtained by the action of (CHa)*O on w-chlorop-aminoacetophenone in 4 aV AcOH as described above. It was
-
(4) W.C. J. Ross, J . Chem. &x.,183 (1949). (5) Anal. results obtained were within ~ k O . 4 7of~ tlieor values (6) Melting points are capillary melting points and are uncor.
888 Journal of Medicinal Chemistry, 1371, Vol. 14, 'Yo. 3
NOTI,: s
TABLE I11 SCREEXING RESULTSOF NITROGEN MUSTARDS FROM A ~ I N O P H I ~ N Y L T H I . ~ Z ~ L E ~ .
N0.b
TestC system
Dose, mg/k
Animald w t diff,
wt,g, or
g
survival!
Survivors
Tumore
- C) d a y s , T I C - 1 . 0 10.0/9.0 -0.1 8.8/9.0 -0.3 9.3/9.0
Cures ( T
facilities to carry out the present work. One of the authors (J. D. 31.) wishes to thank the X n i s t r y of Education, Government of India, for the anard of a fellowship.
T/C,
R
400 0 4 /4 111 200 0 97 4 /4 100 0 105 4 /4 100 0 AA 3/3 33 0 3/3 10 0 3/3 3 0 3/3 DL 200 0 3 -22.0 27 7/15 0 184 7/7 100 0 - 0 9 . 0 19/13 126 7/7 A0 0 -02.0 17/15 113 7/7 25 0 106 -02.0 16/1.5 7/7 3 WhI 400 0 0 .i/3 8 13 -10.0 6/6 2 3LE 400 0 93 1 . 3 8 8/9 4 6/6 92 0 . 7 8 7/9 4 200 0 616 93 1 . 2 8 8/9 4 100 0 6/6 3/3 AA 330 0 100 0 3/3 33 0 3/3 3/3 10 0 3 WLI 330 0 --5 0 3 9/6 1 63 616 3 3LE 400 0 8 3/9 1 91 0 9 4 /4 200 0 -0 4 8 8/9 1 96 4 /4 9 3/9 1 102 100 0 -1 0 4 /4 AA 330 0 313 100 0 3/3 33 0 3/3 10 0 3/3 5 W M 330 0 47 616 1.0 3.5/7.3 3 3LE 400 0 -1.8 8.8/8.4 104 4 /4 9.5/8.4 113 -1.3 200 0 414 0 . 7 8 . 5 / 8 . 4 101 100 0 4/4 a For test procedures see Cancer Chemother. Rep., 25, 1 (1962). * ?;umbers refer to those from Table 11. AA = toxicity; 3 LE = L 1210 lymphoid leukemia; 5 W M = Walker 256 (im); DL = Dunning leukemia (solid). Av wt change of test group minus av wt change of control animals in grams; T = test; C = control. e Tumor wt for 5 WM test system. f Survival days for 3 LE and DL test systems. 1
3LE
Synthesis and Pharmacology of Some Dimethoxy- Substituted Indanamines as Potential Hypoglycemic Agents.
l-Methyl-2-N-(dialkylaminomethyl)5,6-dimethoxyindans SihlIR
CH\h.DR\ L i H I R I *
ihD
B\L\I
Pl'rH\h
Department of Pharmacy, Jadazpiir Vniverszty, Calczctta-32, India, and Department of Applied Chernistrzj, Cntzerszty College of Sczencc and TcchnologU, Calcutta-9, Indaa Receicecl October 12, 1970
I n vieir of reported significant oral hypoglycemic activity among hexahydroindeno [ 1,2-c]pyrroles (I) and their hypothetical degradation products, indanamines, a large number of such coinpoundz were iynthesized and screened for oral hypoglycemic activity as reported Thii paper is concerned with the 5ynthesis of some dimet hoxy-5ubztituted indanamines along with the salient features of their biological activities. These conipounds may be considered to have originated by the fission along the dotted lines in the indeno [1,2-c]pyrrole structure and subsequent alkylation a t the generated basic center.
I
I1
Chemistry.-Et hy1 2-(3,4-dirnethoxybenzyl)acetoacetate5 was cyclized n-ith polyphosphoric acid t o ethyl 3-methyl-5,6-dimethoxyindene-2-carboxylatein 85% yields6 The corresponding carboxylic acid was reduced recrystd (CSI-IS),yield s55yL,llmp 121 '. Anal. (C,tH&lN03) with KaHg and converted t o the acid chloride; t,his C, H, K . was treated with appropriate primary or secondary A mixt of this halo ketone (2.57 g, 0.01 mole), thiobenzamide amines t'o yield amides. The amides were converted (1.5 g, 0.011 mole), and abs EtOH (1.5 ml) was heated a t reflux t'g t'he desired amines by LAH reduction. The overall temp for 3 hr. The solvent was removed under reduced pressure, and the residue was dissolved in H20 and decolorized. The reaction sequence is outlined in Scheme I. filtrate on basifying ( N H 4 0 H )gave the required thiazole which All compounds reported in Table I were prepared was recrystd (EtOH-HZO). They All the 4-( p-[N,N-bis(2-hydroxyethyl)amino]phenyl]-2-sub- by a method similar to that described were first screened for hypoglycemic activity.' Blood stituted thiazoles were prepared similarly. 2-Phenyl-4- ( p - [N,N-bis(2-chloroethyl)amino]phenyl] glucose determinations were made at different intervals thiazole.-To a suspension of 2-phenyl-4-{ p- [N,N-bis(2-hydroxyup t,o 24 hr after dosing, using tolbutamide as reference ethyl)amino]phenyl]thiazole (1.7 g, 0.005 mole) in CsHa (15 ml) standard. Compounds 8, 9, and 14 showed appreciable was added POC1, (2.3 g, 0.015 mole). The mixt was heated genthypoglycemic activity in both normal- and alloxanly a t reflux temp for 1 hr. The dark red soln was cooled, and the diabetic animals. solvent was removed i n uucuo. The oily residue was poured onto ice and left overnight, neutralized (NaHC03),and extd (EtlO). Pharmacology.-Groups of 8 normal, healt,hy, male The Et20 exts were washed (H20)and dried (NaZS04),and the rabbits, weighing 1.5-2.0 kg \\-ere used for screening solvent was removed. Residue crystd (hexane) gave t'he desired hypoglycemic activit,y. The animals were fasted overN-must ard. Acknowledgment.-The authors are greatly indebted to Dr. H. B. Wood, Chief, Drug Development Branch, Cancer Chemotherapy National Service Center, for his cooperation and for malting the screening data available, and to A h , A I . T. Jaoltar for microanalyses. They are grateful to Dr. N. IC. Dutta, Director, Haffkine Institute, Bombay, for providing
(1) S . C . Lahiri and 13. P a t h a k , J . M e d . Chem., 8, 131 (1965). (2) S . C. Lahiri a n d B. P a t h a k , Indian P a t e n t .\pplication 105,586 ( J u n e 4, 1966). (3) S . C . L s h i r i a n d B. P a t h a k , J . Pharm. Sci., 67, 1013 (1968). (4) S . C. Lahiri a n d N . C. D e , J . .Wed. Chem., 11, 900 (1968). (5) J . Koo, J . A7ner. Chem. Soc., 76, 2000 (1953). (6) J . KOO,ihid.. 76, 1891 (1953). (7) Some of these compounds XISO exhibited appreciable hypotensive a n d moderate muscle relaxant activities though t h e y do not possess significant antimicrobial activity.
