888 Journal of Medicinal Chemistry, 1371, Vol. 14, 'Yo. 3
NOTI,: s
TABLE I11
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.
SCREEXING RESULTSOF NITROGEN MUSTARDS FROM A ~ I N O P H I ~ N Y L T H I . ~ Z ~ L E ~ . Animald w t diff, N0.b
TestC system
Dose, mg/k
Survivors
g
Tumore wt,g, or survival! days, T I C
- C) -1.0 10.0/9.0 -0.1 8.8/9.0 -0.3 9.3/9.0
Cures ( T
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 7/7 126 100 0 - 0 9 . 0 19/13 7/7 A0 0 - 0 2 . 0 17/15 113 7/7 25 0 106 - 0 2 . 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 3/3 330 0 AA 100 0 3/3 33 0 3/3 3/3 10 0 3 WLI 330 0 616 --5 0 3 9/6 1 63 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. Pathak, J . M e d . Chem., 8, 131 (1965). (2) S . C. Lahiri and B. Pathak, Indian Patent .\pplication 105,586 (June 4, 1966). (3) S . C . Lshiriand B. Pathak, J . Pharm. Sci., 67, 1013 (1968). (4) S . C. Lahiri and N . C. De, 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 and moderate muscle relaxant activities though t h e y do not possess significant antimicrobial activity.
Journal of Medicinal Chenzislry, 1071, 1'01. 14, >Yo. 0 889
NOTES
TABLE I 1-M ETHYL-2-N- (DICARUOX YAMIDO)-j, 6-DIM ETHOX Y l N D A N S ( II A )
AND
l - M l ~ ; T H Y L - 2 - ~ ~ - ( D I A L K Y L A M I N O M E T H Y L ) - 5 , 6 - D I M I ~ ~ T I I O X Y I N D A (11) NS
IIA
Compds
1 2 3 4 5 6
R2
RI
Me Et n-Pr n-Bu
Me
Et n-Pr n-Bu n-Pr n-Bu
H H
Me 7 Me Et Et 8 n-Pr n-Pr 9 n-Bu n-Bu 10 H n-Pr 1! n-Bu 12 H Me 13 n-Pr 14 n-Bu hle Tolbutamide a From EtOAc and EtOH.
163-168 170-174 184-190 193-196 186-192 195-200
(0.60) (0.15) (0.10) (0.10) (0.25) (0.20)
122-126 142-145 165-168 138-142 137-138 135-140 142-146 158-162
(0.80) (1.50) (1.50) (0.10) (0.25) (0.10) (0.40) (0.60)
From EtOAc.
1 1 . 1 Zk 1 . o 2 1 . 4 Z!C 1 . 3 1 7 . 2 31 2 . 9 11 .G + 1.7 14.2 f 2 . 3 13.1 i 3 . 2 1 3 . 3 3= 1 . 7 1.5.6 i 2.X 2 2 . . i Zk 2 . 6 showed correct aiial. foi,C, 11, S .
192-193" 17G- 1 77h 168-170'' 230-232(~ 173-177" 169-170' 167-168' 15G-l.57C
1.5236 1.5183 l..i160 1 ,502.5 1.5142 1,5140 1.5150 1.5120
Crystd from PhH.
H NaHg
C02H 1.
2*3.73= 3 . 8
Experimental Section11
SCHEMI.: I
M e O m c H 3 MeO
3 7 . 1 Zk 3 . 7 :35.0 i 4 . 1
SOCI?
MeO COZH
IIB MeO M e O a c H 3 CONR,R,
H
LAH
I1
IIA
night (1s hr), H?O being allowed ad libitum. After taking venous blood of t8hefast,ing rabbit.s, t,he animals \\-ere given t,he compounds as hydrochlorides in s o h a t 25 mg/l.cg by stomach t,ubc and blood glucose concn \vas observed every hour up to 24 hr. The maximum fall of blood glucose concn was observed betrveen the 9th and 12th hr. The blood gliicosc e~t~imat~ion was carried out, follo\ving the procedure of Hagedorn and Jensen.8 Using a set of G albino rats (180-200 g) and the same dose level, blood sugar lowering of similar magnitude was also observed. Compounds 8, 9, and 14 which showed appreciable activity in normal animals were further tested 011 alloxan-diabetic rats and rabbit^,^^^^ the results are shown in Table I.
l-Methyl-5,6-dimethoxyi~dan-2-carboxylic Acid (IIB).-l!;t.tiyl 2-(3,4-dimethoxyberi~yl)a~~ctoacctates was cyclized with polyphosphoric acid (PPA) at 100" foi, 2 hr with thorough stiri.ing to yield ethyl 3-methyl-S,G-dimethox~iiidcrie-2-carbosylate i r i Xe5f,~; yield. A better yield (927; ) was obtained using coned II,SO, (!%%,; previously cooled to - 10') at, - 5 to 0" for 30-45 miii. The corresponding carboxylic acid w:w ot)tained t)y alkaliiic hydrolysis followed by acidification. The acid was reduced with NaI-!g, crystallized from hot HzO, mp 13:3-134". A n d . (Cj3Hl6O4)C, H . l-Methyl-5,6-dimethoxyindan-2-earbonyl Chloride.--A solii of SOC12 ( 1 . 2 moles) i i i dry PhTT \vas added slowly with slirriiig t,o a siispeiisioii of IIH ( 1 molt) i i i PhII a t room tenip. Tht? resiiltiiig mist' was ht=:ited o i i :I w: hath :Lt 40-50' for :;O r n i i i aiid excess SOCI, was reriiovcd iiiider rediiced prcssiirc. The acid chloride WRJ foiind to he therriiolqbilc : i i d n':is thcircfore i i o t dist d . 1-Methyl-2-.~-dialkylcarboxamido-5,6-dimethoxyindans (IIA).-The criide acid chloridc ( 1 rnolr) \viis added drop\vi.e with coiistaiit stirriiig to :t mist of : L I I appropriate primary o r secondary amiiie ( 1.3 mole>) : t i i d SaOl! solii ( l o f ' ; , 1 mole) cooled i i i ail ice bath. The :imides wcic cstd with Et.0 o r P h l l aiid distd iiiider redwed pressrirc. l-MethyI-2-.~-dialkylaminomethyl-5,6-dimethoxyindans (11) were piepd by the reduct ioii of t h e corrcrpoiidiiig c:trl)osamidc ( 1 mole) with 1,AII ( 1 . 2 moles) i i i dry E t 2 0iiiider iefllis for S-12 hr. The amiiies were isolated aid extd with F X 2 0 a i d distd under rcdriced prersiire. 111sonic c.aws, secwiid:try amiiics were methylated by heating wit.ti a mist vf I!CO.II mid CII& :it 93-100".'* The bases were characterized as their hydrochlorides (Table I).
Acknowledgment.---l'lw:wthow :IW grnt(4ul t o L h . AIax\\.ell Gordoii and I h . ,Joscpli 1,eiii of I3rist.ol 1,uborat,ories, Sjvracuse, S.1'., for t h(>bio1ogic;il evulu:~t.ioii of some of t>hest?compouiids i n hypoglyccmic, antimicrobial and v:iriow otlwr fioldi; of chcmot h(>r:Lpj.. ~
(8) 11. C. Hagedorn and B . N . Jensen, Biochrm. Z.,lS5, 4 6 (1923); 197, 92 (1923). (8) J . J. Pincus, J. J . Iiurwitz, and M . E . Scott, I'roc. S O C .E I ~ B. i d . M e d . , 86, 553 (1951). (10) M . A . Root and J. Ashrnore, Arch. E z p . Pafhol. I'harmakol., 248, 1 1 7 (1964).
(11) IVIiere analyses are intlicate(l only h y symlmls of t h e rlements, analytical results obtained for these rlemcnts uxre vitliin jzO,-!(;G of t i l e theoretical values. .ill melting p o i n t a are corrrctrtl and were determined in Gallenkarnp apparatus. Boiling i J o i I l t S are in corrected (12) J\-. E . Baclirnann, Org. S!,!t., 2.5, 8!, (IQI:),
