Joriinal of Mcdzcinal Chemzstry, 1.970,
r\'OPES
1 j > -\-o. 6
1229
Experimental Section'
T.\DLY; I Oral dose causing 5 0 % reduction in food consumptiona EDja =tS Z I I (mglky) ~
Comyd
1-01.
Compounds 1-34*and S9 were prepared according to piiblished methods. The preparation of 36 was straightforward, except for the hydrolysis of the benzenesulfonylmethylamiiiomethylbenzhydrol with H2SO4, where oxidn to the beiizopheiioiie occurred, requiring an additional step of reduction. Compoiind 37 was prepared by ring cleavage of the substituted tetrahydroisoquinoline with AcsO, a method already employed for cleavage of tetrahj-drocarbolines,'O isoindolines,* and dihydroisobeiizof imns.9 4-Chloro-4'-(methylaminomethyl)benzhydrol(36). 4-Chloro4' aminomethylbenzhydrol.-4 - Chloro - i'-cyaiiobeiizopheiioiie (12.8 g ) was reduced with LAH (THF) (4 g), in the iis.ual way: yield 11.5 g (86%); mp 90" from EtOH-EM-pet ether; hydro-
8.8 & 2 . 3 6.8 f 2.1 4 0 . 0 =t 8 . 4 4.5.0 i 1 4 . 6 54.0 & 8 . 1 .57.0 =t 11.0 11-y ti244c 6 0 . 2 =k 9 . 3 a 24 rats per test. b S E ~= I Standard error of mean. 5-pChloropheiiyl[6,7]beiiz-l~4-diazociiie. See ref 4 and AI. I. Gliickmann, Pharmacologist, 7,146 (196,;).
iimphetaniiiie Feiifluramine I>iethylproprioii Cloforex Phenmetraziiie Compound 9
-
T.\I~LI, I1 Kl
TU.
1 2 :3 4 5 0 7 8 9 10 11 12 13 14 1-i 16 17 18 19 'LO 21 'L2 23 24 25
11
26 27 28 %!I 30 31 32 33 34 33 36 37 Racemate.
H
H
4-CH3 4-OCH3 4-SCH3 4-F
H H H 3-CI H H
H H H 4,6(OCHj)2 H H H
H .XI H
H H H H
H H H H H H 5-CI .XI H H H H See formula See formula See formula Dextrorotatory isomer.
H 2-e1 3-c1 4-C1 4-C1 4-C1 4-C1 4-C1 3-CFj 4-Br 3-CF3 H
H 4-C1 4-C1 4-C1 441 4-C1 4-C1 4-C1 4-CH3 4-C1 4-C1
4-F H H 4-C1 4-C1 4-C1 4-C1
e
R4
R3
R2
H
OH OH
H
OH
H
OH
H
OH
H H H
H
OH OH OH OH OH
H H H
OH
H H
OH
H
OH OH OH OH OH OH OH OH OH OH OH OCOCI OCOCHI OH OH OH CO2CzHj CO~CZHI H OCzHj CHI
H H
OH
H H H H H H H
H CHJ COCl COCHj COzC2Hs COXzHj CO2C2Hj CO?C*H, C 02 C2 H j H H
H
Laevorotatory iaomer.
Only in the last few years have iiolated examples of compounds with different structures become known, which compounds were claimed to have anorexigenic proper tie^.^'^ We wish to report the relationship between structure and anorexigenic activity in a group of substituted aminomethylbenzhydrols, which differ chemically and pharmacologically6 from the typical appetite suppressants. (4) C . K. Cain, Annu Rep. .Wed Chem., 1967, 50 (1968). ( 5 ) E. DeFelice, S. Bronstein, .4. Cohen, Curr. Ther. Res. Clzn. B x p . 11, 256 (1969). (6) J. T. Oliver, t o be published.
chloride, mp 240-215" (EtOH). Anal. (CIIHIICISO.HC1) C, H, C1, X. 4-Chloro-4'- (S-methyl-AV-benzenesulfonylaminomethgl)benzhydro1.-The primary amine described above (8.1 g ) \Tab acylated (7) Melting points mere taken on a Fisher-Jones apparatus and are uncorrected. Microanalyses were performed by Dr. C. DaesslP, Montreal. All analytical samples have nmr spectra in agreement with their structures. Where analyses are indicated only by symbols of t h e elements, analytical results for those elements were within i0.4% of t h e theoretical values. ( 8 ) K . Freter and M.Gotz, Can.J. Chem., in press ( 1 9 T O ) . (9) K. Freter, E. Dubois, a n d .4. Thomas, J. Heterocycl. Chem., 7, 159 (1970). (10) K. Freter, H. H. Hubner, H . M e n . H. D . Schroeder, and I
