182 Journal ofMedicina1 Chemistry, 1975, Vol. 18, No. 2
bold, J . Org. Chem., 32, 2180 (1967);(b) P.Aeberli and W. J. Houlihan, ibid., 34, 165 (1969). ( 6 ) P . Aeberli, G. Cooke, W. J. Houlihan. and W. G. Salmond. J Org Chem., inpress. ( 7 ) P. Aerberli, M. Eberle, and W. J . Houlihan, unpublished results, 18) J . S.McKechnic and I. C . Paul, J . Chem. Soc. B, 984 (1968). 19) J . H. Gogerty, C. Penberthy, L. C . Iorio, and J. H. Trapold, J . Pharmacol. Exp. Ther., in press. (10) L. 0 . Randall, W. Schaller, G. A. Heise, E. F. Keith. and R. E . Bagdon, J . Pharmacol. Exp. Ther., 129, 163 (1960). (11) C . R. Ferster and B. R. Skinner, “Variable Ratio in
Houlihan, et a i . Schedues of Reinforcement,” Appleton-Century-Croft, New York, N.Y., 1957,pp 391-414. (12) M. Phillips, J . Amer. Chem. Soc., 49,473 (192;). (13),J. Kaisen, Justus Liebigs Ann. Chern., 257,95(1890). (14) V. Weinmayr, J . Amer. Chem. Soc., 74,4353(1952). (18) M .S.Newman, J . Amer. Chem. SOC.,78, 5004 (1956). (16) J. G . Topliss, L. M . Konzelman. N. Sperker, and F. E . Roth, J . Med. Chem., 7,453(1964). (17)P.Kovacic and C. Wu, J . Org. Chem., 26,762(1961j . (18) D.Peltier, C. X.Acad. Sei., 236, 1972 (1953). (19)F. H.Pinkerton and S. F. Thames, J , Organometui. Chem , 24,623(19701.
Anorectic Agents. 2 . Structural Analogs of 5-(p-Chlorophenyl)-2,3-dihydro-5H-imidazo[2,l-a]isoindol-5-ol Paul Aeberli, Phillip Eden, John H. Gogerty, William J. Houlihan,* and Chris Penberthy Re.\mrch and Development Department, Sandoz Pharmaceuticals, East Hanover, ?\iewJerse? 07936 Received August 23, 1971 h variety of structural modifications of the anorectic agent 5-p-chlorophenyl-2,3-dihydro-5H-imidazo[2,l-a]isoindol-
5-01 ( l a ) was prepared and evaluated for anorectic activity. All of the modifications resulted in complete or considerable loss of activity relative to la. Scheme I1 In the preceding paper1 from our laboratories it was reported that 5-aryl-2,3-dihydro-5H-imidazo[2,l-u]isoindol5-01s ( 1 ) represent a novel class of anorectic agents. From this group of substances the p-chlorophenyl analog l a (mazindol, Sanorex) was found to be an effective and potent appetite suppressant in humans.2 In an attempt to determine some of the structural features that are needed for anorectic activity in 1 we have prepared a series of compounds where ring A has been modified by (a) the introduction of a second double bond (3), (b) enlargement to a six- (8) and seven- (9) membered ring, and (c) an additional ring fused a t the 2,3 position (12). Two additional modifications, 14b and 15b, where the C&5n bond in 1 was opened and the aroyl group in 3 transferred to the imidazole N atom were also prepared and evaluated for anorectic activity. Chemistry. The synthesis of the compounds needed for this study is described below. Treatment of 1 with refluxing acetic acid resulted in the expected dehydrations to the 5-aryl-5H-imidazo[2,l-a]isoindoles 2. Conversion of 2 to its sodium salt by sodium hydride in DMF followed by oxygenation4 resulted in the
0 5. n = 3 6,n=3
c
Scheme I
I
8or9 1
H‘
2 10
3
4
formation of the 2-(2-imidazol-2-yl)benzophenones 3 rather than the tautomeric 5-aryl-5H-imidazo[2,l-u]isoindol5-01s 4 (Scheme I). The structure of 3a and 3b was confirmed by ir, nmr, and the presence of a characteristic benzophenone uv maximum5 at 258 and 260 mp, respectively (Table I). The condensation of a 2-aroylbenzoic acid with 1,3-d1
Journal of Medicinal Chemistry,1975, Vol. 18, No. 2 183
Table 11. Anorexic Activity in Rats
Table I. Ultraviolet Spectral Dataa Maxima, m p (E) No.
95% EtOH
3a
258 (23,000)
3b
260 (18,500)
8a
238 270 225 275
(13,195) s h (4,465) (26,485) s h (5,300)
230 270 282 225 271 226 269
s h (21,580) s h (4,890) (2,655) (18,500) (4,700) (25,500) s h (4,700)
8b ac 9a
9b 12a
227 (15,700) 269 (4,880) 276 (4,760)
Food consumption, ‘3& controls“
95% EtOH-HC1 241 266 243 265 240 268 226 243 273 234 268 282 229 273 228 241 270 223 266
(14,730) (18,900) (16,500) (14,300) (14,625) (4,265) (22,050) sh (14,000) s h (4,800) (16,800) (4,200) (1,800) (16,200) (4,400) (21,900) s h (11,000) s h (4,100) (12,800) (13,500)
mg/kg
LD50,
No.
R
poa
1 hr
4 hr
mg/kg pon
la lb 3a 3b
4’-C1 3’, 4’-C12 4’41 3’,4‘-C&
13.0 32.2
H
38.5 58.7 91.8 100.3 100.5 112.8
> 400
Ea
25 25 50 50 25 25 25 25 25 25 50 25
8b ac 9a 9b 9c 12a 12b 14a 14b 15a 15b
4’-C1 3 ‘,4’-c 12
H 4’-C1 3 ’,4’-C 12 4’-C1 3 ’,4 ‘-C 12
50 50 50 50
82.9 85.7 102.2 88.5 63.7 68.7 80.8 99.3 64.8 91.1
122.9 124.3 66.9 79.5 65.0 100.0 97.3 78.8 95.4
353 600 > 400
> 400 305
>400 400 400 > 400
> >
“See pharmacology testing in the Experimental Section for details.
aSee Experimental Section for details.
Experimental Section aminopropane or 1,4-diaminobutane in refluxing xylene Chemical Synthesis. Melting points were determined in a gave the 10b-aryl-1,3,4,lOb-tetrahydropyrimido[2,l-a]i- Thomas-Hoover capillary melting point apparatus and have not soindol-6(2H)-ones 56 and the llb-aryl-1,2,3,4,5,1lb-hex- been corrected. For all compounds listed in Table III pmr spectra were obtained on a Varian Associates A-60 spectrometer in CDC13 ahydro-7H-[1,3]-diazepino[2,1-a]isoindol-7-ones 6,e respecor DMSO-de and ir spectra (KBr) were determined using a Pertively (Scheme 11). Following the procedure1 used to prekin-Elmer Infracord. In all cases the spectra were consistent with pare 1 compounds 5 and 6 were treated with LiAlHa in the assigned structure. The uv spectra for a selected group of THF to give the labile alcohols 7. A solution of these comcompounds (Table I) were obtained in 95% EtOH or 95% EtOH-2 pounds in THF-MeOH was treated with a stream of air N HCl (9:l) solvent on a Cary Model 15 spectrophotometer. ( 0 2 ) to give the 6-aryl-2,3,4,6-tetrahydropyrimido[2,l-a]i-Thin-layer chromatography (tlc) were carried out on compounds soindol-6-ols7 and the 7-aryl-2,3,4,5-tetrahydro-7H-diazepScheme I11 ino[2,1-a]isoindol-7-ols~~~ (Scheme 11). The structures of 8 and 9 were established by ir, nmr, and uv in 95% EtOH (Table I). The uv spectra of 8 and 9 in 95% EtOH-HCl (Table I) are very similar to those in 95% EtOH indicat1. LiAIH,, ing that these compounds have little tendency to form the protonated benzophenone tautomer 10 ( n = 3 or 4). In contrast, compounds 1 have been shown1 to exist as the protonated benzophenone tautomer 10 (n = 2) in the same solvent. 12 11 Following the same procedure given in Scheme I1 the trans-4b-aryl-4b,5,5a,6,7,8,9,9a-octahydro-llH-isoindolo[2,1-a]benzimidazol-ll-ones 11 were converted to the trans11-aryl -5a, 6,7,8,9,9a-hexahydro-llH-isoindolo[2,l-a]benzimidazol-11-01s 12 (Scheme 111). Inspection of the uv spectrum of 12a (R = H) in 95% EtOH and 95% EtOH-HCl (Table I) revealed that this compound also did not form the protonated benzophenone tautomer 13 in any significant amount. Compounds 14 and 15 were prepared from 2-phenylimidazole or 2-phenylimidazoline and the requisite benzyl or 13 aroyl halide in refluxing THF. Pharmacology. The anorexic activity in rats, as deterX X mined by the free-feeding method of Randal1,g is given in Table 11. In comparison with the standard 5-aryl-2,3-dihydro-5H-imidazo[2,1-a]isoindol-5-ols la and lb all the modifications listed above resulted in complete or considerable loss of activity at the doses used for testing. These findings suggest that any modification of ring A 14a, X = H2 15a, X = H2 or disruption of the C5-Csa bond in 1 would lead to substances with weak or no anorectic activity. b, X = O b, X = O
OR
qR
184 Journal offvfedicinal Chemistry, 1975, Vol. 18, No. 2
Houlkhan.
P t UI
Table 111. Physical Properties
xo
MP, "C (rec ry stn
.
R
solvent)"
Procedure, L weld
L m p 1 r 1c a 1 for mu 1a --
2a 2b
3a 3bd 5a 5b 5c 6a 6b
6c 8a 8b 8c 9a 9b
9c 1l a llb 12a 12b
14ad 14b 15a 15b
4'-C1 3', 4'-C1, 4'-C1 J ' , 4'-C1,
H 4'-C1 3', 4'-C1, H 4'-C1 3', 4'-C1, H 4'-C1 3', 4'-C1, H 4'-C1 3', 4'-C12 4'-C1 3', 4'4212 4'-C1 3, 4'-Clb
107-108 (A) 112-114 (B) 175-176 (C) 291-293 (C) 181-183 (D)' 152-154 (D) 188-190 (D) 180-182 (A)' 138-140 (D, 193-195 (E) 228-230 ( F I R 254-255 (G) 245-248 (H) 224-226 (I)h 241-243 (J) 246-247 (K) 183-185 (A) 181-183 @) 189-192 (H) 227-230 (H) 218-220 (N) 109-111 (0) 90-92 (A) 149-151 (P)
A, A, B, B, C, C. C,
85 65 74
C. C, D, D, D, D, D, D,
65
c,
c, C, D, D, E, E, E, E,
70 87 70 65 75 28 47 45 25 29 29 35 35 45 15 25 63 71 78 73
-
ilnalysei
__
___--
___I_
C HI C l C HIOCl C , H.,ClN,O C,H,,Cl N 0 C H,SO c' I f , C1N-O c HI,Cl& 0
C. H, C!, h e . M, C I h c , 5 , CI.'\
C H Clh 0 C , H,C1,N:O c, H, N,O C I - H CIKqO C -H C1 X 0 C HI S-0 C H,ClN,O Cj HI C l > N , O C-IH, C1U 0 C-OH+C1 rU-0 C H, C l U - 0 C ,H,C1 'i0 C , H,,CI-h C H,,CINuO c IL3C1S C, HI C1N 0
u, fi, c ,
C . H, C1. \
C , H, C l C , ir.
c!. u
c, €1, C'I C, H, L, 0 C , 11, C l , \
c. H , c1, u c, I I , h, 0 c, 11, C l , \ c. If, C!. \ i, it, h
c, H, c1. c. 1%. c1, v -\
e , I
