J . Med. Chern. 1982,25,231-234 gel G; Et,NH-EtOAc, 1:20). Anal. (C14HzzNOzC1) C, H, N, C1.
cis -N-Acetyl-2-(3,4-dimethoxybenzyl)cyclopentylamine (5). Acetyl chloride (1.6 g, 20 mmol) in 10 mL of CHzClzand ESN (2.4 g, 24 mmol) were added to a stirred solution of crude 3 base (4.0 g, 17 mmol) in 40 mL of CH2C1, a t 0-5 "C. After 5 min the reaction was warmed to room temperature and stirred for 16 h. The CHzCl, solution was extracted with 5 N HCl, 3 N ",OH, and saturated NaCl solution, and dried over Na2S04,and the solvent was removed in vacuo to give a pale yellow oil. Crystallization from EtOAc-hexane gave 1.1g (23%) of white crystals: mp 65-67 "C (anal. sample, mp 80-105 "C); NMR (CDCl3) 6 4.07 (br, 1 H, NCH), 2.65 (m, 2 H, Ar CH2), 1.86 (s, 3 H, COCHJ, 1.10-1.80 (m, 6 H, CH,CH,CH,); TLC R, 0.37 (silica gel G; acetone-ether, 1:20). Anal. (CI8H23N03) C, H, N.
trans -N-Acetyl%-(3,4-dimethoxybenzyl)cyclopentylamine (6). Compound 6 was synthesized from 4 (as above) in 16% yield white crystals, from EtOAc-hexane; mp 103-105 "C (anal. sample, mp 106-107 "C); NMR (CDC13) 6 4.42 (br, 1 H, NCH), 1.98 (s, 3 H, COCH,), 1.24-1.82 (m, 8 H, Ar CH,, CH,CH,CH,); TLC R f 0.34 (silica gel G; acetone-ether, 1:20). Anal. (Cl6Hz3NO3)C, H, N. Cardiovascular Experiments. Forty mongrel dogs of both sexes with an average weight of 10 kg (range 3.5-20 kg) were injected with morphine sulfate (5 mg/kg) and anesthetized with sodium pentobarbital (20 mg/kg iv). Surgical anesthesia, as evidenced by lack of corneal reflex, was maintained with additional
231
barbiturate ( 3 4 mg/kg) as necessary. The animals were intubated endotracheally, and the right femoral artery and vein were cannulated. All injections thereafter were made through the venous cannula. Injection volumes were adjusted to 2.0 mL/10 kg and followed by 2-3 mL of 0.9% saline containing 10 units of heparin/mL. Arterial blood pressure was recorded with an RP 1500 pressure transducer and a desk-top model (DMP-4B) physiograph. Mean arterial blood pressure was calculated as diastolic blood pressure plus one-third pulse pressure. At the start of each experiment, atropine (1 mg/kg) was given to eliminate vagal control of heart rate. Autonomic nervous system responsivity was tested with norepinephrine (0.1 pglkg), isoproterenol (0.1 pg/kg), and dopamine (3-20 pg/kg). The catecholamine solutions contained ascorbic acid (0.02%) as antioxidant.
Acknowledgment. We are grateful to Smith, Kline & French Laboratories, for their generous gifts of phenoxybenzamine hydrochloride and cimetidine and to Robins Research Laboratories for kindly supplying metoclopramide hydrochloride. The internal research support of the Therapeutics and Toxicology Laboratory, Department of Pharmacology and Toxicology, University of Louisville School of Medicine, is acknowledged. The authors also acknowledge the expert editorial assistance of Ms. Carla A. Wagar in the preparation of this manuscript.
Synthesis and Orexigenic Activity of Some 1-Methyl-4-piperidylidene-Substituted Pyrrolo[2,1-bI[ Slbenzazepine and Dibenzocycloheptene Derivatives David C. Remy,**+Susan F. Britcher,t Paul S. Anderson,t Patrice C. BBlanger,*Yves Girard,* and B. V. Clineschmidtt-1 Merck Sharp & Dohme Research Laboratories and Merck Institute for Therapeutic Research, West Point, Pennsylvania 19486, and Merck Frosst Laboratories, Pointe ClairejDorval, Quebec, Canada H9R 4P8. Received August 31, 1981 The synthesis and orexigenic activity of some unsubstituted and Bz-carboxylic acid substituted l-methyl-4piperidylidenepyrrolo[2,1-b] [3]benzazepine and dibenzocycloheptene derivatives are described. lO,ll-Dihydro-3carboxycyproheptadine (7c) has been selected for clinical evaluation as an orexigenic agent based on its low threshold dose for increasing food consumption in cats (0.031 mg/kg PO) and its lack of undesirable central nervous system activity. The levorotatory enantiomer of 3-carboxycyproheptadine(Id)and the 9-carboxypyrrolobenzazepinederivative 4f also possess orexigenic activity, but with these compounds such activity diminishes sharply below 0.25 mg/kg PO. The unsubstituted l-methyl-4-(5H-pyrrolo[2,1-b] [3]benzazepin-ll-ylidene)piperidine(4d)and its 6,ll-dihydro analogue (4a)are comparable to cyproheptadine (la)in promoting hyperphagia in cats.
One of the more useful clinical attributes of the antihistaminic-antiserotonin drug cyproheptadine (la) is
FX
weight gain in both children and adults with essential a n o r e ~ i a in , ~children ~~ with pulmonary tuberculosis or chronic pulmonary condition^,^ in patients with chronic hepatic disease^,^ in individuals suffering from anorexia nervosa,6-* and in those patients having a generally debilitated c ~ n d i t i o n . ~ The levorotatory (absolute configuration &pSb) but not the dextrorotatory enantiomer of 3-methoxycyproheptadine (lb) has also been reported to possess
I
CH3
(1) J. W. Saleh, M. U. Yang, S. A.Hashim, and T.B. Itallie, Clin.
la, X = H b, X = OCH, c, X = CO,C,H, d, X = CO,H
Res., 24(3), 503A (1976). (2) G. J. Pawloski, Curr. Ther. Res., 18(5), 673 (1975). (3) P. Zanetti and G. Castelli, Clin. Ter. (Rome),66(4),375 (1973). (4) A. K. Farra, Praxis, 62,798 (1973). (5) J. Inouye and F. Ishihara, Shinryo Shinyaku, 10(5), 1089 (1973). (6) S. C. Goldberg, R. C. Casper, and E. D. Eckert, Psychopharmacol. Bull., 16(2),29 (1980). (7) K. A. Halmi and S. C. Goldberg, Psychopharmacol. Bull., 14(2), 31 (1978). (8) S. C. Goldberg, K. A. Halmi, E. D. Eckert, R. C. Casper, and J. M. Davis, Br. J. Psychiatry, 134, 67 (1979). (9) W. Molleney, 2.Allgemeinmed. Landarzt, 48(12),607 (1972).
stimulation of appetite with a concomitant increase in food consumption (hyperphagia)and gain in total body weight.' Accordingly, l a has been used to promote appetite and
*
Merck Sharp & Dohrne Research Laboratories. Merck Frosst Laboratories. Merck Institute for Therapeutic Research.
0022-2623/82/1825-0231$01.25/00 1982 American Chemical Society
232 Journal of Medicinal Chemistry, 1982, Vol. 25, No, 3
Remy et al.
Table I. Food Consumptiona av grams consumed compd (t) - l d
(-)-ld (i)-ld
4 a C,H,O,d 4c,HCle 4d.C,H,04 4f.HCle 7c.HCle cyproheptadine ( l a )
dose, m g / k PO 0.50 0.25 0.50 0.25 0.50 0.25 0.50 0.25 0.50 0.25 0.50 0.25 0.50 0.25 0.50 0.25 0.50 0.25
t
30 min
SD:b control day/test day
60 min
71 i 13/68 t 22 68 i 32/66 i 42 72 t 35/108 t 32c 62 c 1 7 / 7 6 c 1 6 1 1 6 t 30/147 t 32c 108 i 241129 c 22c 1 1 7 t 391204 i 6OC 9 1 i 38/175 c 2gC 92 i 33/109 t 36 NTf 1 3 3 i 51/189 t 4gC 1 1 3 i 33/172 t 2OC 78 i 24/93 t 24c 73 i 37/98 t 3 l C 84 t 38/105 t 49 68 i. 20/89 t 32c 1 3 5 i 47/190 i 63c 1 0 9 t 34/165 t 34c
94 f 19/96 i 1 7 86 t 31/91 i 44 1 0 2 t 331124 t 36c 90 t 25/109 i 1gC 1 6 0 c 34/203 ?: 35c 147 i 31/179 i 3gC 137 t 35/219 t 55c 1 2 4 f 39/212 c 42c 1 2 5 t 45/142 f 32 N T ~ 148 f 44/217 t 4 l C 1 3 4 i 40/208 t 37c 1 1 4 i 231129 t 2gC 1 1 2 i 46/128 t 3gC 102 t 42/155 t 67c 1 0 2 c 26/127 t 1gC 157 t 50/221 t 5OC 1 2 9 f 35/200 i 4 l C
methylcellulose
180 min
-
1 2 5 i 161141 t 25c 137 t 411138 t 48 149 c 36/188 t 4gC 1 3 3 c 30/169 i 26c 219 c 34/273 i 42c 1 9 1 5 25/236 i 3gC 166 c 32/234 c 4gC 1 7 5 i 50/239 c 4 l C 1 7 3 i 43/193 i 30 NT~ 1 9 3 t 46/243 t 33c 1 8 3 i 461239 t 37c 170 t 35/194 t 45c 1 7 6 t 40/210 i 52c 134 t 45/221 t 84c 1 4 5 c 30/170 t 1 5 c 194 t 50/256 c 35c 179 t 451231 i 52c 1 8 1 t 401195 t 33 210 t 391198 +- 4 1 1 9 5 t 55/184 t 52
a See Experimental Section for a description of the pharmacological testing. Each compound, except 412, was tested a t two dose levels, 0.50 and 0.25 mg/kg, using 10 cats per dose level. Represents a significant increase in food consumption, p
