Journal of Medicinal Chcmislry, lY?O, Vol. l;, .Yo. 6
Noms
Compound No. oi Lase
Dose, mg/kg
TetxaLenanne antagonism
Yes ( p t o k ) No No
:1 8 12
2-CH2CI-I(CH3)lr'I12.11Cl 2-CO(CH2),KMe2.HC1 2-COCHZSCdHio.HC1
200 200 200
13
2-CIiOHcIIJCJI1".
2 ,i 50 100
IICl
200
No
VelllLle
PEG PEG PEG
+ AIeC + h1eC + MeC
PEG
+ n1cc
14
l-O(CH2)2NEt2' HC1
200
No
I120
1.i
2-O( CHz)zNEt?.HC1
200
No
XLOI-I
1233
Remarks, number o i animals
Slight exophthalmos (3,':3),mydria.qir ( 3 31 F o apparent effect.s (3 '3) Xoderate ptosis (1/3), low posture, moderat,e decrease in motor activity, bradypnea (1/3), prostration (1!3), int,ention tremors, dyspnea ( l / 3 ) , respirat,ory arrest (1/ 3 ) , death (1/:3), at,axia ( 2 i 3 ) , high post,nre (l/3),slight exophthalmos ( 2 / 3 ) , abnormal gait ( l / 3 ) , \Teak grasp reflex (113)~moderate hypothermia (1/3) Slight hypertonia (213) No overt signs (313) High body posture (3,'3), fine body t,remors (2/3), piloerection (1/3), abnormal gait (2/3), moderate hypersensitivity to t'ouch (3/3), marked salivation (1,'3), toe-walking (1/3) Fine body tremors ( 3 / 3 ) ,high body posture ( 3 / 3 ) , moderate hypersensit.ivity t80 t,ouch (1/3), abnormal gait (3/3), marked salivation ( 2 / 3 ) , marked rhinorrhea (1/3), descended testes ( 1 3 ) Slight, hypersensitivity (1U), slight decrease in mot'or activity (1/3), moderate ptosis (1/3) High body posture ( l / 3 ) , slight. increase in motor activit,y (1/3), slight exopht,halmos ( 2 / 3 ) , slight mydriasis (113)
a All compounds were administered once orally to male Wist,ar rats (210-273 g), usiially at 200 nig ,kg, ill H2O or a mixture of 5?; polyethylene glycol (PEG 400) and 95% methylcellulose (Methocel). Overt, effects and tetrabenazine antagonism were recorded. For the latter effect, one animal of each dose level was inject,ed ip wit,h 16 rng of tetrabenazine :kg 3 hr after dos'iiig. Tetrabenazine is 9,IOdimethoxy-1,2,3,4,6,7-hexahydro-3-isobutyl-2-oxo-llbH-ben~o [a]yuinolixine.
mmoles) and 2 ml of piperidilie in dry C6Hs was allowed to ion of the EtOH-Et20 mother liquors furnished 1.5 g of a yellow stand overnight, filtered from pptd piperidine.HC1, aiid washed crystalline material which was (erroneously, vide infra) believed t,o be more 8.HCI and was reduced directly wit,h 0.3 g (8 mmoles) (HzO). Shaking the CsH6 soln with 10% aq HC1 gave a yellow ppt (3.1 g, 88%) of 12.HC1. The free base, liberakd with NaOH of LAH in dry Et20 for 1 hr. hfter the usual work-up by in HzO, was recrystd from Et20-pet et,her, mp l12-114°. Anal. decomposition with HtO, drying (Na2SOa), and acidi$calion with Et2O-HCI, 0.8 g of a salt was obt'ained, mp 205-208" (from (CisHigNO) C, H. Anal. 2-(1-Hydroxy-2-piperidinoethy1)biphenylene(13).-To a soh1 Et,OH-EtzO), mass spectrum (70 eV) m/e 283 (&I+). of LAH (0.2 g, 5 mmoles) in dry Et20 was added dropwise, (Cl8Hl9Cl2N):calcd C, 67.51; H, 5.97. Found, C, 67.61; H, a t 0' under N2, a soln of 1.1 g (4 mmoles) of 10 in 40 ml of EtiO. 6.25. This salt must be 2-(l-chloro-2-methylene-3-dimethylamino- After stirring at 26" for 1 hr, H2O was added, and the Et20 s o h was filtered, dried (NazSOd), and worked up. Ethereal HC1 propy1)biphenylene. HC1 (9) (Ar = 2-biphenylyl). It must pptd 0.7 g (56%) of 13.HC1, mp 230-232" (from EtOH-EtSO). PiaOH Anal. (CisHz2ClNO) C, H. ArCHCIC(=CH~)CH~NAIe~~HCl __f 1-(2-Diethylaminoethoxy)biphenyIene (14).--A mixture of 9 1-hydroxybiphenylenes (2.5g, 15 mmoles), NaH (1 g, 20 mmoles, ArCHOHC(=CH2)CH2NXez 5Oy0 in mineral oil), and 50 ml of dry PhMe was refluxed for .i 10 hr, and then cooled. A s o h of 2.3 g (20 mmolea) of EtzN(CH2)yCl have originated from the Xannich product, ArCOCH(CH2Nhle2)a by LAH reduction which effected both reduction of the keto group (cf. 13)and deamination in the alkaline medium.10 When an aq soln of 9 was made basic wit'h lOy0 KaOH, the amino alcohol 10 was obtained in 50y0 yield, mp 84-85"; m / e (70 eV) 265 (M+). Anal. (ClsHlsNO):calcd C, 81.47; H, 7.21. Found: C, 80.95; H, 7.48. 2-(3-Dimethylamino-l-hydroxypropyl)biphenylene(ll).-The base 8 was reduced with LAH as described for the reduction of 13 below. The resulting amino alcohol 11 was converted into its HC1 salt in EhO; yield 557,, m p 170-171" dec (from EtOHEtnO); m / e (70 eV) 253 (M+). Anal. (C1,H&lNO) C, H. 2-Piperidinoacetylbiphenylene (12).-A soln of 7 (2.5 g, 11 (10) C / . F. F. Ulicke, Ory. React., 1, 303 (1'342).
in dry PhPlIe was added, and the mixture stirred and refluxed for 19 hr. It was decompd with ice-dil HC1 and extd (EtZO). The aq layer was made basic (105% NaOH) and the product extd into EttO, dried, and worked up. The oily base was converted into the hydrochloride in dry EtsO, yield 1.5 g (33c70),mp 145147' (from EtOH-Et20), m-/e (70 e k ) 267 ($I+). Anal. (CNHaClNO) C, H. 2-(2-Diethylaminoethoxy)biphenylene(15) was prepared similarly from 2-hydroxybiphenylene.11 The salt 15.HCl crystallized from EtOH-Et,O, mp 135-136,5', ni/e (13 eV) 267 (\I+), yield 31YG. Anal. (C18H22C1XO) C,H. (11) J. 31. Elatchly, .J. F. W, lIoOmie, and S. 3000 (1962).
L).
Thatte. J . Chem. Soc.,
