of a 4-arylpiper.azine or piperidiric ring as another variant of the substitution of the amino group seemed of interest, in view of the multitude of activities associated with 1-substituted 4-phe~iylpiperidine~arid -l--pheriylpipera~iries.~Quite early in this study it was observed that 4-phenyl-l-(3-amino-4-pyridyl)piperazine’ (I) had significant anticonvulsant, antireserpine, specific internuncial blocking, and weak, but definite, hypotensive, antipyretic, and anti-j-hydroxytryptamine activities. The novelty of this series for anticonvulsant activity added to the interest in them. I n a study of the structure-activity relationship of this series systematic variations were introduced in different parts of the molecular architecture of I. The various types of compounds synthesized in this study are typified by the general formulas 11-X.
I
11, 2-pyridyl 111, 4-pyridyl “,N-R
Experimental Section’s ‘ 9
VI
IV, 2-pyridyl V, 4-pyridyl
VII
VIII, 2-pyridyl IX, 4-pyridyl
HN>cH~I,-N~N-
the appropriate 2-chloro-3-nitro-, lo -l-cliloro-3-nitro-, 11 :md 4-chloro-3-nitro-5-bromopyridi1ies~~ and 4-chloro-3nitroquinolinel with various arylpiperazines and arylpiperidines followed by reduction of the resulting nitro compounds. 1,4-Bis(aminopyridyl)piperazines were prepared by condensation of the appropriate haloriitropyridines with 0.5 molar equiv of piperazines and 1 molar equiv of triethylamine followed by reduction of the resulting nitro compounds. 4-Aryl-l-(4-pyridyl)piperazines(111,R’ = R ” = H ) were obtained by condensation of 4-chloropyridine SoxideI4 with S-arylpiperazines in toluene followed by catalytic reduction of the resulting pyridine N-oxides. 1-(4-,4niino-3-pyridyl)4-phenylpiperazine(VII) was prepared by the condensation of 3-bromo-4-nitropyridine l-oxideI5 with S-phenylpiperazine followed by catalytic reductioii 1,4-Bis(p-2- or 4-pyridyl)ethylpiperaziries and homopiperazines (VIII and IX, X = (CH2)2;n = 2 or 3) were prepared by the pyridylethylation16 of piperazine and homopiperazine with 2- and 4vinylpyridine. 1,i-Bis(p-4-piperidylethyl) piperazine resulted from the catalytic reduction of the corresponding pyridine derivative (IX, X = (CHJ,; n = 2 ) . 1,4-Bis(cumethyl-2- or -4-pyridylmethy1)piperazines (VIII and IX, n = 2 ; X = CH,CH) were secured by the condensation16 of 2- and 4-cu-bronioethylpyridine~~~ with pi peraz ine,
n
N-Arylpiperazines.-\tiile most of the X-arylpiperazines wet’e ali,rwiy kiiown, some which were unknown were prepared by the geriet,:rl method outlined below :tiid are described i n Table I. A mixture of the appropriate aniline (0.3 inole) and bis(P-chloroethyl):tmine hydrochloride (0.3 mole) it1 1-butairol (200 ml) w a s refluxed for 24 hr. The reactioii mix1ui.e was cooled and powdered aiihydi.ou5 K,COJ (0.15 mole) was added and 1,efluxing contiriuecl fur ali(Jther 48 hr. The re:tctiori mixtui’e was filtei,ecl hot, the
T.IBIXI N-P€~ENYL~~P~I~~\z~sEs
( c H ~ ) . ~ H
-yo
N---
I’lienvl
Up iniin) o r
si1 t i - t ituent
mp, u c
Calcd
Found
IIl-CF3n
IICl 232 IICl 17Y-I74 141!-14;i (bath)
10.5 12.2
10.48 12.38
P-F 3,4-(C€IaO)a
HCI 172 IICl 233-236 7s HC1 194-196
12.93 10.83 12.6 10.83 12.6
12.78 10.93 12.5 10.62 12.93
X
No.
R=CH3, aryl, aralkyl R’=H, NO2, NH2 R”=H, Br, NO2, NH2 R/”=H, OH n=2,3 X =CH>CH,, CH(CH3)
1 2
ljt-crLO
3 4
(0.2.; nim)
The 4-arylpiperazines required in this study were 5 2,4-(CI130)2 prepared by the condensation of the appropriate 160-163 (bath) anilines with his-P-chloroethylamine hydrochloride8 ( 0 . 5 mm) essentially according to the method of Prelog and a A. S. F. Ash, A . 31. Creighton, and IT‘. R. Wragg [(>lay and Bluzeli. Baker Ltd.) British T’ateiit 948,747 (Feb 5 1064); C h ?ti. Abstr., 60, 1‘2029 ( 1964)] reported nip 250-25:%ofor the hydrobromide. 4-4ryl-1-(3-amino-2- or -4-pyridy1)piperazines (I1 and 111), 1-(3-amino-2- or -4-pyridyl)+phenylpiperi(10) Y. .\hmad and D.€1. Hey. J . C h r m . Soc.. 4516 (1954). dines (IV and V), and l-ary1-4-(3-amino-4-quinolyl)(11) H. Krriger a n d F. G. L l a n n . 7hi.l. 2 i 5 5 (1955). ( 1 2 ) V. 0. liremer Ann.. 529, 200 (l!J38). piperazines (VI) were prepared by the condensation of
’
( 5 ) P. A . J. JansJen. A . 11. Jareneau, a n d C . J. E. Niemegeers, J . Pharmacol. Ezptl. Therap.. 129, 2 7 1 (1960). (6) H. G. hlorren, V. Bieneft, a n d A . 111. Reyntiens, “Psychopharmacological Agents,” Vol. 1. AI. Gordon, Ed., Academic Press I n c . , S e w York a n d London, 1964. p 251. ( 7 ) A. Ahmail, G . I
