860
Synthesis and Central Nervous System Depressant Activity of New Piperazine Derivatives and Related Compounds. I I
Ninety-three N',S'-disuh~tituted piperazine derivative4 i r i wliicii tile N'siil)~t.it,~ieiit.s :&re:rlamiiio)ethyl a i d the upyl, %-(%'-hvdlos!.etho~:v)etii?.I, lohexyl, tieuzyl, in-rnet,hyl- :ind lrja siil,st,ituents are methyl, 2-h p-t-l)ritylbenzyI, p-chloro-a-pheri , pheriethyl, phenyl, chlorii- miti r i hosypheriyl, tolyl, 2-pyridy1, 2pyrirnidyl, or 2-thiazolyl have been synthesized. So have some N,N'-disuhstit,rited ethylerietiiamiiies i i i which the substituent is p-chloro-cu-pheiiylbellzyl arid N' -ubstitueuts are alkyl groups 01' N'is x part of morpholiiie o r piperidine. Screening for CXS activitv revealed that; some coitipoiirids possessed sigriificant CNS tiepressaiit activity. h few compoiinds exhibited promising antihi;tamiiiic. activity i i i esperinieirtal animals.
I
CSS-ACTIVEPIPERAZISES. I11
September 1969
number of 1,2-diphenylethylamines have shown analgetic and CKS depressant activities.s Chemistry.-Sl- [3 - (p-Chlorophenyl) - 3 - phenylpropyll-N4-(substituted)piperazines(I,A = CHtCH2) were synthesized by the condensation of 3-(p-chlorophenyl)3-phenylpropionyl chloride with different S-monosubstituted piperazines followed by the reduction with LAH. N1- [w-(p-Chloro-a-phenylbenzyloxy)alkyl]-S4(substituted)piperazines [I, A = O(CH,),, O(CH,),], S 1 - [ p (p-chloro- a-phenylbenzylmercapto)ethyl]- N4-(substituted)piperazines (I, A = SCH2CH,), and SI-[B-(pchloro - a-phenylbenzy1amino)ethyll- S4(substituted) piperazines (I,h = SHCH,CHJ mere prepared by condensing o-(p-chloro-a-pheriylbenzy1oxy)ethylor -butyl chloride. B - (p-chloro - a - pheriylberizy1mercapto)ethyl (ah loride, arid 6- (p-chloro-a-phenylberizylamino)ethyl (ahloride hydrochloride, respectively, with varioua S-monosubstituted piperazines in the presence of EtJ in EtOH. S-(p-Chloro-a-phenylbenzyl)-S'- (substituted)ethyleriediamiries arid S1[p-(1,2-diphenylethylamino)ethyl]S4-(substituted)piperxziries were prepared by the contlensatiori of d-(p-chloro-a-pheny1benzylamino)ethyl chloride hydrochloride or /3-(1,2-dipheriylethylaminojethyl chloride hydrochloride with various amineu. The physical constants. yielda, recrystallization solvents and ariulytical dat:i of the compound are given in Tables 1-111. Pharmacology.-The gross observation of intact mice, the spontaneous motor activity, and potentiation of barbital hypnosis revealed that some of the compounds in these series possessed good C S S depressant activity. Kone of the compounds had any significant analgetic activity (narcotic or nonnarcotic). A few compounds exhibited significant antihistaminic activity. The results of the pharmacological evaluations, including cardiovascular study and antihistaminic activity of the compounds tested, are given in colums 3-8 of Tables 1-111.
Results and Discussion Iri general, t,he C S S depressant activity as seen by the decrease in mot'or activity was in t'he following descending order according to the nat'ure of the bridge -Ajoining p-chloro-a-pheriylbenzyl and piperazine moiet'ies in the general formula I : SHCH,CH, > CH,CH2 > C:H,CO > SCHZCH, > OCHZCHZCHZCH, > OCH,CH,. The substituents It 011 the K4position of the piperazine :ilso influenced the depressant activity. In t,he ethyleiiediamirie series (I, A = SHCH,CH,), compounds 73 and 80-82 exhibited significant CKS depressant activity. The replacemerit of the piperazine group either by ti heterocyclic :imine like morpholine, piperidine, or alkyl- or di:ilkylamiric reduced the activity. When p-chloro-a-pheIiylbeIizy1 moiety was replaced by 1,2diphenylethyl, the activity was considerably reduced. Diphetiylprupioiianlide8 (I,-1= CII,CO) a i d the correupoding diphertylpr.upylamirle8 (I, A = CH,CH,) exhibit,ed n d d to tiurked CNS depressant activity. The, (8) 1'. R a u . P. U. S a t t u r , G . S. Sidlni, S . K. Sogani, 8. 11. Zalreer. 8. 9. Mandrekar, Y. H. Setliy. U. IHmCli'iaO dioxalate CzaHa2CIXsOz C~aHaoClN3.dioxalate C~HaoCli'ia.dimaleate CziHa2CINa' dimaleate CnHa2CINa' dioxalate CziHnCIN3 CnHaClN3. dimaleate CaoHasCIXa CaoHasClNs. dimaleate C31HaoClNs C3iHiaClNa dimaleate Ca2HasCIzNa CzsH2;ChNa. dimaleate CzsHaoClNaO C2sHaoClNa0 CisHaoClN3 CzIHnClNI Cz3HmClNa C ? a H d l N s dimaleate C2zHzClNaS C2zHxCINaS. dimaleate
.Inalyses
C , H , i'i C. H , N C , H , i'i i'i Ir;
C , H, N N C. H, N C, H . N
li
mg/ kg ip
pression,e mg/k
400
(-1
300 400
(-)
60
(-)
50
70& in motor act. of miced
(-1 (-1 (-1
162
60
70
L-
800
100
(-1
C H, 9 C H,S C H , h-
800
100
(-1
C, H , li
N
N
c, €I, li C, H , 3-
!i2
800
135
150 800
60
65
601
io
Ir;
N, s C, H, S S
A , lIe2CO; E, E t O H ; Ego,907; Et,OH: E t , Et,O; H, n-C61114; P, i-PrOH; W, H20. * Yields reported are the results of single experiments and are based on 3-(p-chlorophenyl)-3-phenylpropionyl chloride (in case of the compounds of odd numbers from 1-25), ?;-monosubstituted piperazines (in case of 27-67), p-(p-chloro-a-phenylbenzy1amino)ethyl chloride hydrochloride (in case of 67-1001, and P-(1,2-diphenylethylamino)ethylchloride hydrochloride (in case of 101-111). Yields are calculated for the materials melting not less than 2-3" below the highest melting point, obtained. c Mice were observed during the toxicity tests. The lowest dose at which ,significant depression was noted in mice is recorded in this column. Depression a t doses greater than 40% of the LDjo is not considered t o be significant and is indicated as negative ( - ). d The study of motor activity of a group of six mice was done on an actophotometer for 10 min before and 1 , 2 , and 4 hr after administration of the compound (dose 0.1LDjo). The peak effect is given here. Less than 50% decrease in motor activity was not considered to be significant and is indicated as negative ( - ). e The negative, moderate, and marked antihistaminic activity of the compounds tested in dogs is noted as (-), (+), and (++), respectively, in this column. The other significant effects on blood pressure of dogs were also given in this column as footnotes. Produced 607, potentiation of barbital hypnosi. atn solventa yieldh
K
NO.
101
XI e
102
PhCHr
IO.{
106
m-hIetliyll~enzyI p-t-Butylhenz>-I p-Chloro-o-phen?.ll,enz).l o-;\Iethoxyihrn.vI
IO7 108 109 110 111
p-&lethoxyplieni-l 2-Pyridyl 2-Pyrimidyl 2-Pyrimidyl 2-Ttiiszolyi
104
IO5
See corresponding foot,notes ihe effect lasted for 2 hr. '-0
I 1'10 tioii
54 53
1: 1.:
iii
E-Et &tit 11
H kr E
n
Table I.
-17 .53
11
h
43 46
53 62 65 ;, 6 51
\Ill or h p (mm), "C 210-219 (7) 170-171 258-260 der 255-265 ( 5 )
.\nnIyse.
N
c. H , N c, FI, s N c. ir. s N c. I I , s c. H, N
88-89 260-2i3 17) 126-128 208-210 99-101 112-113 113-114 226-232 der
C. 11, N C. H , S c,IT, N C'. H , S
84-85
Coinpoiitids solidified
. 1
uii
atailding.
c:. 11, s,s 5 0 ( , Liiihibitioii of ACh respuirse after 10 i t i i i i ;
nil) \v&s :dded drop\vke with -1irring t o aii ice-cooled s(diio f riiuiioetliaiiulaIiiiiie (til g, I riicile) i i i pyridiiie ( 7 5 1111).
Stirriuy was coiitiriued for ti h r at I ' O U I I ~ temperature aiid the niixture was theii heated oil a steam bath for 10 hr. Pyridine \vas distilled off under diminished pressure, and the residue was treated bvith ice-II& arid extracted ivith E t 2 0 . The cumbined Et& extracts were dried (Sa2ROa)and concentrated, arid the resiilting oil was distilled in z~acuo. The fraction distilliirg at
(14) (a) E. ( ; n > n n p and F. Colin [British Patent l,lO9.50!2 t.Ipri1 I O . 1068); Cksm. Ahstr.. 69, R.5937m (1968)) prepared this compound t l ? t l i t ' ratalytic reduction of t i l e Schiff haae obtained from ~ - ~ ~ l i l ~ ~ r ~ ~ t ) ~ n ~ ~ t ) l and monoetlianolarninP. (1,) 11, H e 1 mp 230-232".
September 1969
CSS-DEPRESSANT PIPERAZINES
p- (p-Chloro-a-pheny1benzylamino)ethylchloride hydrochloride was obtained in 71% yield by the action of SOC1, on b-(p-chloroa-phenylbenzy1amino)ethyl alcohol in CHCl, following the usual techniques; it w&s crystallized from EtOH, mp 23C-232O.l4b Anal. (C1&1&13N) C, H, E.
~-[N-(Methyl)-N-(p-chloro-a-phenylbenzyl)amino]ethyl Alcohol.-A mixture of p-(p-chloro-a-pheny1benzylamino)ethyl alcohol (2ti.15 g, 0.1 mole), HCOOH (10 ml, 98%), and HCHO 141 ml, 37-41%) was refluxed for 6 hr. Most of the HCHO aiid HCOOH were removed by distillation under diminished pressure. The residue was made alkaline with cold 5 N KaOH and extracted with EtaO. The combined Et20 extracts were dried (NaaSO4) and concentrated and t,he residue was distilled in vacuo. The fraction distilling at 184-190' (6 mm) was collected, yielded 18 g (65%). Anal. (C16H~&lPr'o)N. P-[N-(Methyl)-N-~p-chloro-a-phenylbenzyl)amino]ethyl chloride hydrochloride was obtained as an oil by the actioti of SOCln 0 1 1 the corresponding alcohol and was used directly for further . condensation. p-(1,2-Diphenylethylamino)ethyl chloride hydrochloride wits prepared in 91 Toyield by the action of SOClz on the ctorresponding alcohol16 as usual and crystallized (EtOH), mp 212-218" dec. L4Wl. (CieHigC1nN)X. p-[N-(Methyl)-N-(1,Z-diphenethyl)amino]ethylchloride hydrochloride was prepared from 0-( 1,2-diphenylethylamino)ethyl alcohol hydrochloride, following the method described by Kerwin, et al.16 N~-[~-(p-Chloro-a-phenylbenzyloxy )ethyl]-N4-(2-pyridy1)piperazine Maleate (37).-To a mixture of 5-(2-pyridy1)piperazine (1.63 g, 0.01 mole) and EtJ (2.0 g, 0.02 mole) in EtOH (20 ml), was added a solution of P-(p-chloro-a-phenylbenzy1oxy)ethyl chloride" (3.09 g, 0.11 mole) in EtOH (10 ml) and the reaction mixt,ure was refluxed for 25 hr. The solvent was distilled off, (15) L. H . Goodson, C . J . W.Wiegand, and J. S. Splitter, J . Am. Ckem. Soc.. 68, 2174 (1946).
(16) J. F. Kerwin, T. F. Herdegen, R . Y. Heisler, and G . E. Ullyot, i b i d . , 72, 3983 (1950). (17) N. Kato, et d . , Japanese Patent 5028 (Sept 4 , 1951); Chem. S h s l r . , 47, Y362h (1953).
865
and the residue was treated with cold 40y0 NaOH till alkaline and extracted with EtnO. The combined EtzO extracts were dried (NaaS04)and concentrated. The resulting oil was t'aken up in 20 ml of EtOH and added to a solution of maleic acid i n EtOH. The solid thus obtained was crystallized. N- (p-Chloro-~-phenylbenzyl)-N'-(2,6-xylidino)ethylenediamine (97) was prepared by the condensation of 0-(p-chloro-apheiiylbenzy1amino)ethyl chloride [obtained by the basificatioii of 9.5 g, 0.03 mole, of 8-(p-chloro-a-phenylbenzy1amino)ethyl chloride hydrochloride] with 2,6-xylidine (3.63 g, 0.03 mole) following the method described for 37. The resulting oil was distilled in vacuo and t'he fraction distilling at bp 230-242' (7 mm) was collected. The free base was converted to its maleate d t . N-(p-Chloro-a-phenylbenzy1)ethylenediamine(83).--h soliitioii of p-chloro-a-phenylbenzyl chloride (23.7 g, 0.1 mole) in pyridine (25 ml) was added dropwiae with stirring to an icecooled solution of ethylenediamine (24 g, 0.4 mole) in pyridine (50 ml). The reaction mistri1.e was stirred at room temperature for 16 hr atid then heated o n a steam bath for 1 hr. Pyridine was distilled off at diminished pressiire, cold H 2 0 was added to the residue, and the reaidiie was extracted with Et%(). The combined Et& extracts were dried (SalS04) and coiicentritted. The residual oil was distilled in vacuo and the port,ion distillirig between 176 and 182' ( 2 mm) was collected. The other compounds reported in Tables 1-111 were obtained by the condensation of appropriate halides with various Nmonosubstituted piperazines or appropriate amines, following the method described for 37. 111 case of amines having low boiling points, excess of xmiiies was taken, eliminating the use of triel hylamine. The resulting products were crystallized wheii solid or converted into the appi,opriate salts or distilled under vacuum when an oil.
Acknowledgment.--We wish to thank Mr. :\I. T. Jaokar for elemental microanalyses and Mr. S. I
