September, 1963
1
BENZYLPIPERAZIXES.
54 1
TABLEI11 D~ETHYL ARYLMALONATES AND ARYLCYANOALKYLMALONATES
-Calcd.. 70--
Yield, R‘
H
H CH3O CH3O c1
c1
RZ
H H H H
H
H CHs CH3 CHa C Ha OCHzO OCHzO
Ra
CHzCN CH(CH:3)CN H CHzCN H CHZCX H CHzCS H CHzCX
B.P.,
C. (mm.)
115-116 (0.4) 140-142 (2) 146-147 (1.0) 160-170 (1.2) 140-142 (1.0) 155-160 (0.4) 150-152 (2.2) 150-170 (2.2) 174-175 (0.6) 157-160 (0.1)
C
H
65.32 66.43 63.16 62.94 57.59 58.15 68.16 67.53 59.98 60.20
6.23 6.57 6.81 6.27 5.54 5.21 7.63 6.97 5.75 5.37
%
63.5 34.6 72 39.2 73 42.2 39.0 43.0 81 32.0
butyrate hydrochloride in 150 nil. of absolute ethanol was saturated at ice bath temperature with gaseous hydrogen chloride and then was stored at room temperature for 4 days. The crude
%---
-----Found,
N
..
.. ..
4.59
..
4.52
.. 4.63
..
4.39
C
H
N
66.59 68.35 62.12 63.33 57.51 59.20 67.92 67.57 59.74 60.57
6.03 6.70 6.42 6.28 5.61 4.96 8.16 7.11 5.31 5.40
.. .. .. 4.70
..
3.91
.. 5.00
..
4.10
crystalline precipitate, m.p. l58-159’, was isolated and recrystallized from ethanol t o give 8 g. (OOyo)of product, m.p. 150160”.
Synthesis and Pharmacological Study of New Piperazine Derivatives.
I. Benzylpiperazines J. R. BOISSIER, Znstitut de Pharmacologie, Facult6 de Me’decine,Paris
R. RATOUIS, S.C.R.A.T., IO4 Bis, rue Pelleport, Paris AND
C. DUMONT
S.Z.F.B .-DZAitfANT, La Plaine-Saint-Denis (Seine) Received iyovember 29, 1962 Twenty-three 1,4-disubstituted piperazines have been prepared, in which the I-substituents are benzyl or its mono- or polyalkoxy-, or alkoxyhydroxy- derivatives, and the &substituents are phenyl, chloro- or methoxyphenyl, pyridyl, methylpyrazinyl, chloro- or methoxypyridazinyl. They have been studied systematically for potency against epinephrine and histamine on the isolated guinea pig seminal vesicle, in comparison with ergotamine and promethazine. Some compounds show potent activity against epinephrine, and all present very weak histaminolytic effects. The adrenergic blocking action observed in vitro was verified in anesthetized dogs.
Adrenolytic, sympatholytic, and antihistaminic properties have been described in I-phenylpiperazine’ and derivatives2: hypotensive, vasodilatator, and neuroleptic effects have also been reported in series of 1-aralkyl piperazines. h series of new benzyl piperazines (Table I) of type I (1) (a) D. Bovet a n d F. Bovet-Nitti, “IIBdicaments du systeme nerreux v6gBtatif,” S. Karger, S. A . , Bile, 1948, p. 247; (b) L. W. Roth. J . P h a r m a 110, 157 (1954); ( e ) V. Prelog and G. J. Driea, Collection Trao. C h i m . Tchecosloo., 6, 497 (1933). (2) (a) E. Cerkovnikov a n d P . Stern, Arkhiu. K r m . , 18, 13 (1946); (b) B. B. Llorphis, L. W.R o t h , and R. K. Richards, Proc. Soe. E r p t l . B i d . M e d . , 101, 174 (1959); (c) D. F. Marsh and J. F. O’Leary. Federation Proc., 12, 34& (1953); (d) 3. F. O’Leary, Federation Proc., 12, 355 (1953); (e) J. F. O’Leary, Am. J . hfed. Sci., 226, 111 (1953); ( f ) J. E. Owen and T. Verhave. J . Pharmncol. E z p t l . Therap., 122, 5 9 4 (1958); (9)I. H. Page, R. W.Wolford, a n d A . C. Corcoran, A r c h . I n t e r n . Pharmacodyn., 119, 214 (1959); (h) A. P. Swain and S. K. Naegele. J . Am. Chem. Soc., 7 6 , 5091 (1954). (3) (a) J. R. Boissier, C. Dumont, R. Ratouis, a n d J . Pagny, Arch. Inf e r n . Pharmacodyn., 133, 29 (1961); (b) J. Mills, XI. M. Boren, a n d N. R. Easton, Abstracts, 132nd National Meeting of the -4rnerican Chemical Liociety, New York, N. Y., 1957. p. 11-0; (c) R. L. LIoffitt and R. K. S. J i m , Federation P m c . , 16, 461 (1950); (d) G. Quesnel. R. Chalaust, €1. Schmitt, G. Kroneberg, a n d H. Schmitt, Arch. I n t e r n . Pharmacodyn., 128, 17 (19FO); (e) N. H. Ychimmel a n d J. R. Beerm, Antibiot. M c d . Clin. Thera p y , 6 , 25 (1958); ( f ) G. Stille, W.Braun, a n d BI. K a l t e r , ArzneimittelForuch., 7, 225 (1957). cot. E z p t l . Therap.,
has been prepared where Ar = phenyl, mono- or polyalkoxyphenyl, or alkoxyhydroxyphenyl and R = phenyl, chlorophenyl, methoxyphenyl, pyridyl, methylpyrazinyl, chloro- or methoxypyridazinyl. These piperazine derivatives were obtained by five general methods according t o the scheme A ArCHLCl
B ArCHO
+ +
n
HN-NR
H N-NR
C ArH
iC H 2 0
+
\
\ r-7 1
HN-NR
-ArCHZN
-
NR LJ
D ArCON-NR n A
E ArCH2N-NH
+
XR
In method A, benzyl chlorides (whether isolated or not) were condensed with twice the theoretical amount
342
= = 3 3 ?I
re
m
A
1 . t -y
A A
:xl- 3 i I) 3. .
=.
1-
- .x % . m. s w
"1
'3 c9
c t- 1- ?' 4 ? C I-
4-44 ' . c. ?
-
I-
2 I-
BENZYLPIPERAZIXES
September, 1963
543
TABLE11'
RNA*H
u
Yield,
B.p., C .
hl.p.,
R
(rnm.)a
0C.b
R
Compound
Formula
-Calcd., C
7'--H
-Found, C
%H
XXIV 2-CsHsSzC 62 115-117(0 3) CBHUN~ 60.65 7 92 60.6 7.9 48.36 5.59 48.5 5.6 101 CsHiiClNa XXV 3-C4H&lKZ" 54 55.6 7.5 55.65 7.26 3-CsHsN20e 60 82 CgH14340 XXVI 65.8 8.6 56 C13H20N202 66 07 8.53 ~,~-(CH,O)ZCGH,CHZ' 70 135-140 (0.5) XXVII a Uncorrected. b Uncorrected, determined with a Kofler hot stage microscope. 0 CsHsK-2: 3-methylpyrazinyl monohydrochloride salt crystallized from 2-propanol, m.p. 198". Anal. Calcd. for CSH14N4.HC1:C, 50.34; H, 7.04; C1, 16.51. Found: C, 51.0; H, 7.1; C1, 16.5. C4H2C1Nz: 6-chloropyridazinyl C1: calcd., 17.85; found, 18.0. e CsHsNlO: 6-methoxypyridazinyl. f From 3,4-dimethoxybenzyl chloride9 and piperazine according to the procedure reported for l-ben~ylpiperazine.~eThe dihydrochloride salt has been r e ~ o r t e d . 3 ~ Purities of all distilled monosubstituted piperazines were determined by gas chromatography using a Prolabo apparatus \%-itha thermal conductivity detector (column: 4 m. long, 6 mm. diameter, packed with C 22 firebrick coated with 20% by weight of Rhodorsil silicone oil, temperature: 240", carrier gas: hydrogen). Retention time: 8 t o 10 min. With compounds prepared from anilines, chromatograms showed a trace of these materials even after 3 rectifications (retention time: about 2 min.). @
of ic'-monosubstituted piperazine in a solvent in which the K-monosubstituted piperazinium chloride obtained was insoluble. I n method B, condensation of an aldehyde with an amine and hydrogenation under pressure over Raney nickel catalyst were performed in one step. In method C, the well known RIannich procedure was followed. In method D, the intermediate amide (from the reaction of an acid chloride with an amine) was reduced using lithium aluminum hydride. Method E (used only in case of a fairly mobile halogen atom in the R X compound) was essentially the same as method A. Several K-monosubstituted piperazines were prepared according to previously reported procedure^.^ I n Table 11, descriptive and analytical data are listed for additional compounds of this type. Synthetic details for these derivatives are given in the Experimental part. The adrenolytic and antihistaminic activities were studied on the isolated guinea pig seminal vesicle according to the method of Stone and L ~ e w . The ~ results are presented in Table I. For comparative purposes, in the same conditions, EC50 for ergotamine against epinephrine was found 0.02 pg./ml. and EC50 for promethazine against histamine 0.001 pg. /ml. Compounds V,XIV, and XVII had the most potent inhibitory effect against epinephrjne. All the compounds presented rather weak and easily reversible histaminolytic effects. The adrenergic blocking effect observed in vitro has been confirmed on anesthetized bilaterally vagotomized and atropinized dogs. Blood pressure was recorded from the carotid artery. The intravenous injection of V, XIV, and XVII produced suppression of hypertensive response to epinephrine respectively at 5 mg./kg. for V, and 0.5-1 nig./kg. for XIV and XVII. Higher doses provoked reversal of epinephrine hypertensjon.
Experimental 1-(3-Methyl-2-pyrazinyl)piperazine(XXIV).-A
mixture of 43
g. (0.5 mole) of anhydrous piperazine, 32 g. (0.25 mole) of 2(4) (a) 1-Phenylpiperazine, K. Fujii, K. Tomino, and H. U'atanabe, J . P h a r m . S O C . J a p a n , 74, 1052 (1954); (b) chlorophenylpiperazines, C. B. Pollard and T. H. Wicker, J. A m . Chem. Soc., 76, 1853 (1954); ( 0 ) methoxyphenyl-lpiperazines, C. B. Pollard and J. B. Christie, J . Org. Chem., 23, 1333 (1958): (d) l-(%pyridyl)piperazine, K. L. Howard, H. W. Stewart, E. -4. Conroy, and J. J . Denton, ibid., 18, 1484 (1953); ( e ) 1-benzylpiperazine, R. Baltzly, J. 9. Buck, E. Lorz, and W. Schon, J. A m . Chem. Soe., 66, 244 (1944). ( 5 ) C. A . Stone and E. R. Loew, J. Pharmacol. Ezptl. T h e r a p . , 106, 226 (1952).
chloro-3-methylpyrazine,6 26.5 g. (0.25 mole) of anhydrous sodium carbonate, and 150 ml. of l-pentanol was refluxed for 5 hr. with stirring. After cooling, separation of salts and distillation of the organic phase gave XXIV. Bis 1,4-(3-methyl-2-pyrazinyl)piperazine was obtained by crystallization from methanol of the distillation tailings, m.p. 178". Anal. Calcd. for CllHJ6: C, 62.20; H, 6.71. Found: C, 62.15; H, 7.0. 1-(6-Chloro-3-pyridazinyl)piperazine(XXV).-A solution of 505 g. (2.6 moles) of 149 g. (1 mole) of 3,6-di~hloropyridazine,~ piperazine hexahydrate, 225 ml. of acetone, 200 ml. of Rater, and 18 ml. of hydrochloric acid (sp. gr. 1.19) was slowly heated while a rather violent starting of the reaction was observed, and then refluxed for 3 hr. After cooling, 57, of insoluble bis 1,4-(6chloro-3-pyridaziny1)piperazinewas separated; m. p. 352" (from dimethylformamide). Anal. Calcd. for C12H12C12S8: C, 46.31; H, 3.89; C1, 22.79. Found: C, 46.4; H, 3.6; C1, 23.0. Acetone was removed from the filtrate by vacuum distillation. The aqueous phase was extracted 3 times with chloroform. The dried chloroform layer was concentrated and the residue crystallized from an acetone-petroleum ether mixture to give XXV. 1-(6-Methoxy-3-pyridazinyI)piperazine (XXVI).-l-(6-Chloro3-pyridaziny1)piperazine (49.6 g., 0.25 mole) was dissolved in a yodium methoxide solution prepared from 8.5 g. of sodium in 300 ml. of methanol and heated in an autoclave at 130-140" for 4 hr. Water (20 ml.) wm added to the mixture, salts were separated, and methanol was evaporated in vacuo; the residue was extracted with chloroform, the extracts were concentrated, and the solid was recrystallized from heptane. Method A. 1-(3,4-Dimethoxybenzyl)-4-phenylpiperazine(V). -A solution of 93.25 g. (0.5 mole) of 3,4-dimethoxybenzyl chlorides and 162 g. (1 mole) of 1-phenylpiperazine in 800 ml. of anhydrous xylene was heated under reflux for 3 hr. After cooling and separation of about 100 g. (0.5 mole) of 1-phenylpiperazine hydrochloride, the solvent was evaporated in vacua and crude V was crystallized. 1-(3,4-Dimethoxyben~Ij-4-(2-methoxypheny~)piperazine Hydrochloride (XIV).-Following the same procedure, 1-(3,4dimethoxybenzyl)-4-(2-methoxyphenyl)piperazine was obtained as an oil after concentration of the xylene phase. To a solution of 36 g. (0.105 mole) of this base in 50 ml. of absolute ethanol was added 0.1 mole of 2 absolute ethanolic hydrogen chloride. After standing overnight at O", crude (XIV) was separated by filtration and recrystallized. Method B. 1-(3-Methoxy-4-hydroxybenzyl)-I-phenylpiperazine (VIII).-A mixture of 30.4 g. (0.2 mole) of vanillin, 35.6 g. (0.22 mole) of 1-phenylpiperazine, and 200 ml. of ethanol was heated for 3 hr. at 110' in a 1-1. autoclave, under an hydrogen initial pressure of 80 kg. at 20", over about 6 g. of Raney nickel catalyst. After cooling the catalyst was removed and the alcoholic solution was concentrated to about 80 ml. and allowed t o stand for 24 hr. at 0". Crude VI11 was collected and recrystallized. (0) G. Karmas and P. E. Spoerri, J . $m. Chem. Soc., 74, 1580 (1852).
(7) R. H. Mizeoni and P. E. Spoerri, ibid., 73, 1873 (1951). (8) M. Tiffeneau, Bull. aoc. chim. France, 9, 930 (1911).
Method C. 1-(2-Hydroxy-5-methoxybenzyl)-4-phenylpiperazine (VII).-To an ice-cold mixture of 24.8 g. (0.2 mole) of Ihydroxy-4-methoxybenzene and 32.4 g. (0.2 mole) of I-phtmylpiperazine in 90 ml. of ethanol and 50 nil. of water m s :ttldcd 20 nil. of aqueous formaldehyde solution. After stirritig for 45 hr. at room temperature, crystalline VI1 its filtered :tilt1 rerrystallized. Method D. 1-(3,4,5-Trimethoxybenzy1)-4-phenylpipiperazine Hydrochloride (X).-A solution of 23.05 g. (0.1 mole) of 3,4.6trimethoxybenzoyl chloride and 16.2 g. (0.1 mole) of 1-phenjdpiperazine in 150 nil. of anhydrous chloroform was refused for 2 hr. and evaporated t o dryness t o give a solid which vas rem?-stnllized from a chloroform-toluene mixture (1 : I ) t o give 1-(3,4,5trimethoxybenzoyl)-4-phenylpiperazine hydrochloride in 60(:, yield; ni.p. 216'. Antrl. C:tlcd. for C2CH&1-U.'01: C, tit.13; 11, 6AI ; CI, $).0:4. l+'oimd: C, 60.0; H, 6.4; C1, 9.4. The hydroc!hloridc was converted quantitatively t o t h e i r t v \)use hy alkalinization of nn :qrieous solution and recr~st,:~lliz;itiuri froin isopropyl ether; 11i.p. 13-1-133". Anal. C:~l(rd.for Cn&,S~O,: C, 67.3'3; I f , 6 . 7 , . 1 " u u l i t l : c,67.7; I i , ti.T.5. This base was also prepared by mixing ti solution of 4.6 g. (0.02 mole) of 3,4,5-triniethox?.benzi)~-lchloride in 10 ml. of anhydrous chloroform with a solution of 3,?4 g. (0.02 mole) of l-phenylpiperazine and of 1 .G g. of pyridine in 10 n i l . of anhydrous chloroform. After standing for 5 d:iye :Lt room tetnperature and washing t wiw with 20 nil. of water, the ~ ~ h l o r o f ~\vas ~ r mremoved in N C C I I O . 1ile cq-stalline residuo wrts recr\st:rllizecl froiii isopropyl ether tri
,.
Substituted 2,3-Dihydro-1,5-benzothiazepin-4(5H)-ones and 3,4-Dihydro-2-phenyl-(2H)-1,6-benzothiazocin-5(6H)-ones
The sjntliesis of substituted 2,3-dilij dro-1,5-bcn~:otlii~zepiri-4~.5H)-oncs :ind thtxir alkylation is described. Tlie preparation of 3,4-dili~dro-2-pl1enyl-2H-l,6-benzotliiti~o~in-~(6H)-ori~~ :tnd 6-(?-dimethylaminoethyl)-3,4dili~dro-Z-plienyl-2H-1,B-bcnzothiazo~in-~(6H)-~ne Iigdrocliloride is also rcpxtcd. Tlirec of tlicse compounds were found to be highly effective in calming rats with lesioris in the septal tireit of tlir>brain. 111 extension of our studies on substituted 2-phenyl1,~-beiixothiaxiii-3(4H)-oiies, we have prepared a number of related 2,3-dihydro-l..',-benzothiazepin-4 (,iH)-oiies (Table 11) and :3,~-dihpdro-'-plieiiyl-2H-l,fi1)ciizothiaxociii-5(GI3)-ones. The iiiteriiiediate 2,;2-dililvdro-l,T,-benzo~liiazepiii-~(ejI€)-oiieb(Table I) ~vereobtained by heating 2-aminobeiizcnethiol (or 2-amino-4-chlorobenzenethiol) ivitli t lie appropriate cinnamic, phenylcrotonic, or furanacrylic acid according to a procedure used for the pwparat ioii of 2,3-dihyd ro-2-methyl- 1,S-benzothiaxepin4(;H)-olie arid the 2-phenyl analog.2 The compounds listed in Table I1 were obtained hy addition of a slurry of tlic appropriate 1,5-benzothiazepin-4(5H)-nne in tolueiit to a slurry of sodamidc in tolucnc; tlic rebultiiik solution mas treated witli the correspondiiig babically-substituted alkyl chloride aiitl t lie mixturc niniiitaiiied u ~ a l l yat 60-GSo for 3 hr.. 'l'lie yield i i i tliis alkylation reaction is dependent o i l the stability of t h e t)eiiaotliiaztpiii-~(~H)-oiic to iiiig calc:nragc> under the reaction coiiditioiis and tlie rearI I I ~ i a ~ ~A.l ~ Saabo o , . \ r i d .J. \Villiams, J . 3 1 d Chem.. 6, 2 1 1 ( I 1 2 ) \\ 11 1111lr arid J . H. J % h t voltli, J . Chrm. SOC.,2738 (1927)
i
tility oi tlie alkyl halide. The alkylation of ? , M i liydro-2-plieiiyl-l)5-benzo thiaxepin-4 (5H)-one with 2cliiiietliylaiiiiiio~t114.1 cliloridr gave a 30yG yield of purified product ( 3 , Table 11); whereas tlie reaction with t h e l ( w rtactive X-dimethylariiinopropyl chloride gave only a !)?() yield of 6 and G3YGof 2'-(3-dimethylaniinopropylthi~)ciniiamanilide.~The formation of the lattw product was not surprising since treatinelit of %.3-dih~dro-2-phe1iyl-l,3-beiizotliiazepiii-4(jI-I)one with 10% potassium hydroxide was reported to yield 2,'-i~iercaptociiinamanilide.2 Hecause of the low reactivity of 2-(S-benzyl-Sniethy1aniino)rtliyl chloride under the above conditions, tlic wrrc,poiidiiig bromide was used in the reaction with .',:~-diliydro-2-phenyl-l,5-benzothiazepin-4(jH)-one t o give 5. The lioniologous 8-membeid ring systeni, 44-diliydro-~-plienyl-l,(j-beiizotlii~ zocin-.j(GH)-one, was prcpared as show11 on the following page.
