May 5, 1957
VASODILATOR AND ADRENERGIC BLOCKING AGENTS
and extracted with ethyl acetate. A small amount of chloroform was added and crystallization was induced by scratching. An analytical sample was not obtained. The free acid I11 was decarboxylated by heating in several solvents, including methyl ethyl ketone, 2-propanol, aceto-
[COXTRIBUrION FROM THE ORGANIC CHEMICAL
2221
nitrile and pyridine. The ‘yield of crystalline acetyl Pmethyltryptophan was always near 3070. Decarboxylation in water or toluene, which did not dissolve the acid 111, led to red tar.
URBANA,ILL.
RESEARCH SECTIOB, RESEARCH DIVISIOB, LEDERLE LABORATORIES, CAN CYANAMID COMPANY]
AMERI-
Vasodilator and Adrenergic Blocking Agents. I. 1,4-Disubstituted Piperazines and Related N-Phenylethylenediamine Derivatives BY F. L. BACH,JR., H. J. BRABANDER AND S. KUSHNER RECEIVED SEPTEMBER 10, 1956 The syntheses and physiological properties of a series of 1,4-disubstituted piperazines arid ?;-pheiiylethyleiiediamirie derivatives are described. Also a discussion dealing with the importance of the phenyl and pyridylpiperazine nuclei in developing strong adrenergic blocking agents of this type is included.
In recent years a considerable number of compounds exhibiting strong vasodilator or adrenergic blocking action have been described in the literature.’ However, because of undesirable side effects and poor oral activity, very few of these agents have found therapeutic application in the treatment of peripheral vascular disease. Two classes of compounds which have received considerable attention for their ability to inhibit responses to epinephrine are the 6-diaralkylaminoethyl chlorides and the aralkylimidazolines. I n our laboratories, pharmacological testing indicates that l-methyl-4phenylpiperazine (I) is also an effective vasodilator and adrenergic blocking agent. To elucidate the structural requirements necessary for activity in this compound, we prepared a series of K-phenylethylenediamine derivatives. These diamines are related to products which would be formed by a scission of the piperazine ring of the active structure2 I. The diamines were
the simple isosteres derived from the parent compound I where one amino group is substituted by lower alkyls were relatively inactive6 when compared to Priscoline’ which was used as a standard. However, a marked increase in vasodilator activity was observed when these substituents were replaced by di-n-propyl or benzyl groups. An extension of this work was the reconstitution of a piperazine ring to include one of the terminal N-atoms of the N-phenylethylenediamine structure. This led to the synthesis of a series of 1[p-(N-ethyl-N-phenylamino) -ethyl]-4-substituted piperazines which are described in Table 11. Preparation of these compounds involved a condensation between the p- (N-ethyl-N-phenylamino)-ethyl chloride monohydrochloride and 1-substituted piperazines in refluxing ethanol using sodium bicarbonate as an acid acceptor. The biphenylpiperazine analog was synthesized stepwise by condensing the appropriate haloalkylamine with diethanolamine to yield N-ethyl-N’,N’-di-(/?-hydroxyethyl) N-phenylethylenediamine. In the next step, reductive cyclization of the di-(P-hydroxyethyl) amino portion of the molecule with 4-aminobiphenyl was accomplished in poor yield by subjecting a solution of the two reactants in dioxane over copper chromite to approximately 93 atmospheres of hydrogen for 7 hr. a t 250’. An inspection of the syiithcsizecl by thc iriteractivii of one iiiolecular activity ratings listed in Table 11 reveals a sharp equivalent of P-(N-ethyl-N-pheny1ainino)-ethylchange in biological response when the N-methyl, chloride monohydrochloride with two molecular acetyl and carbethoxy groups in the piperazine equivalents of the appropriate primary or secondary moiety are replaced by phenyl, 2-pyridyl or 2amine in a refluxing water-ethanol solution. De- (6-methyl)-pyridyl radicals. Based on these findrivatives of a similar nature have been tested as ings a study of the scission products of I has by a antihista~nines.~,~ The fact that structural similari- circuitous route established the importance of not ties exist between adrenergic blocking agents and only the phenyl piperazine but also the pyridyl compounds which antagonize spasmogenic sub- piperazine nucleus as a center of activity. It is stances, such as acetylcholine and histamine, has also apparent that strong vasodilatation and adrenbeen discussed by B ~ r g e r . ~ As shown in Table I, ergic blocking action* are obtained when the simple alkyl substituent in I is replaced by a p-(N-ethyl(1) L. S. Goodman and A. Gilrnan, “The Pharmacological Basis of N-phenylamino) -ethyl chain 11. Preliminary studTherapeutics,” 2nd Ed., T h e hfacmillan Co., New York, N. Y . , 1955, (Bibliography), pp. 592-595. ies indicate that compound I1 is orally active in (2) W. T. Forsee and C. B. Pollard, THIS JOURNAL, 67, 1788 the test animal. (1935).
(3) A. M. Staub, A n n . I n s f . Parleur, 63, 400, 420, 485 (1939). (4) B. N. Halpern, Arch. I n l c m . Pkarmacodynamie, 68, 339 (1943). ( 5 ) A. Burger, “Medicinal Chemistry,” Vol. I, Interscience P u b lishers, Inc., N e w York, N. Y.. 1951, p. 359.
(6) See footnote (a), Table I , for explanation of vasodilator activity. (7) 2-Benzyl-4,5- imidazoline monohydrochloride. (8) See footntoes b a n d c, Table I, for explanation of adrenergic blocking action.
2222
L. BACH,JIC., H. J. BRABANDER A I ~ DS.KUSHNEK
17.
TABLE I C,Hs) CI-12CII2R
C:6HbX(
Yield,
R
-P\"cH,* -N(CHi) z E l h -N(CHZCHZOII)Z/.~ -N(n-C1H7)tf -NHCHzCsH6
48 60
58 28 31
52
h1.p. or b p , "C. Mm. 179-181d 199-200d 195-200 1.5 121-122 0.5 157-161 0.5 185-188
--
Empirical formula CiIHioCl*Nz CizHnClzXa CikHdT'zOn CiaHzaNn CI~H~NI ClrHprCliNsd
Vol. 79
7 . -
C 52.8 54.3 86.7 77.5 80.3 02.3
Analyses, Tu----------. Cdcd.-----Found-H N CI C II PIT C1 8.0 11.2 2 8 . 3 52.4 8 . 1 11.0 2 7 . 9 8 . 3 10.6 2 6 . 8 5 4 . 5 8.5 1 0 . 6 26.2 9 . 5 11.1 6 6 . 3 10.0 1 0 . 8 1 1 . 3 11.3 76.9 11.1 11.7 8 . 7 11.0 80.6 9 . 0 11.1 7.; 8 . 6 21.7 62 2 7.7 8 . 9 21.5
Vaso. dilator0 activity
Adrenergic blocking action
DC
Ib
(7
I+
0 0 I+
4+
o
n
4+
I+
l i
I+ 2+
0
>I+"
Vasodilator activity vms determiiied in the isolated perfused rabbit ear (all compounds tested as hydrochlorides i!i 0.1% solution using buffered, perfusion fluid as diluent). The vessels of the ear were constricted by the addition of epinephrine t o the perfusion fluid and the increase of venous effluent measured by a drop recorder was the index of vasodilator nr adrenergic blocking action. Ratings of 0 , 1, 2, 3 or 4+ were assigned to compounds which showed, respectively, 0-:, 6-69, 70-120, 121-170 or > 170% of Priscoliiie activity. When a compound showed strong vasodilator activity in initL I screening, the possibility of adrenergic blocking activity was investigated in the anesthetized dog. I represents intensity of adrenergic blockade measured in % inhibition or reversal of intravenous epinephrine pressor response. A rating of 0,1 ( ' r 2+ was assigned t o 0-19, 20-50 or 51-100% inhibition. Partial reversal and complete reversal were rated 3 + and 1-t. respectively. D represents duration of adrenergic blockade. A rating of 1, 2, 3 or 4 + was assigned to durations of 4 hours. submitted for testing as diliydrochlorides in 1.0% aqueous solution. 0 The sign > was used when an experiment was discontinued before duration nf action ended. h See Experimental. i Dihydrochloride prepxred by passing hydrogen chloritl L through ethereal solution of basic material. a
:(I
3l.p. or b.p.. OC. Mm. 0.5 138-142 192-197 .5 214-216 .5 186-189 200-202 205-210 .2 223-224 .5 225-227 225-228 218-220 .5 2 20-2 2 2 235-240 .6 214-216 11.5- 116 ?21-224 210-21R B 2 13-2 1r, 205-210 .I 2 12-21 2 225-230 2ri
2!1
21(~,-218
Yield,
%
25 26 95'
49 51
59 30
G2 8 1.1
35 63
Bmpiricrl formula
I
38
C 73.0 69.8 61.7 66.9 54.0 77.7 89.7 69.5 63.0 69 5 63.0
74.3 1'37.2 81 0
