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Патент USA US2404219

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Patented July 16, v1946
John W. Cusic, Skokie, Ill., assignor‘ to G. D.
Searle .& (30.. Skokie, 111., a corporation 0111'
‘ linois'
No. Drawing ‘Original application October 7,.
I943‘, S'erial‘No. 505,355. Dividecl'and this am?i- ,
cation: May 12, 1945, Serial No. 593,541
"_ _
2 Claims. (01. 260,-—29_3)
This invention relates to new compositions
" or that the nitrogen is itself‘ a part: ot a cycloa
of matter which maybe advantageously used
aliphatic’ ring.
invention relates to new compositions of matter
which are tertiary aminoderivatives of dihydro- I
anthracene. These new compounds may be
represented by the formulae:
; 2"
of such preparation:
by the interaction of an alkali metal derivative
of dihydroanthracene with an appropriate di
alkylaminoalkyl halide or N-methyl-‘i-halogene
piperidine. The following is a detailed example
.I have‘found that the compositions of the
present invention‘may be conveniently prepared
as antispasmodic agents. ' More particularly, the
I OHr—C1\12
0% Gib-CH2/NR
wherein n stands for the integer 2 or 3 and R
and R1 each represent an unsubstituted alkyl
group containing not more than four carbon
atoms. It will be noted that these compounds
1 I.
A solution of butyl lithium in dry ether is pre
pared in the usual manner from 27.4 grams of
n-butyl bromide and 2.8 grams of lithium. This
15 solution is added gradually to a solution or sus
pension of 18.0 grams of dihydroanthracene in
dry ether, and the resulting solution re?uxed for
about two hours. The whole operation is pref
erably conducted under an atmosphere of
nitrogen. At the end of this time, 15 grams of
'y-diethylaminopropy1 chloride are added, and the
resultant mixture stirred for twelve hours or
are structurally quite similar; those of Formula
more without heating. A small amount of ‘alco
II can be derived from Formula I (where n is 3
hol is added to decompose any unreacted organo
and R1 is an ethyl group) by a simple attach 25 metallic compounds, and‘the reaction mixture
is extracted with dilute hydrochloric acid. The
,ment of the R1 group to the ?rst carbon in the
side chain. These compounds have been tested
acid extract is made alkaline, and the free base
and found to be powerful and useful antispas—
recovered by ether extraction of this alkaline
modic agents. Only the compounds represented
liquor and subsequent evaporation of the ether.
by Formula II above are claimed in this appli 30 It is an oil which can readily be ‘puri?ed by
cation; the compounds represented by Formula
vacuum distillation; it boils at 1737-175° centi
I are claimed in applicant's original application,
grade at 6 millimetres of pressure.
. Serial No. 505,355, ?led October '7, 1943, of which
The free base readily forms salts with acids,
the present application is a division.
most of which are solid, crystalline compounds
The prior art has disclosed several different
which are more convenient to handle for use
categories of synthetic antispasmodic agents,
as Inedicinals. Further, the salts are in general
most of which, however, have been characterized
by the presence of some functional group (as,
for instance, an ester group) in addition to the
readily soluble in water, whereas thefree base
is quite insoluble in water.
These salts may be
obtained by neutralizing a solution of the base
tertiary amine group in the molecule. Blicke 40 in dry ether with an absolute alcoholic solution
(Journal of American Chemical Society, volume
of the desired acid. Thus, the hydrochloride
61, pages 91 and 771) has disclosed a series of
was obtained as a crystalline compound which
tertiary amines, free of other functional groups,
melts at 181-183° centigrade.
some of which are stated to be active as anti
The above example is merely illustrative; use
spasmodic agents. However, those stated to be 45 of other aminoalkyl halides or of 4-halogen-N
active are invariably characterized by the
alkylpiperidines in the same procedure will yield
presence of two aralkyl or hydrogenated aralkyl
the corresponding amines and salts thereof.
groups attached to the nitrogen atom; con
Among other compounds, I have thus prepared
versely, those which contained two simple alkyl
the p-diethylaminoethyl, the c-dibutylamino
groups On the nitrogen atom (as in the present 50 ethyl, the ,B-diethylaminopropyl and the N-meth
invention) were all stated to be inactive. The
yl-piperidyl-4-derivatives of 9,10-dihydroanthra
antispasmodic agents of this invention thus
cene, together with their hydrochlorides and other
notably differ from those disclosed as active
by Blicke in that they have the one aralkyl group
In determining the utility of these substances
characterized by the dihydroanthracene nucleus, 65 as antispasmodic agents, I have found that
9- (p-diethylaminoethyl) -‘9, IO-dihydroanthracene
I claim:
1. New compositions of matter comprising tel‘!
hydrochloride isfa preferred compound. Illus-‘
tiary amines of the formula:
trative of its utility as an antispasmodic agent is
the fact that, when tested on isolated strips 01‘.
rabbit intestine or uterus, it has shown a powerful
relaxing‘ effect; both on untreated muscle and on
muscle which had previously been stimulated by a
drug such as acetylcholine or histamine. Quanrfpj f
titatively, its potency equals or surpasses thatofv V
such drugs as the diethylaminoethyl: esters‘ oi
?uorene-9-carboxylic acid or of diphenylacetic '
10 v.
acid, both of which are ?nding acceptance among
the medical professions in-thi's country,:and ap-‘ 7'1
NR '
wherein R represents an alkyl group containing
not more than four carbon atoms.
3 , proaches that of atropine.
A new composition of matter comprising
15 9— 2.
(N=methylpiperidyl-4) -9, 10- dihydroanthracene
shown to be approximately as potent as the above
'y-diethylaminopropy1 Y derivative 7 v was
cited compound in similar tests. otherswill vary" “ I
of the formula; . ' 1.;
among themselves somewhat, but all constitute
I a group of powerful antispasmodic drugs. They
also vary somewhat among themselves in toxicity, 20
but in each case theitoXic dose is greatly‘ in excess
of the therapeutically effective dose;j,s0' that these
compounds may be safely'administ‘ered to man or
' animals ,-in effective doses without untoward side
It is tobe understood that the amino com
pounds referred to .in the?appended, claims ‘are
intendedto refer .to the bases describedtherein;
whether they be in the form .of the free base or
of a salt with a non-toxic acid.
' ’
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