The Manufacture or Preparation and Production of New Medicinal Compounds.
Year: 1896

page_text: Date of Application, 17th Jan., 1896
Complete Specification Left, 16th Oct., 1896-Accepted, 21st Nov., 1896
PROVISIONAL SPECIFICATION.
The Manufacture or Preparation and Production of New Medicinal
Compounds.
I JAMES YATE JOHNSON of 47 Lincoln's Inn Fields in the County of London
Gentleman do hereby declare the nature of this invention (which has been
communicated to me from abroad by The Limited Liability Company trading
under the style of Vereinigte Chininfabriken Zimmer & Co. of Frankfort-on-the-
Maine in the German Empire) to be as follows:-
It is well known that salicylate of soda, salipyrine, malakine, and other
preparations have been employed as remedies for rheumatism. These agents,
when used in greater, or smaller, doses, exercise a certain anti-rheumatic action,
but they are at the same time in part apt to affect, more or less injuriously, the
function of the heart whilst some of them do not act upon the heart at all.
Sufferers from rheumatism are frequently very sensitive as regards their cardiac
functions, and in some cases suffer from a weak heart, therefore the employment of
such agents as remedies for rheumatism gives rise in many instances to injurious
secondary effects; or, where it is desirable also to favourably influence the action of
the heart, they fail to do so.
This invention has for its object to prepare medicinal matters which, while
exercising a powerful anti-rheumatic action, at the same time very beneficially
influence the action of the heart. This result is attained according to the present
invention by preparing derivatives of paraphenetidine, or paraanisidine,-not, as
has been usual in the case of malakine, by means of the phenol series, but by the
aid of the hydroquinone series, and thus the alkyloxy-group of phenetidine or
anisidine and the alkyloxy-group of an aldehyde of the hydroquinone series are
present in the same compound. The derivatives of gentisinaldehyde have proved
to be satisfactory agents for the accomplishment of this object. The preparations
thus obtained act upon the heart in such a manner as to regulate and invigorate
its action tending to moderate the pulsations and to increase the pressure of the
blood; an action which digitalis alone has hitherto been known to produce. The
preparations or compounds forming the subject of this invention, have, however,
this advantage over digitalis, that in addition to being free from any poison, they
can, owing to the individuality of their chemical nature, in all cases, be exactly
and reliably dosed, which is not the case, with the poisonous digitalis preparations,
owing to the irregularity of their composition. The effect of the latter is therefore
frequently unreliable and may in many cases be converted to an injurious character
in addition to which owing to their cumulative action, digitalis preparations are apt
to prove positively poisonous, which is never the case with the products obtained in
accordance with this invention. Furthermore the products according to this
invention are not liable to produce the unpleasant secondary effects upon the
digestive organs and nerves, which in many cases characterise digitalis
preparations.
According to the experiments which have had the result herein before indicated,
the product of the present invention constitutes condensation products from para-
phenetidine or para-anisidine on the one hand, and metamethoxysalicylaldehyde or
meta-ethoxysalicylaldehyde on the other, and these products are excellent
cardio-tonic and anti-rheumatic agents, besides being free from the objectionable

page_text: 14 kilogrammes of gentisinaldehyde are mixed with 14 kilogrammes of para-
phenetidine and 10 kilogrammes of spirits of wine in a distilling vessel; the alcohol
is slowly distilled off and the mixture heated for some time at a temperature of
from 120 to 140°.Ceutigrade.
The dark red mass thus obtained is crystallized from benzene or dilute alcohol.
It is obtained from benzene in the form of small, stout, salmon-coloured needles
(paradioxybenzylidene paraphenetidine), which disintegrate on exposure to air.
From alcohol the substance crystallizes in reddish-yellow leaflets, melting
at 119-120° Centigrade.
25.7 kilogrammes of this compound are then dissolved in 125 kilogrammes of
alcohol, 5-6 kilogrammes of caustic potash dissolved in the minimum quantity
of water being then added. When cold the mass is mixed with 11 kilogrammes
of hydrobromic ether and heated for several hours in a reflux apparatus, the
operation being very carefully conducted at first. Excess of hydrobromic
ether may be used, and hydrochloric or hydroiodic ether may be substituted
. for it.
The required product (meta-ethoxysalicylidene paraphenetidine) having the
constitution CH
OC₂H
N ==
он
OC,H CH, separates, on cooling, in large,
CH
brownish-yellow plates. It dissolves with great difficulty in water, but is readily
soluble in hot alcohol, benzene, ether and chloroform, and it dissolves in alkalis
forming a yellow solution. Mineral acids resolve it into paraphenetidine and
meta-ethoxysalicylaldehyde. The melting point is about 99° Centigrade. By
employing bromide of methyl instead of bromide of ethyl the corresponding

page_text: EXAMPLE 2.
Instead of alkylating at a subsequent stage of the operation, alkylated gentisin-
aldehyde (meta-alkyloxysalicylaldehyde) may be condensed with the para-
phenetidine. Thus 13-7 kilogrammes of paraphenetidine may be dissolved in
30 kilogrammes of spirits of wine and be treated with 15-2 kilogrammes of
meta-methoxysalicylaldehyde, the mixture being heated for a considerable period
and then allowed to cool, when the required meta-methoxy-compound crystallizes
out, the meta-ethoxy-compound is obtained in a corresponding manner by the
application of the meta-ethoxyaldehyde.
The mode of treatment may also be modified by condensing meta-alkyl-
oxysalicylaldehyde with para-amidophenol, and then alkylating the product.
Thus 152 kilogrammes of metamethoxysalicylaldehyde may be dissolved in
15 kilogrammes of alcohol, and be treated with 10.9 kilogrammes of para-
amidophenol, the alcohol is then slowly distilled off and the residue heated for
some time at from 120 to 140° Centigrade. The product of the reaction is
crystallized from alcohol. This product, consisting of metamethoxysalicyliden-
para-amidophenol, forms reddish-brown prisms which melt at 161° Centigrade.
By ethylating in accordance with well known methods, the corresponding
phenetidine derivative is obtained. If, instead of the meta-methoxysalicylaldehyde,
molecular proportions of the meta-ethoxysalicylaldehyde be employed, meta-
ethoxysalicylidenpara-amidophenol will be obtained, which crystallizes in red
needles and melts at 1850 Centigrade, and this may be couverted into the
corresponding phenetidine compound by ethylation.
In employing para-amidophenol gentisinaldehyde may be also used to start
with, in which case a double alkylation of the resulting condensation product will
have to be effected.
13.8 kilogrammes of gentisinaldehyde should in this case be dissolved in
12 kilogrammes of alcohol, and treated with 10-9 kilogrammes of para-amidophenol,
the process being continued in accordance with the directions given in Example 3.
The dioxybenzylidene para-amidophenol thus obtained crystallizes in reddish-
yellow needles, which melt at 192° Centigrade, and is soluble to a limited extent.
in water and readily soluble in alcohol and ether. This product may be converted
into para-dioxybenzylidene paraphenetidine by means of one molecule of halogenic
ether in the usual manner, and then by further treatment with methylic haloid or
ethylic haloid there can be obtained therefrom meta-methoxysalicylidenpara-
phenetidine or the corresponding meta-ethoxy-derivative. The last mentioned
derivative may also be obtained directly by ethylating the para-dioxybenzylidene-
paraphenetidine with two molecular proportions or an excess of halogenic ether.
The para-anisidine derivatives may be prepared in an analogous manner, the
metamethoxysalicylidenpara-anisidine having the constitution

page_text: and being brownish yellow crystals with a melting point of 82° Centigrade, whilst
the metaethoxysalicylidene para-anişidine has the constitution
The Manufacture or Preparation and Production of New Medicinal
Compounds.
I, JAMES YATE JOHNSON, of 47 Lincoln's Inn Fields, in the County of London,
Gentleman, do hereby declare the nature of this invention (which has been com-
municated to me from abroad by The Limited Liability Company, trading under
the style of Vereinigte Chininfabriken Zimmer & Co. of Frankfort on the Main in
the German Empire) and in what manner the same is to be performed, to be
particularly described and ascertained in and by the following statement :-
It is well known that salicylate of soda, salipyrine malakine and other
preparations have been employed as remedies for rheumatism. These agents
when used in greater or smaller doses exercise a certain anti-rheumatic action, but
they are at the same time in part apt to affect, more or less injuriously, the
function of the heart, whilst some of them do not act upon the heart at all.
Sufferers from rheumatism are frequently very sensitive as regards their cardiac
functions, and in some cases suffer from a weak heart, therefore the employment
of such agents as remedies for rheumatism gives rise in many instances to injurious
secondary effects; or, where it is desirable also to favourably influence the action
of the heart they fail to do so.
This invention has for its object to prepare medicinal matters which, while
exercising a powerful anti-rheumatic action, at the same time very beneficially
influence the action of the heart.
This result is attained according to the present invention by preparing derivatives
of paraphenetidine or para-anisidine, not, as has been usual in the case of malakine,
by means of the phenol series, but by the aid of the hydroquinone series, and thus
the alkyl oxy-group of phenetidine or anisidine and the alkyloxy group of an
aldehyde of the hydroquinone series are present in the same compound. The
derivatives of gentisinaldehyde have proved to be satisfactory agents for the
accomplishment of this object. The preparations thus obtained act upon the heart
in such a manner as to regulate and invigorate its action tending to moderate the
pulsations and to increase the pressure of the blood, an action which digitalis alone
has hitherto been known to produce. The preparations, or compounds forming
the subject of this invention have, however, this advantage over digitalis, that in
addition to being free from any poison, they can, owing to the individuality of
their chemical nature, in all cases, be exactly and reliably dosed, which is not the
case, with the poisonous digitalis preparations, owing to the irregularity of their
composition.

page_text: 14 kilogrammes of gentisinaldehyde are mixed with 14 kilogrammes of para-
phenetidine and 10 kilogrammes of spirits of wine in a distilling vessel; the alcohol
is slowly distilled off and the mixture heated for some time at a temperature of
from 120° to 140° Centigrade.
The dark red mass thus obtained is crystallized from benzene or dilute alcohol
It is obtained from benzene in the form of small stout, salmon-coloured needle
(paradioxybenzylidene paraphenetidine) which disintegrate on exposure to air. From
alcohol the substance crystallizes in reddish-yellow leaflets, melting at 119°—120°
Centigrade.
25-7 kilogrammes of this compound are then dissolved in 125 kilogrammes of
alcohol, 5-6 kilogrammes of caustic potash dissolved in the minimum quantity
of water, being then added. When cold the mass is mixed with 11 kilogrammes of
hydrobromic ether and heated for several hours in a reflux apparatus the operation
being very carefully conducted at first. Excess of hydrobromic ether may be.
used, and hydrochloric ether or hydroiodic ether may be substituted for it.
The required product (meta-ethoxysalicylidene paraphenetidine) having the

page_text: In employing para-amidophenol gentisinaldehyde may be also used to start
with, in which case a double alkylation of the resulting condensation product will
have to be effected...
13.8 kilogrammes of gentisinaldehyde should in this case be dissolved
in 12 kilogrammes of alcohol, and treated with 10-9 kilogrammes of para-amido-
phenol; the process being continued in accordance with the directions given
in Example 3. The dioxybenzylidenepara-amidophenol thus obtained crystallizes
in reddish-yellow needles, which melt at 192° Centigrade, and is soluble to a
limited extent in water and readily soluble in alcohol and ether. This product
may be converted into para dioxybenzylideneparaphenetidine by means of one
molecule of halogenic ether in the usual manner, and then by further treatment
with methylic haloid or ethylic haloid there can be obtained therefrom meta-
methoxysalicylidenparaphenetidine or the corresponding meta-ethoxy-derivative.
The last mentioned derivative, may also be obtained directly by ethylating the
para-dioxybenzylidenepara-amidophenol with two molecular proportions or an
excess of halogenic ether.

page_text: The para-anisidine derivatives may be prepared in an analogous manner, the
meta-methoxysalicyliden para-anisidine having the constitution
and being brownish yellow crystals with a inelting point of 82° Centigrade, whilst
the meta-ethoxysalicylidenepara-anisidine has the constitution
OH
OCH₂
CH
OC₂H-CH3
N ===
CH
and is also in brownish-yellow crystals with a melting point of 88° Centigrade.
Having now particularly described and ascertained the nature of the said inven-
tion and in what manner the same is to be performed, I declare that what I
claim is :-
1. The manufacture or preparation of anti-rheumatic agents which are also
capable of exercising a favourable action upon the functions of the heart, i.e. either
metamethoxysalicylideneparaphenetidine or meta-ethoxysalicylidene parapheneti-
dine, or either of the corresponding compounds of para-anisidine; the method of
preparation mainly consisting in condensing either para-phenetidine, or para-
anisidine with alkylated gentisinaldehyde (metamethoxysalicylaldehyde or meta-
ethoxysalicylaldehyde) either directly or indirectly, by substituting gentisin-
aldehyde for the alkylated aldehyde, or para-amidophenol for the paraphenetidine
or para-anisidine or by making both such substitutions and in each of these latter
cases subsequently alkylating.
2. The manufacture or preparation of the new products according to the several
processes given in the foregoing examples.
3. The new articles of manufacture such as are hereinbefore defined as being
the products of this invention.
Dated this 16th day of October 1896.
and is also in brownish-yellow crystals with a melting point of 88° Centigrade.
Having now particularly described and ascertained the nature of the said inven-
tion and in what manner the same is to be performed, I declare that what I
claim is:
1. The manufacture or preparation of auti-rheumatic agents which are also
capable of exercising a favourable action upon the functions of the heart, i.e. either
metamethoxysalicylideneparaphenetidine or meta-ethoxysalicylidene parapheneti-
dine, or either of the corresponding compounds of para-anisidine; the method of
preparation mainly consisting in condensing either para-phenetidine, or para-
anisidine with alkylated gentisinaldehyde (metamethoxysalicylaldehyde or meta-
ethoxysalicylaldehyde) either directly or indirectly, by substituting gentisin-
aldehyde for the alkylated aldehyde, or para-amidophenol for the paraphenetidine
or para-anisidine or by making both such substitutions and in each of these latter
cases subsequently alkylating.
2. The manufacture or preparation of the new products according to the several
processes given in the foregoing examples.
3. The new articles of manufacture such as are hereinbefore defined as being
the products of this invention.
Dated this 16th day of October 1896.
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.