The Manufacture of Certain Bodies suitable as Remedies.
Year: 1894

page_text: Date of Application, 22rd Mar., 1894
Complete Specification Left, 24th Dec., 1894-Accepted, 9th Feb., 1895
PROVISIONAL SPECIFICATION.
The Manufacture of Certain Bodies suitable as Remedies.
1, AUGUST ZIMMERMANN, of 6 & 7 Cross Lane, St. Mary-at-Hill in the City
of London, Merchant, (a communication to me from abroad by The Chemische
Fabrik auf Actien (vormals E. Schering) of 170 & 171 Mullerstrasse, Berlin), do
hereby declare the nature of this invention to be as follows:-
The Chemische Fabrik auf Actien (vormals E. Schering) was the first to
suggest the substitution of an organic base for lithia or other inorganic alkalies in
the therapeutical treatment of uric acid diathesis.
The following considerations
led up to this.
Gout is well known to be caused by retention of uric acid in the system. The
extremely insoluble uric acid deposits in the body as such or in the form of
its difficultly soluble sodium salt and thereby produces gouty symptoms. As
although the urates of the alkalies dissolve with difficulty, but still are more easily
soluble than uric acid itself, therefore up to the present the employment of alkali
carbonates or alkaline waters has been the basis of the medicinal treatment of gout
and stone.
Consequently it was a new idea to introduce an organic base in place of the
inorganic alkalies in the hope that perhaps one of these organic bases would prove
to form a more readily soluble salt with uric acid than the alkalies like soda,.
lithia etc.
The prospect was the more promising because it was found that the
organic bases, in distinction to the inorganic alkalies, with which they otherwise
compare very closely in chemical behaviour, exhibit a very variable behaviour
towards uric acid especially. The Chemische Fabrik auf Actien (vormals:
E. Schering) established a greater solvent power of uric acid in the case of
a number of organic bases as compared with inorganic bases. The discovery of
this fact did not however fully open the way to the employment of these bases as
solvents of uric acid in the system. The general principles determining the
possibility of employing an organic base as a gout remedy could only be established
by numerous experiments. The requirements found necessary to be taken into
consideration in deciding as to the adaptability of a base as a uric acid solvent, are
the following:
1. The base must form a very easily soluble salt as compared with the alkali
urates, even in excess of uric acid.
2. It must be absorbed by the system when taken into the stomach.
3. It must not be decomposed in the system, as is the case with many organic
bases; on the contrary it must pass through the system undecomposed if its solvent
power is to be developed in the body.
4. It must not produce any disturbances in the system, but must be generally
indifferent. It must not have a caustic or a toxic action.
From a large number of substances that partially but not completely fulfil these
conditions, piperazine was selected as completely answering all requirements and
has as a matter of fact rendered excellent service as a gout remedy.
Further The Chemische Fabrik auf Actien (vormals E. Schering) has found that
such bases which have a caustic action, but otherwise fulfil the above conditions,
may also be employed as solvents of uric acid in the system if introduced in the
form of a salt easily liberated or decomposed in the system. It has been

page_text: discovered that well crystallised salts of different bases with carbonic acid or
organic acids can be prepared, which develope a solvent action on uric acid in the
system, varying in degree according to their character. Thus, for instance,
tetraethylammonium hydroxide cannot be employed as such in concentrated aqueous
solutions. In a concentrated state the base possesses caustic properties similar to
those of caustic potash. This caustic character is not however possessed by the
carbonate of tetraethylammonium or by the salts of tetraethylammonium with
organic acids. The latter are decomposed in the system into the carbonate, which
can develope a similar solvent action on uric acid though not to such a high degree
as the free base, which is itself converted into the carbonate in the system. Tetra-
ethylethylenediamine, hexaethylethylenediammonium hydroxide and others exhibit
a similar behaviour.
The preparation of the carbonates is effected by the action of carbonic acid upon
the aqueous or alcoholic solutions of the respective bases, or by leading a stream of
carbonic acid gas over the anhydrous base. The preparation of salts of organic
acids is effected by mixing the bases with the respective organic acids in equivalent
proportions, according to whether a basic or acid salt is desired, in aqueous or
alcoholic solution. The salts partly crystallise out of the solution, partly are
obtained by evaporation. The following salts have been prepared which were not
hitherto known and which are oxidised to carbonates in the system.
1. Piperazine tartrate.
2. Tetraethylammonium tartrate.
3. Piperazine-tetraethylammonium tartrate.
4. Piperazine citrate.
5. Tetraethylammonium citrate.
6. Piperazine sodium tartrate.
7. Piperazine potassium tartrate.
8. Piperazine lithium tartrate.
9. Tetraethylammonium sodium tartrate.
10. Tetraethylammonium potassium tartrate.
11. Tetraethylammonium lithium tartrate.
12. Tetraethylammonium carbonate.
13. Tetraethylammonium acetate.
14. Piperazine lactate.
15. Tetraethylammonium lactate.
Date this 21st den of Marah 1201
COMPLETE SPECIFICATION.
The Manufacture of Certain Bodies suitable as Remedies.
I, AUGUST ZIMMERMANN, of 6 & 7 Cross Lane, St. Mary-at-Hill, in the City
of London, Merchant, (a communication to me from abroad by The Chemische
Fabrik auf Actien (vormals E. Schering) of 170 & 171 Müllerstrasse, Berlin) do
hereby declare the nature of this invention and in what manner the same is to be
performed to be particularly described and ascertained in and by the following
statement:-
The Chemische Fabrik auf Actien (vormals E. Schering) was the first to
suggest the substitution of an organic base for lithia or other inorganic alkalies in
the therapeutical treatment of uric acid diathesis. The following considerations
led up to this :-
Gout is well known to be caused by retention of uric acid in the system. The
extremely insoluble uric acid deposits in the body as such or in the form of

page_text: As
its difficultly soluble sodium salt and thereby produces gouty symptoms.
although the urates of the alkalies dissolve with difficulty, but still are more easily
soluble than uric acid itself, therefore up to the present the employment of alkali
carbonates or alkaline waters has been the basis of the medicinal treatment of gout
and stone.
Consequently it was a new idea to introduce an organic base in place of the
inorganic alkalies in the hope that perhaps one of these organic bases would prove
to form a more readily soluble salt with uric acid than the alkalies like soda,
lithia etc.
The prospect was the more promising because it was found that the
organic bases, in distinction to the inorganic alkalies, with which they otherwise
compare very closely in chemical behaviour, exhibit a very variable behaviour
towards uric acid especially. The Chemische Fabrik auf Actien (vormals
E. Schering) established a greater solvent power of uric acid in the case of a
number of organic bases as compared with inorganic bases. The discovery of
this fact did not however fully open the way to the employment of these bases as
solvents of uric acid in the system. The general principles determining the
possibility of employing an organic base as a gout remedy could only be established
by numerous experiments. The requirements found necessary to be taken into
consideration in deciding as to the adaptability of a base as a uric acid solvent, are
the following:-
1. The base must form a very easily soluble salt as compared with the alkali
urates, even in excess of uric acid.
2. It must be absorbed by the system when taken into the stomach.
3. It must not be decomposed in the system, as is the case with many organic
bases; on the contrary it must pass through the system undecomposed if its solvent
power is to be developed in the body.
4. It must not produce any disturbances in the system, but must be generally
indifferent. It must not have a caustic or a toxic action.
From a large number of substances that partially but not completely fulfil these
conditions, piperazine was selected as completely answering all requirements and
has as a matter of fact rendered excellent service as a gout remedy.
Further The Chemische Fabrik auf Actien (vormals E. Schering) has found
that such bases which have a caustic action, but otherwise fulfil the above
conditions, may also be employed as solvents of uric acid in the system if intro-
duced in the form of a salt easily liberated or decomposed in the system. It has
been discovered that well crystallised salts of different bases with carbonic acid
or organic acids can be prepared, which develope a solvent action on uric acid in
the system, varying in degree according to their character. Thus, for instance,
tetracthylammonium hydroxide cannot be employed as such in concentrated
aqueous solutions. In a concentrated state the base possesses caustic properties
similar to those of caustic potash. This caustic character is not however possessed
by the salts for instance of tetraethylammonium with organic acids. These salts
prepared with organic acids, carbonic acid excepted, are converted in the system
into the carbonate be it by direct oxidation or by the action of the bicarbonate of
the blood in consequence of a twofold transformation of the organic acid salts with
the bicarbonate. The carbonate can develope a similar solvent action on uric
acid though not to such a high degree as the free base, which is itself converted
into the carbonate in the system. Tetraethylethylenediamine, hexaethylethylene-
diammonium hydroxide ethenylethylenediamine and others exhibit a similar
behaviour.
The preparation of the carbonates is effected by the action of carbonic acid
upon the aqueous or alcoholic solutions of the respective bases, or by leading
a stream of carbonic acid gas over the anhydrous base. The preparation of
salts of organic acids is effected by mixing the bases with the respective
organic acids in equivalent proportions, according to whether a basic or
acid salt is desired, in aqueous or alcoholic solution. The salts partly crystallise

page_text: out of the solution, partly are obtained by evaporation. The following salts have
been prepared which were not hitherto known.
1. Piperazine tartrate.
2. Tetraethylammonium tartrate.
3. Piperazine-tetraethylammonium tartrate.
4. Piperazine citrate.
5. Piperazine salicylate.
6. Tetraethylammonium citrate.
7. Piperazine sodium tartrate.
8. Piperazine potassium tartrate.
9. Piperazine lithium tartrate.
10. Tetraethylammonium sodium tartrate.
11. Tetraethylammonium potassium tartrate.
Tetraethylammonium lithium tartrate.
12.
13. Tetraethylammonium carbonate.
14.
Tetraethylammonium acetate.
15. Piperazine lactate.
16. Tetraethylammonium lactate.
17. Ethenylethylenediamine citrate.
18. Ethenylethylenediamine salicylate.
Having now particularly described and ascertained the nature of my said inven
tion and in what manner the same is to be performed, I declare that what I
claim is :-
:-
1. The new remedial products substantially as described.
2. The manufacture of the carbonic salts of organic bases such as tetraethyl-
ammonium, tetraethylethylenediamine, hexaethylethylenediammonium hydroxide by
the action of carbonic action upon these bases substantially as described.
3. The manufacture of organic acid salts of the bases referred to in the
Specification by the action of such organic acids as for instance tartaric, citric
acetic, lactic, and salicylic acids upon the base in molecular proportions substantially
as described.
4. The manufacture of mixed organic acid salts by the action of poly-basic organic
acids upon two or more of the previously mentioned organic bases, substantially as
described.
Dated this 18th day of December 1894.
AUG. ZIMMERMANN.