ITEM NO. 24 
*J?ILH NO. XXm-17 
COPY NO. 23 
CONFIDENTIAL 
Britl.h COvCiro-H 
Uniljd. Stales CONflU„aj. 
PROFESSOR DOCTOR WERNER 
SCHULEMANN 
MALARIOLOGIST 
CONFIDENTIAL 
COMBINED INTELLIGENCE OBJECTIVES 
SUB-COMMITTEE CONTIDSHTIAL 
INTSRT11WS WIT I TROTS 3 SOI DOCTOR WSRNBl SCMJLSMARX 
MALARIOLOGI ST 
TORMULT OT BOXV UVITSR81TT 
Reported By 
Co meander CIAHLBS L. McCAlTIY (MC) U.S.H.R. 
Major MOHBOB X. THZSMAN, 8nC, A.D.S. 
Doctor IAMILTON SOUTIWORTI, U.8.T.I.S. 
CIOS Target Hoaxer 2U/1J d 
Medical 
COMBIFID I9TXLLI3BNCX 01JBCTIY1S SUB-COMMITTEE 
S-2 Dlrielon, SMART (Rear) ATO U13 
CONTIDXNTIAL CONFIDENTIAL 
OF CONTEND 
'v 
Subject Page No. 
Introduction 3 
Interview by Commander McCarthy and Major Freeman. 
(Section I) 
General Information 3 
Organization of Institute at University of Bonn and at 
Bad Oeynhausen 4 
Report on use of Atebrin and of Chinoplasmin in 
257 soldiers with benign tertian malaria 6 
Experimental research on antimalarials. Description 
of methods used. 6 
Chemical Formula and Synthesis of S-ll 9 
Miscellaneous information secured from Professor 
Schulemann 10 
Section II 
Interview by Doctor Southworth 
Recent work of Professor Werner Schulemann 11 
S Series of Compounds 11 
General comments on antimalarials 13 
Other drugs 14 
Conclusion 15 
Appendices 
1. Structural formulae of S Series of compounds 16 
II. Schulemann*s modified Giemsa staining technique 27 
III. Diapromin - prophylaxis tests in malaria 28 
infection by mosquito and blood transmission - 
F. Sioli. 
Composition of teams : as shown on page I 
£2&FIDEJiT!4L CONFIDENTIAL 
Introduction! 
This report consists of two separate interviews with 
, Professor Doctor Werner Schuleman, The first was conducted on 9 
and 10 May 194$ by Major Monroe £• Freeman, Sn.C., A.U.S. and 
Commander Charles L.McCarthy (M.C.) U.S.N.R. and the second on 
2$ May 194$ by Doctor Hamilton Southworth U.S.P.H.S. The two inter- 
views cover essentially the same material but, since they differ 
materially in detail and presentation, both are being included in 
the report. 
Section I 
Interview by Commander McCarthy and Major Freeman. 
General Information! 
Prof. Dr. Werner Schuleman is $7 years of age and speaks 
fluent English. Prom 1918 to 1936 he was head of the Pharmaceutical 
Department of the I.G. Farbenindustrie Plant at Elberfeld. He left 
that company for personal reasons and Bonn University as 
Prof, of Pharmacology and Director of the Institute of Pharmacology. 
In 1924# together with Frits SchBnhftfer and August Wingler, he 
discovered Plasmochin, the first synthetic antlmalarial. For this 
he received the Emil Fischer Medal from the German Chemical Society 
in 1928*. Schulemann is also the discoverer of Phanodorm and many other 
new chemical compounds which are now widely used as local anesthetics. 
He received the Mary Kingsley Medal from the Liverpool School of 
Tropical Medicine in 1938. In 1939 he gave a series of lectures 
sponsored by the University of London, at The Wellcome Research 
Institution. 
Since leaving the employ of the I.G .Farbenindustrie, he has 
continued to work on synthetic antlmalarials, particularly on a new 
group of compounds designated the 'S1 group and comprising seventeen 
related substances. Compounds of this group were synthesised in 
1928 and patents taken out by the I.G. Farbenindustrie Company. They 
were tested by Dr. Roe hi and found to have no chemotherapeutic value. 
Since termination of his contract with the I.G. Company, in 1941 % Prof. 
Sehuleman has been connected with thd partially subsidized by the 
Sobering Chemical Co. of Berlin, This firm now makes S-ll, the 
most Important member of this group, end holds the patent rights to 
it. 3-11 has never been placed on the market and only enough has 
been made to supply Prof. Schulemann for his experiments. 
Schulemann is a graduate in medicine as well as a chemist, and 
for the past five years has been civilian consultant on anti-malarials 
to the German National Research Council (Reichsforschungsrat) , On IB October 1944 his Institute at Bonn was completely destroyed 
by bombing. He sent his three chemical assistants mentioned below 
to Berlin to work in the Pharmacological Institute under Prof. Heubner. 
Work on the »S» Group had scarcely started there when they were bombed 
out in January, 1945. No further chemical investigation has been done 
since October 1944. 
A number of experimental animals and mosquitoes Infected with 
Plasmodium galllncum and P. cathemerlura were rescued at Bonn and 
used as a nucleus to set up a temporary laboratory in the three 
top floors of the Cwynhausem Reserve Hospital. This hospital of 450 
beds received a large number of chronic malaria cases and the labor- 
atory was able to carry out blood studies on the toxicity of atabrin, 
quinine hydrochloride and plasmochin. 
fiMWlMrtlpn Of Institute at University of Bonn and at Bad 
poynhftypen. 
Upon affiliation with the University of Bonn, Prof. Sohulemann 
began the organization of an Institute for research on malaria, tryp- 
anosomiasis, . and other transmissible diseases. This organization 
was fairly well established and all divisions outlined below were 
operating when the laboratories were destroyed in October 1944. Div- 
isions and Professional Staff at the University of Bonn wore as 
followsI 
Directors Prof, Schulemann, 
Investigations on Protozoa, Malaria, and Trypanosomiasiss 
Dr. Hermann Wurmbach, Fr&ulein Luise Kratz. 
Investigations on Bacterial Infections* 
Dr. Oesterlein, Dr, Krelser, Dr. Ching (now dead) 
Pharmacology and Toxicology: 
Prof, Schulemann, Dr. Lopf. 
Synthetic Chemistry: 
Dr. Obstcrlein, Dr. Saure, Dr. Zlrfas. 
Animals: 
Herr Dohm. 
The additional laboratory assistants and cleaners are not listed. 
Funds supporting this work came from the following sources: 
a) For equipment and supplies: 
1) University of Bonn 22,000 RM 
2) Deutsche Forschungsgemeinshaft 25,000 « 
3) Special Fund, Ministry of Educ- 
ation 5.000 " 
(Approx). 50,000 " per yr. 
4) Additional funds were provided (if needed) by 
Sobering Pharmaceutical Co., Berlin. b) Salaries sere paid by: 
1) Ikiiversity of Bonn. 
2} Deutsche Forschungsgemelnschaft 
3) Sobering Pharmaceutical Co. 
thi e8?*"OUJ°58 °f lncom* have the laboratory of 
the University of Bonn were abandoned. 
Conversations with Prof. Schulemann indicated that the chief 
a^iV^ty Bonn was research malaria. Work on the bactericidal 
effects of some barbiturate compounds had been under way, but had 
not progressed far. The Division of Pharmacology and the Division of 
I*? Synthetic Chemistry were funding S 
of the malarlal Investigations. The Chemistry division had synthes- 
ized a series of drugs for possible use as antimalariala and the 
!hfrma!!:L°F 80(1 Ecology had studied their toxicity. 
Itost of the data and the records of these investigations were lost 
when the laboratories were destroyed in October 1944. 
Schulemann moved to Bad Oeynhauaen in October 1944 and set up 
J *n?11 Juratory of about 10 to 15 rooms on the upper floors of 
the Koenlghof Reserve Hospital. Owing to limitations of equipment, 
space, and staff, activities were cut to a minimum. No facilities for 
chemical work were available, so the chemists, Dr. Oesterlein, Dr. 
Saure, and Dr. Zlrfas, went to Berlin in November 1944 to work under 
Dr. Heubner at the laboratories of the Pharmacological Institute. 
Bomb damage to the laboratories in Berlin stopped all chemical work 
in January 1945. 
* ?eynhausen laboratory. Dr. Schulemann, Dr. Wurmbach, 
and Fraulein Kratz continued the mosquito breeding work, maintained 
the selected strains of malaria, and were able to continue some of 
the histopathologlcal studies on infected canaries. 
Personnel 
1) Prof. Schulemann. 
2) Prof. Wurmbach, zoologist and parasitologist, a "Sender- 
fuhrer" In Wehrmacht uniform but not an Amy medical 
officer. His status is that of a specialist for 
scientific research. 
3) Frtuleln Luise Kratz, civilian assistant. 
A) Herr Dohm, civilian assistant, care and breeding of 
experimental animals. 
5) Dr. Oesterlein) All civilians, last know whereabouts- 
Dr. Saure. ) Berlin, January 1945, 
Dr. Zlrfas ) 
6) Other personnel at University of Bonn, whereabouts not 
known at present. 
According to Prof. Schulemann, the studies on 3-11 can be continued 
without serious delay if the following faculties can be obtained} a} New laboratory quarters 
b) Transport of equipment, animals, mosquitoes, and birds from 
Bad Oeynhausen. 
* c) Maintenance of present personnels 
Dr* Schulcmann, Dr. Wunabach, Priulein Krata, Herr Doha 
d) Chemical laboratory, equipment and supplies for synthesis of 8-11. 
e) Chemists! Dr. Saure, Dr. Zirfas to carry on chemical work. 
Report on. uae of atabrin and of chlnoplasmin in 257 soldiers with 
bflnlfB tertian Ml art*i 
In order to get some data on the problem of treatment of relapses 
in benign tertain malaria. Prof. Schulemann and his assistant treated 
a large group of soldiers at Godesberg with atabrin alone and another 
group with chlnoplasmin. The plan of treatment was as follows! 
Group Is Atabrin - one intravenous injection daily for two days 
with dosage of 0*03 grams - then three injections daily 
• for 3 days with dosage of 0.01 grams. Relapses occurred 
at rate of 27% to AO%. (Only an estimate as there was 
not a long time follow up). 
Group II s Chlnoplasmin (Quinine hydrochloride 0.10 grams plus 
plasmochin 0.03 grams). One tablet t.l.d. for 14 days. 
In severe cases - 21 days. Relapses occurred at rate 
of 8% to 10%. 
Tablets of sodium salixylate were given at the same time as the 
chlnoplasmin and the urine was treated with FeClo, and tested with a 
colorimeter for a purple color. Actual talking of the medicaments 
could be controlled in this way. From these experiments Schulemann 
concluded that atabrin was far from the ideal drug for treatment of 
malaria because of the large percentage of relapses. Although the 
combined use of quinine and plasmochin gave excellent results in 
the treatment of relapses, a new drug for the treatment of the origl- 
»ai attack and for causal prophylaxis of malaria was needed. He 
began chemical studies and animal (canary) experiments with a group 
of compounds which had been synthesized in 1928 at I.G. Farbew- 
industrie at Elberfeld. There were seventeen of these which were 
known as the •S* Group. After seven years of pharmaceutical trial 
he found only one compound known as S-ll (S-eleven) to have value as 
an antimalarial in non-toxic doses. A description of his methods of 
research and results follows. 
Experimental research on antimalarlals. 
Description of methods used. 
A) The Roehl method in which canaries were injected with blood cont- 
aining malaria parasites in which treatment of the disease was begun 
shortly (2 to 6 hours) after infection and continued for 6 consecutive 
days. This will be designated as the "old test method" in the 
description below. B) The Schulemann method In which canaries were injected with spor- 
ozoites taken directly from the salivary gland of an infected mosquito. 
The injection is made with a fine glass canula into a pea-sized, sharply 
demarcated deposit of fat on the anterior chest wall just external 
to the outer border of the pectoralis major muscle. This fatty are* 
can be easily and constantly found by moistening and brushing aside 
the feathers over the breast area. This site is chosen rather 
than a wing because its immobility permits injected .aterial to 
remain localized for a sufficient time to allow a good development 
of parasites before dissemination through the tissues. 
In this method treatment is not begun until the 4th day after 
injection - a sufficient interval to allow development of tissue 
types of parasites. Treatment was continued daily for 6 days. 
This method will be called the "new test method" here. All medica- 
tion was introduced directly into the stomach of the canary with a 
flexible hollow tube (Roehl) seven and one-half centimeters long. 
C) A group of 5 infected canaries was used as untreated controls 
and each antimalarial drug was given to 5 canaries. Two strains 
of plasmodia were used, i.c., P. gallinaciura and P. cathemerium. 
Experiments were carried out with natural quinine, its four optically 
active derivatives, atabrin, plasmochin and the new antimalarial 
known as S-ll# After death of the canaries, or at stated intervals, 
sections of tissues were stained with a new modification of Giemsa*s stain 
In this way the tissue phase (exo-erythrocytic phase) of the devel- 
opment of the life cycle of the parasite was worked out and the path- 
ological effects produced by the toxins liberated by the parasite were 
studied in the brain, liver, lung, spleen, etc. Schulemannfs 
nidified Giemsa staining technique is given in Appendix II. 
D) These studies proved definitely that some of the parasites develop 
inside the endothelial cells while others develop outside these cells. 
Prof. Schulemann believed that he was the first person to prove 
this point, but he was Informed that this had also been done in the 
United States about three years ago. His work, which was demonstrated 
to us in slides and beautiful colored drawings, is ready for public- 
ation. 
A summary of his experiments follows! 
1. Old test method of RoehlI 
a) Comparison of synthetic quinine (Rabe) and natural quinine, 
Racinat (* *) (—) ) 
Optically active ) The same effect as natural 
Optically active (—) ) quinine. 
Racinat (*-) ) 
Optically active (*-) ) No effect at all. 
Optically active ; b) New ant1malarials S-9, S-10, S-ll compared with quinine* 
S-9 -No effect at all. 
S-10 -Only trace of activity, 
S-ll -In dilution of It200 about the same effect as 
quinine hydrochloride in dilution of 1 to 500. 
•' By this method it was found that S-ll shows 
only one-half the efficacy of quinine; it is not 
useful in the treatment of new actue malaria 
infections• 
2. New Test Method (Schulemann) (Infection with sporosoites and waiting 
four days before beginning treatment)• 
a) Controls and all infected canaries treated daily for six 
days with 0.5 ccm. per 20 grams of bird of: 
1) Quinine hydro chloride in a dilution of 1 to 500. 
2) Atabrin « " " ,f 1 to 300. 
All canaries died on the ninth or tenth day after infection. 
* From these observation Schulemann believes that quinine 
and atabrin by this method have no effect at all, that is 
to say, no effect in treating relapses. (By waiting four 
days and allowing the development of the tissue phase of 
the parasites a stage of Infection simulating a relapse in 
produced)• 
b) Controls and all infected canaries treated daily for six 
days with 0.5 ccm. per 20 grams of bird of: 
1) Plasmochin in a dilution of 1 to 5000. 
2) S-ll « " " « 1 to 200. 
The infection was attenuated and death of the birds did not 
occur until as late as the twentieth day, or not at all. 
It was concluded that S-ll in a dilution of 1 to 200 was 
of the same value as plasmochin in a dilution of 1:5000 but 
that S-ll was much less toxic since no cyanosis was produced 
by S-ll. Prof. Schulemann felt that the first step had been 
accomplished in finding a substance which effects the exo- 
erythrocytic form of malaria. He hoped that by continuation 
of this work a new remedy effective for (l) causal prophy- 
laxis, and (2) treatment of relapses, could be found. Because 
the records were lost in the bombing at Bonn on IS October 
1944-, no exact figures on the lethal dose of S-ll in birds 
were available. The approximate figures are as follows: 
l/2 c.c. of a dilution of 1-200 per 20 grams of bird is 
the safe dose for experiments. 
l/2 c.c. of a dilution of 1-100 is the border-line dose. 
l/2 c.c. of a dilution of 1-50 is the lethal dose. 
S-ll has never been used in human malaria. During these 
experiments with plasmochin he came to the conclusion that the toxic effects (cyanosis, etc.) of the drug were due to embarrass- 
ment of the circulation resulting from the drug*s action on the nyoc- 
ardium rather than production of toxic substances in the blood stream. 
c . In h4s pathological studies Schulemann was assisted by Prof. 
Wunnbach. They found all stages of destruction of the liver, lung, 
spleen and lymph glands due to toxins produced by the parasites, and 
believed that the vague symptoms of pain in various parts of the body 
in latent malaria could be thus accounted for. The lymph spaces in 
brain were filled with plasmodia. He hade use of the liver puncture 
technique of Prof. Gfctzeit. (professor of Medicine at Breslau 
University) in living birds to follow the course of the infection, 
and considers this technique a distinct aid in the diagnosis of 
latent malaria in humans• The Henry flocculation test was of no 
diagnostic value in the diagnosis of latent malaria of birds. 
Chemical Formula and Synthesis of S-ll. 
Synthetic organic compounds, described in detail in Appendix 1, 
were synthesized by Prof. Schulemann and his associates about 1928 
for I.G. Farben (D.R.P. 499826) at Elberfeld. According tocProf. 
Schulemann, Dr. Rbehl concluded that these compounds had no value in 
malaria therapy, although laboratory reports subsequently obtained 
from Prof. Schulemann indicate some chemotherapeutic activity. Nothing 
was done with these compounds until Prof. Schulemann revived his 
interest in them at the University of Bonn in 1941- At this time a 
series of seventeen closely related compounds were synthesized by 
Dr. Saure and his assistants and some preliminary estimates of their 
antimalarlal activity were made. One of these compounds, S-ll, was 
selected for further study. 
Prof. Schulemann described, as S-ll the original compound synthe- 
sized in 1928. This compound was 4 N bis (diethyl amino ethyl) amino 
diethyl cateoholate. It was synthesized by nitrating the diethyl 
ether of catechol in the 4 position, reducing with tin and hydroch- 
loric acid, and heating the amine for 5 hours at 135° 0 with an 
excess (3-4 mols.) of chloro ethyl diethyl amine. This last step 
gave yields of about 30£. 
Subsequent; study of the laboratory reports (Appendix l) obtained 
from Prof. Schulemann Indicate that Dr. Saure synthesized 17 derivat- 
ives of N (diethyl amino ethyl) aniline (or N bis diethyl amino ethyl 
aniline) which had one or two methyl, methoxy, ethoxy, or chlorine 
groups substituted in the ring in various combinations and positions. 
These products were designated S-l. S-2. S-3, etc; and from this S-ll 
appears to be 4 N is (diethylaminoethyl; amino, 2 chloro, ethyl phen- 
olate. It was prepared by chlorinating phehacetin, removing the 
acetyl group by hydrolysis, and condensing the amine with chloro 
. ethyl diethyl amine as described above • The product was a yellow 
oil in 13% yield. 
The compounds were synthesized by Dr. Saure, and according to 
Prof. Schulemann, were obtained as hydrochloric salts, made up as a 1°* in 1$ solution Beaded in glass ampoules by Sobering 
Co*, Berlin* The compound is said to decompose slowly when exposed 
to air, but in sealed ampoules remains stable for several years* 
Miscellaneous Information secured from Prof.Sahulumann, 
A description of a new lens and condenser for the use with the 
ordinary microscope. This is called a Phasenkrontrast Einrichtung 
(Phase-contrast apparatus) and permits the observation of tissue 
differentiation in fresh unstained specimens in a manner considered 
superior to anything we have had at our disposal to date. The appear- 
ance of the tissue cells strands is that secured by reflected light 
and that seen in the darffield* It was stated that only twelve of 
these apparatuses have been manufactured to date by Carl Zeiss (Jena), 
and that Prof. Schulemann secured his exemplar from the German 
Research Council* For three years previous to his departure Prof. Schule- 
raan and a large number of assistants, particularly Dr*A*Zipp (where- 
abouts unknown at present) had been working on a new idea in chemo- 
therapeutic s, i.e., the action of a new group of phenobarbital compounds 
on bacterial infections such as those caused by the pathogenic 
streptococci. Although no definite report on this field of investig- 
ation could be secured because of destruction of all records, Prof. 
Schulemann stated that the progress made was so satisfactory that the 
work would be continued at the earliest possible moment. 
Prof .QUtzeit, Professor of Medicine at Breslau and consultant 
in medicine to the National Research Council of Germany, has developed 
a new method of liver puncture used in the study of known malaria in 
birds and humans and also used for diagnosis of latent malaria in 
humans* He was able to make a positive diagnosis by stained smears 
obtained by liver puncture and start treatment with Plasmochin long 
before symptoms of relapse appeared* 
The following list of doctors to contact for knowledge of advances 
in medicine made during the war in Germany was given us by Prof. 
Schulemann. 
Prof. Dr. Handloser - General Oberstarzt - Chief of all medical 
services of Army, Navy, and Air Force* 
Prof. Dr. Schreiber - Adviser in hygiene to Nat* Research Council, 
Prof, Dr. Gttzeit - Consulting Internist to Prof* Handloser and 
member of Nat. Res. Council - also Prof* of Medicine at Univ* 
of Breslau. 
Dr. Sergius Breuer - General Secretary of Nat. Res.Council. A 
man who is well informed of all its activities. 
Prof. Dr. Spatz - Head of Brain Research Institute at Kaiser 
Wilhelm Institute, Berlin - Buch. 
Prof, Dr. Heubner - Director of Pharmacoldgical Institute at 
Univ. of Berlin; has made extensive studies of toxicology 
of blood malaria. 
Prof. Dr. Herzberg - Specialist in Virus diseases (Influenza and 
Epidemic Hepatitis) was at Greifswald on the Baltic Sea. Prof, Dr. Martini - Entomologist now at Bad Nauheim, 
Prof. Dr. Nauck - New head of Tropical Diseases Institute at 
Hamburg. Extensive experience with tropical diseases. 
Prof. Dr. Rodenwaldt - Consultant to Army Medical Services for 
Tropical Diseases - formerly at Heidelberg, now at Nauheim, 
Section II 
Interview by Doctor Southworth. 
Recent work of Professor Werner Schulemann. 
Schulemann was picked up by the 9th Army at Bad Oeynhausen. 
Schulemann stated that after moving to Bonn in 1936 he was paid by 
I.G. for 5 years not to associate himself with another commercial 
firm. About 3 years ago, however, he made an agreement with Sobering 
and started wdrk with Dr. Oesterlein developing a series of potential 
antlmalarials originally patented by I.G. in 1927 but rejected by 
Roehl as of little promise. When Schulemann was bombed out of Bonn 
on October 18, 1944-, he salvaged 200 of his canaries, his four mosquito 
strains, and enough equipment to set up anew on the top floor of the 
Koenlgshof Reserve Hospital at Bad Oeynhausen. This British have 
now swept him out, in order to make room for a headquarters, but he 
has been taken under U,S. custody, 
fi r>f Gompounda. 
The original I.G. compounds were the Dimeplasmin series made by 
Kropp and Schulemann. The new series has been made by Schulemann1s 
associate Saure, and the nSn nomenclature results from his name. 
Eighteen of them haye been synthesized (see Appendix I), but the.exact 
numerical orddr was lost when the records were burned at Bonn. The 
most promising, however, is Sll, which has the structure: 
and is estimated by Schulomann to have 1/3 to 1/2 the activity of 
Quinine by the old Roe hi test, 
Schulemann uses cathemerium in his canaries, and prAdtically 
all his testing has been by the Roehl technique. He has devised, 
however, a "New Test”*, wherein sporozoites from infected mosquitoes 
are Injected into the peasized fat-pad which lies lateral to the 
canary*s pectoral muscle. The salivary glands are dissected out, 
mixed with canary serum, and the glands of one mosquitw injected into each bird by means of a capillary pipette. About twenty birds 
are used for each experiment, including 4-5 controls and $ treated 
with quinine. So as to compensate for the inevitable delay before 
the last birds are injected, the series of 20 are given a second 
series of Injections in reverse order a few hours later into the 
contralateral fat pad. Thus each gets the salivary sporozoites of 
2 mosquitoes. Treatment is not begun until the 4th day and is then 
continued for 6 days. Schulemann boasts of the fact that he always 
uses groups of 5 birds for each dosage in his tests, while Kikuth 
may use but 1 or 2. In both tests ho also uses only 0.5 cc daily 
per 20 gm. of bird, so that his results with a l/l00 solution corres- 
ond to kikuth*s with 1/200. 
By the old Hoehl test, about 13 S compounds have been tested, 
and only S10 and Sll have shown any activity. With S10 this was 
but a trace, but Sll at 1/200 had about the same activity as Qunlne 
at 1/500. When, therefore, the New Test was devised, Sll was 
chosen for comparative trial. The initial test was interrupted by 
the destruction of Schulemannfs laboratory, and no subsequent ones 
have been possible. Its protocol shows that all 4 control birds 
died on the 9th and 10th days. 5 birds treated with Quinine HC1 
1/500 also died on the 9th-10th days, and 5 dosed with Atebrin 
1/300 died on the Sth-llth days • All these birds showed a high 
degree of parasitemia, andthe compounds appeared to be of no 
benefit. 5 birds, however, were treated with Plasmochin 1/5000. 
They all began to show parasites at the same time as the control 
birds (about day 6), but the number of these remained low and only . 
2 birds died (days 11 and 13) • One bird was killed on day 10 for 
pathological studies, and the subsequent records of the surviving 
2 were lost after the 15th day by the destruction of the laboratory. 
The last group of 5 birds was treated with Sll at 1/200. 1 
died on day 12 but with only a slight parasitemia. Another was 
killed on day 11 for pathological studies. 3 were still alive when 
allrecords were lost on day 15, and one of these seemed to be on its 
way towards a cure. The general course of these birds was very 
similar to those treated with plasmochin. Pathologically, the one 
killed on day 11 was about identical with the plasmochin treated bird 
autopsied on the previous day. In contrast to the controls and to 
those dosed with Quinine or Atebrin, there was little hepatic or 
splenic enlargement and relatively few E-forms. 
By canary tests, Sll is much less toxic than Plasmochin. A 1/100 
solution approximates the MLD, and l/50 is generally lethal. 1/200 
is therefore the maximum tolerated dose. No animal toxicity studies 
have been made. 
Sll is a yellow oil with a B.P. of 205-207° at 3mm pressure. 
It oxidizes readily and is therefore made up by Sobering in sterile 
ampoules of 1 cc volume containing Q.l gm of Sll in water with 0.01 
gm of The dihydrochloride salt is used. Schulemann adds 
19 co of tap water to the contents of 1 ampoule to get his 1/200 Synthesis of Sll is accomplished as follows, according to Saure, 
whom I tracked down at his home near Huckeswagens 
MArlp 
No human tests have been made with Sll, and Schulemann makes no 
definite claims for it. He points out that only 1 side-chain has been 
tried, because the chlorethyldlethylamine required in its production 
was easily available as an intermediary for novAcaine. He also suspects 
’that the diraethoxy derivative would be more active than the diethoxy# 
(Dlmeplasmln itself) • Saure made some of this but lost it . Schulemann 
believes he has a group of compounds which needs further study and 
development and which premises to have a Plasmochln-like action. He 
has made no test of Sll for causal prophylactic action. He believes 
his work is unknown to Elberfeld, but I wonder if Klkuth*s revival 
of interest in related compounds of the Diapromin and Dimeplasmin 
series may not have resulted from rumors as to Schulemannfs work. 
Schulemann maintains his strain of gullSnaceum in roosters hut has 
used it very little during the way* Sll has never been tested against 
it. 
Senary, eoanenta on Anti ilia] arlals. 
Schulemann was sceptical about Sontochin, stating that its only 
advantage over Atebrln was its lack of skin staining. He agreed with 
Klktjth ttad Chinoplasmin was more effective than Atebrln in preventing recurrences of vivax malaria. One of his students named Rinck searched 
the War Office records last summer for follow-ups on 257 cases of 
B.T. malaria treated for 2-3 weeks with Chinoplasmin at the Tropenlaz- 
arett, Bad Godesberg, between July 19A2 and January 1943. 23 relapses 
were uncovered, and allowing for lost records, a relapse rate of about 
•10% was estimated. Comparable cases were treated with atabrin but 
no follow-up had been made when their names and records were lost in 
the destruction of Schulemann1s laboratory. Nearly all the B.T. strains 
were of Mediterranean origin. Schulemann believes in the efficacy of 
Plasmochin combined with Atebrin and continues his interest in Atepe, 
which is Atebrin 0.1 gm and Plasmochin 0,005 gm. He recommended Ate- 
brin 0.05 gm and Plasmochin 0.0005 gm daily as the suppressive for the 
German army, but it was turned down. While admitting that large dose§ 
of Plasmochin cause methemoglobinemia, he feels that there is another 
cause for the cyanosis occasionally shown by patients on 0.01 gm tid. 
In a survey of 100 cases on this dosage at Bad Godesberg he never 
found over 25% raethemoglobin, He suspects that Plasmochin has a direct 
effect on myocardial conduction. 
Schulemann states that he has worked out the life histcry of the 
cathemerium tissue-phases in histological preparations made following 
his method of fat-pad injection. His original slides were destroyed 
at Bonn, and what he has left seem to be EEF in various various stages of 
development. He believes that sporozoites may penetrate histiocytes 
or aray undergo an initial extracellular division. He agrees with 
Missiroli that the number of chromatin granules they contain may 
determine their development and fate. There are generally about 
4 days of tissue-phase development before erythrocytic forms appear. 
. But on one occasion after 48 hours and once after 72 hours, he has 
transmitted the infection by means of blood to clean hires. He 
attributes his success in tracing the development of the E-forra to 
, a modification of the Giemsa staining technique in which mercury bich- 
loride is used in the clearing of the slide (see Appendix II)• Schule- 
mann is also interested in the histopathology of cathemerium malaria. 
The number of E-form to be found in the liver and spleen of untreated 
birds makes him wonder if these locations have been sufficiently 
searched (if necessary after liver puncture) in cases of human malaria. 
By injecting colloidal palladium, Schulemann has stirred up the 
reticuloendothelial system to give a monocytosis in roosters and then 
has tried blood-induction of gallinaceum infection. In 10 birds this 
technique led to an unusual course of the infection. E-forms developed 
more rapidly them normal, and the birds died of cerebral or pulmonary 
■ symptoms. Meanwhile the usual blood infection was reduced by a marked 
phagocytesisof the erythrocytic forms. 
Other Drugs. 
While at Bonn, Schulemann also worked with Oesterlein in an 
attempt to find a new class of antibacterial agents. He steered 
clear of the sulfonamides but sought for other groups of compounds 
which would resembie -S-g NH2 in having an amino group contiguous to two rO groups. For testing he used the culture of hemolytic in 
streptococci in whole blood by the rotating tube method of Ffeld 
and Green, as he felt it was the in vitro technique which most 
closely approximated vivo conditions. He tried 
and also this compound with amino substitutions on the phenyl ring, 
but without success. When, however, one of the nuclear NH2S was 
acetylated, he found a trace of activity. Next he tried barbiturates, 
and with a para-amino-phenyl substitution again found a trace of 
activity. He hopes to continue this work. Before taking up the 
S comooundfl. he also worked for a while with thiazoles of the type 
ii. the hope of find antimalarial activity. He had no 
success and abandoned thed field because synthesis was so difficult. 
Conclusion * 
In his S compounds Schulemann is just reworking the Dimeplasmin- 
Diapromin series which has been pretty well shown to be useless in 
terminating attacks of human malaria. Schulemann, however, is hoping 
these compounds may lead the way to a radical cure. He seems to be 
unaware of the fact that Diapromin, which has the structure 
was tried by Sioli in 1936-7 as a causal prophy- 
lactic and found without activity (see Appendix III) . It seems doubt- 
ful if his lead is a good one, but it is vdry interesting that his 
New Test shows a similarity of action between Plasmochin and Sll. APPENDIX I 
Structural Formulae of S series of Compounds, Zur Darstellung einer Reihe von mftgllchst 141cht zugftnglichen Ver- 
blndungen die elnige Attssicht suf antiplasraodische Wirksamkeit bo- 
ten, wurde als Ausgangspunkt desDJl.P. Nr. 499 826 (Frdl. 17.25L&) 
gewthlt, In dlesem Patent sind eine Anzahl von Benzolabkbmmlingen 
beschrieben, der eingache, Konstitution eine schnelle Darstellung 
4 dieser. bezw. Ahnlicher Verbindungen ermbglichte. 
Von den in oblgem Patent sufgefitthrten Verbindungen wurden dargestellt 
(I) der A-N- Di&thylamlnoathyl-amino-brenacatechlndiAthyiather (Beisp.13) 
(II) und der 4-N-Bis (dl&thvlamoni flthvl) -aralno-brenzcatechlndiathyl&ther 
(Beisp. 14)* Wahrend das Mono-arainoalklierungsprodukt ira therapeu- 
tischen Versuch nur eine angedeutete, schwache Wirkung bei der Infek- 
tion des Kanarienvogels mit Malariaplasmodlen zeigte, brachte das 
Dl-aminoalkylierungsprodukt eine Verzttgerung des Angehens der Ingek- 
tion von einigen Tagen. (Genaueres liber die Wirkungsprlifung weiter 
unteni) 
Im AnschluB an diese beiden direkt dem. D.R.P. cntnornmenen Verbindun- 
gen wurde eine Anzahl weiterer Substanzen dargestellt, bei denen die 
Substituenten und die Stellung der Substltuenten zuelnander und zu 
der zu aminoalkylierenden Aminogruppe variiert wurden. 
So stellten wlr zunAchst aus Anilin das doppelt basisch alkylier * 
Produkt und hieraus durch Nitrosierung und anschlieBende Reduktion 
(III) das. N-Bis(dl&thYla.iinoathyl) -n-phenylendiamin ter. das jedoch ira the- 
rapeitischen Versuch keine Wirkung zeigte. Aus p-Phenetidin wurden 
(IV) sodann das N-Diftthylaminoftthyl -p-nhenetidln und das N-B1s(D18.thy1- 
(V) ABino&thyl)-n-Phenetidin dargestellt, Beide Verbindungen, wie auch 
alle welteren, aeigten im therapeutischen Versuch bei der Vogalmalaria 
keine Wirkung, Aus o-Toluidin wurde durch Kitrierung zum 4-Nitro-2- 
arainotoluol,' Diazotierung und Verkochung mit Schwefelsfture und an- 
schliebende Aethylierung das 4-Nitro-2-Abhoxyloluol gewonnen, Durch 
(VI) Reduktion und Aminoalvylierung kamen wir schlieBlich zum 4-N-Diftthvl- 
(VII) an:inoPthyl-arai no-2-flthcxvtoluo] und zum 4-N-Bis (diathylamino&thyl) - 
amino-2-ftt^oy/toluol. Ails Phenazetin wurde durch Nitrierung und an- 
schl4ebende Abspaltung der Acetylgruppe das 3-Nltro-4-araino-phenetol 
gewennen, das durch Diazotierung und Behandlung mit Gu-Pulver das 
4-Chlorprodukt er‘*ab, welches schVeBI ■* ch durch Reduktion und an- 
(VITI) scbliebenc> Aminoalkylierur.g in das 3-N*Diftthylamin4ftthyl-4-chlor- 
(VTX) phenetol und das 3-N-3i s(di9.thylarninoH.thyl)-A-chlorphenetol tibargo- 
fh:i±t wurde. Weiterh’n wurde aus Phenazetin durch Kochen mit Chlor- 
lauge und anschlieBende Abspaltung der acetylgruppe das 2-Chlor-4- 
aminophenetol dargestellt, das mit ChlorAbhyldiathylarin in das 
(X) AN-DiathYlarainoa.thvl-ainino-2-chlorphenetol Und das 4N-3i s(D18.thvl- 
(XI) nnftthvl)-amino-2-chlorphenetol ubergeflihrt wurde. Das 3-Nitro-6- 
aminoanisol, dargestellt durch Nitrierung und Verseifung von acetyl- 
e-Anisldin, ergab rrit Hilfe der SANDMAYER' schen Reaktion und nach 
Reduktion der Nitrogruppe das 2-Chlor-5-aniinoanlsol, aus dem, wiedetfum 
(XII) mit Chlcr&thyldiAthylamin, das 5N-DiflthylzrdiioAbhyl-amino-2-chloranl- 
(XTr) sol und das 5-K-Bis(di&thvlaminQ&thyl-arnino-2-chlpranisol darge- 
stellt wurde. Durch Chlorierung von Anisol erhielten wir 
scl, das durch Nitrierung und anschlieBende Reduktion in das p-Chlor- 
o-amino-ani sol hbergefliht wurde. Hieraus konnte auf dem llblichen  Wege das 2-N-Di8i,hyXaninoftthyX-amino-4-chXor&nj sol und das 2-N-B3 s(di - 
(XV) ithylamlnoathyD-amlno-A-chloranlsol dargestelXt warden. Aus p-ToXul- 
dln erh5eXten w5r schlieBUch durch Ndtr5erung, Diazitierung und Ver- 
kochung mit Sfture das 4-Oxy-3-nitretoluol, das methyXJert, reduziert 
(XVT) und dann in das 2"N-Diftthvlaminolaminoathvl-aminr-A-methyl&nlSQl und das 
(XVII) 2"N-Bia(dl&thyl»aminoftthyX)-amino-4-methyXanisoX ttbetgeftthrt werden 
konnt©. 
Die 4 zuletzt angeftthrten Produkte warden noch nicht im therapeutiechen 
Versuch geprttft. TherapeuMsche Wirkunggprftfung. 
Die therapefctische Wlrkungsprlifung der beschriebencn Produkte wurde so 
vergenommen, daB die im chronischen Toxversuch (6 Tagc nachcinander 
lang nacheinander - wieder 0,5 cm pro 20 g Vogel - peroral 
und das Blut des am solben Tage d&t der ersten therapeutlschen 
Vogels vom 2. Tage an untcrsucht wurde. 
Ergebnisee. 
Produkt: 
Dosis; _ 
Verzfteerunestape; 
(I) 
4-N -Di&thylamlno&thylami no- 
abgeschw&chter 
brenzoatechindifrbhylftther 
1:200 
Verlauf der Inf. 
(IT) 
N-Bis(diftthylamino&thyl)-amino- 
1:200 
3-8 
brenzoatechind3 Mthyl&ther 
(HI) 
N-B3 s(diathylaminoftthyl) -p- 
lllOO 
0 
phenylendianiin 
(IV) 
N-Ditthylaminoftthyl-p-phenetidin 
1:50 
0 
(V) 
N-B i s(d i&t hy laminoftthyl)-p- 
1:50 
0 
phenetidin 
(VI) 
4-N-DiRthylaraino&thyl-ami no- 
1:200 
0 
2-athoxytoluol 
(VII) 
B5 -amino 
1:200 
0 
2-ftthxytoloul 
(VIII) 
3-N-Diathylaminoathyl-amino-4- 
1:200 
0 
chlorphenetol 
(IX) 
3-N-Bis(di&thylaminoftthyl)-amino- 
1:200 
0 
(X) 
4-K-D i&thy larainoftthyl -amino - 
0 
2-chlorphentol 
1:200 
(XI) 
4-N-B3 s(diftthylaraino&thyl) -amino- 
1:200 
0 
2-chlorphenctol 
(XII) 
5-K-Diftthylaminoathyl-amino- 
1:50 
0 
2-chloranlsol 
(XIII) 
5-N -B i s (d iathylarai nofttyhl)- am 1no- 
1:50 
0 
2-chloranisol) Im Hlmblick auf die weitgehend© cheraische und physikalische Hhnlich- 
keit zwischen Chinolin und Benzthiazol wurden ©benfalls die Versuche, 
©in "Benathiazol-Plasmochln11 zu synthetisieren, die z. Tl, schon von 
den Amerikanern (FOX und BOGEHT: Am.soc.61.2013) und Russen(KNUNYANTZ 
und BENEVOLENKAJA: J.Gen.Chem. .U.d.s.s.R. .7.2A71:C .A.32.2119. (1938). 
aowie auch in Deutschland von WAGNER-JAUREGG und HELMERT (Ber,2fi,935) 
durchgefUhrt wurden, wieder aufgenommen, mit dem Ziel, mBglichst s&mt- 
liche Amino-ben zthiazole in Form ihrer Aminoalkylierungsprodukte zu 
synthetisieren, um dieses Gebiet endgttltig zum AbschluB zu bringen, 
unc. zwar vor allera auch unter Borttcksichtigung der doppekt aminoalky- 
lierten Verbindungen, die von don oben angegebenen Forschern nicht un- 
tersucht worden nind. 
Zur Darstellung der verschiedenen Amino-benzthiazole bedienten wlr uns 
vor allem der HERTZ'schen Reaktion, die in der Elnwirkung von Schwofel- 
chlorlir auf Aniline und anschlieBender alkalischer Spaltung der Kon- 
densatlonsprodukte su o-Aminot iophenolen besteht, welche dann mit 
Ameisens&ur© zu den entsprochenden Benzt iazolen verkocht wurden, und 
der "Rhodanierungareaktion nach D,R.P,A91 223, nach der p-substitu- 
ierte Aniline mit Alkalirhodanid und Brom zu 2-Aminobenzthiazolen um- 
gesetzt werden. 
Von den Benzthiazolderivaten wurden bisher dargestellt; 
2-Ajnino-6-methoyybenzthiazol 
4.-Am lno-6-methoxybenzthiazol 
7-Amino-6-mcthoxybenzthiazol 
6-Aroinobenzthiazol• 
Das 5-Aminobenzthiazol ist synthetisch am schwersten zuginglich und 
konnte bisher nicht erhalten werden, 
* 
Die Honoalkylierungsprodukt© von A- und 7- Amino-6-methozybenzthiazol 
wurden - wie auoh schon frtther berichtet - berelts 1m therapeutischen 
Vorsuch geprttft, Sie zeigten neben hoher Toxizitlt keine Spur von 
Wirksarakeit, Das lUBt sich nur sehr schv/er 
alkylieren, da die 2-Aminogruppe nur schwach basisch ist, Ubor dies© 
Reihe von Produkten, die von Herrn Dr. SAURE bearbeitet wird, soil 
nach AbschluB Untersuchungen genauer berichtet werden. Experimenteller Tell 
I« 4-N-Diathy1aminoathyl-br©nzcat © chi nd iathy1Sther. (Dr#SADRB) 
1) «»thylither; cf.Beilst.VI,799) 
Nitrierung in Eisessig mt Ert03(d ;1,4) ,umkrist .aus wBssr. 
Alkohol. Hellgelb© i\Tadeln. 
Fp:73-75° 
Ausbeut©; 98$• 
2) 4-AminobrenzoatechindiBthylfither; (of.Beilst.XIII,(308) 
P.eduktion von l) rr.it Sn und HC1, Ausathern,Vakummd© still. 
Kp*135°/5mm; farbloses Oel* 
Fp.47-48° 
Ausbeut©; 70$» 
3) 4-N-Diathylaminoathyl-br9nzcatechindiathyiather; 
(D.R.P.499 826,Frdl.17,2548) 
2) mit 1 Mol Chlorathyldiathylamin 3 Stdn.auf 100° ©r- 
hitzen, Heaktionsprodukt in Wasser lOsen, Basengemisoh 
mit Pottasche aussalzen, aueRthern, Vakummdestiilation# 
Ap: 187-190°/3mm; gelbliohes 0©1. 
Ausbeut©; 30 
II* 4-N-Bis(d iathylaminolthy1)-aminobre nzcate ch indi athyiath er•(Dr.S.) 
(D.k.J.499 826,Frdl.l^,2^48} 
Moncalkylierungsprodukt mit 3-4 Mol Chlorathyldiathyl- 
amin umsetzen (5 Stdn.l35°)« Auferbeitung wi© oben. 
: Kp: 213°/5mm* gelbliohes Oel* 
Ausbeut©: 35$. 
Ill* N-Bis(diathylsminoathyl)-p-phenyl8ndiamin: (Dr*SAUHS) 
1) N-Bis-(Diathylaminoathyl)anilin; (C.19301,1697) 
Anilin mit3-4 Mol Chlorathyldiathylamin 6 Stdn.auf 
125° ©rhitzen. Auferbeitung wie Ublich. 
Kp*160°/4mm; gelbliohes Oel. 
Ausbeut©; 76$. 
2) K-Eig{Diathylaminoathyl)-p-phenylendiamin: 
l) in 5n-HCl mit wBssr. NaNop, nitrosieren,LOsung auf 
50° ©rwarman und mit Zn-Staub reduzieren, Alkalisieren, 
mit Pottasche aussalzen, Reiter© Auferbeitung wie ablich. 
Kp.l93-195°/3mm; gelb©s Oel. 
Ausbeut©; 45$. IV. N-Digthylamlno9thyl~p-phetietidln: (Dr .Sitting) 
p-Phenetidin wird mit 1 Mol Digthylamlnoftthylchlorid in 
benzol 1 Std.auf dom siedenden Wasserbad erhitzt. Kristall- 
brei in V/asser ICsen, vom Benzol trennen Auferbeltung wie 
flblich. 
Kp. 147-148°/3mm; farbloses Oel, 
Ausbeute: 60$. 
V. N-3is(digthylamlnogthyl)-p-phenetldin; (Dr.SAURS) 
(IV wird mit 3-4 Mol amino alkyl chi or id 5 Stdn.auf 125© er- 
hitzt. Aufarbeitung wie Qblich. 
Kp.l88-190°/3mm; gelbes Oel. 
Auebeute; 45$. 
VI. 4-Iv-DiBthylaminogthyl~amino~2-athoxytoluol; (Br.SAORE1 
(1) 4-Nitro-2-aminotoluol; (cf.Pellet.XII,844) 
o-Toluidin wird in konz. 3chwefels8ure bei o° mit 
Nitriergemisch (HAOs d;l,4) nitriert. Das abgeschiedsne 
Sulfat wird mit NaOH zersetzt. 
Bp;107°, gelbe Kristalle. 
Ausbeut©; 70$. 
2} 4-Nitro-2-oxytoluol; (cf.Beilst.VI,365) 
1) wird in 10$ iger Schwefelsgure diazotiert. Die Diazo- 
niumsalzlBsung in siedende 30$ige Schwefelsgure einlaufen 
lessen. Nach dem Srkalten filtrieren. 
Fp;118°; gelbe HadeIn. 
Ausbeute; 86$. 
3) 4-Mtro-2*-?thoxytoluol; (cf.Beilst.VI,366) 
2) in alkoholischer KOH mit lodgthyl gthylleren. 
Fp; 61°. 
Ausbeute; 85$. 
4) 4-Amino-2-athoxytoluol; (cf.Beilst.XIII,574) 
3) mit Sn und HC1 reduzieren, alkalisieren und die Base 
mit Wasserdampf abtrieben. 
Kp: 143-146°/!7mm. 
Ausbeute: 70$. 
5) 4-M-Diathylamino9thyl-amino-2-athoxytoluol; 
4) mit 1 Mol ChlorSthyldiSthylamin 3 Stdn.auf 100° 
erhitzen, Aufarbeitung wie flblich. 
Kp; 175-177°/3mm; gelbliches Cel. 
Ausbeute; 50$. .X. <m-B j B(dlithylamlno>thyl) -amlnor2-ftthoxytoluol: (Dr.SA.URE) 
4-Amino-2-&tho3(ytoluol wird mit 3-4. Mol Chlori.thyldiltthyl- 
amin 5 Stdn. auf 130° erhitzt. Aufarbeitung wie ttblich. 
Kpi203-206°/3mraj gelbes Oel. 
, Ausbeute* 4-5$. 
Vin. 3^>DilthylaBlnQ&thyl-amlnQ-A->chlorphenetol; (DR.SAUPE) 
1) 3-Nltro-4.-acetaminophenetolj (Ar *229:4-57) 
Phenazetin wird mit 65$iger HNO3 nitriert. Unkristalli- 
sieren aus Alkohol. 
Fp: 103° 
Ausbeutcs 82% 
2) 3-Nitro-4.-Amlnophenetol: (Ar ,229,460) 
1) mit alkoholisch-wftsseriger KOH verseifen, 
Fp:113°s rot® Nadoln. 
Ausbeute1 94$ • 
3) 3rNitro-4.-chlorphenetol: (Ber*32*157) 
2) wird in 25$igor HC1 bAi 0° diazotiert und hierauf 
unter Rtthren Cu-Bronze zugegeben. Abfiltrieren, Rttckstand 
mit Alkohol auskochon. 
Fp: 47°, aus Alkohol. 
Auebeute 1 53$ • 
4) 3-Amino-4.-chlorphenetols (Ber.32,157) 
3) wird in 25$igor HC1 mit Sn reduziert, Mit rauchENDER 
HC1 Hydrochlorid flllen, alkalisieren, mit Wasserdampf 
abtreibcn. 
Kpi 122-123°Am; farbloses Oel. 
Auebeute: 71$. 
5) 3-N-DiHthylaraino&thJrl-amino-4.-chlorphenetol: 
4.) wird mit IMol Chlor&thyldi&thylamin 5 Stdn. auf 100° 
©rhitzt, Aufarbeitung wie ttblich. 
Kpjl70-173/3mm$ gelbes Oel. 
Ausbeute: 30$. 
IX. 3“N-Bls(diathvlaminoftthvl)—amino-4.-chlorphenetol: (Dr .SAURE) 
3-Araino-4.-chlorphenetol wird mit 3-4- Mol OhlorHthyldi&thyl- 
eunin 6 Stdn. auf 130° erhitzt. Aufarbeitung wie "ubllch, 
Kp:191-19A°/3mni; gelbes Oel. 
, Ausbeute: 25$. 4~N-Digthylaminogthyl-amlno~2~chlorphenetol: (Dr, ZIRFAS) 
1) 2-Chlor-4-eminophenetol: (Ber.32,156) 
Rienazetin wird in ©iner Misohung von Eisessig und HC1 
gelOst und mit einter Chlorlauge - aus haissar, 40%igar 
NaOH durch SSttigen mit Cl-Gas - unter Kflhlung versetzt* 
Daa Produkt scheidat sich ab. Umkrist. aus 60%lgam Alkohol* 
Fp: 132° 
Ausbeuta; 69%. 
Yerseifan der Acetylaminogruppe mit HC1 und Abtrelban 
dar Basa mit Wassardampf* 
Fp: 66°; Weissa Nadaln* 
Ausbeuta: 80%* 
2) 4-R-(djgthylamino gthyl) -amino-2- ohlorphene t ol; (Dr »ZIHFAS) 
£-Ghlor-4-aminophenotol wird mit 1 iiol ChlorSthyldlftthyl- 
amin in Xylol IS Stdn.gekocht* Aufarbeitung wia dblich* 
Kp: 184-1370/3mm" gelbliches Oel* 
Ausbauta: 37%* 
XI* (Dr«aiRFAB) 
2-Ghlor-4-aminophenatol wird mit3-4 LIol GhlorgthyldiHthyl~ 
amin 12 Stdn.auf 130° erhitzt* Aufarbeitung wia ttblioh* 
Kp; 205-207°/3mm; gelbas Del* 
Ausbeuta: 13,5$* 
XII* 5~N-Digthyleminogthyl~amino«-2-chloranlsol; (Dr .giaffAS) 
1) 5-Nitro-2-aminoanisol:lD.R.P# 98 637,Frdl.Y,67) 
mm mm • mm mm mm mm mm mm mm mm mm *p 
Aoet-o-anisidid wird in 65%iger HU03 nitriert, das an- 
fallande Gemisoh mit50%iger SchwelfelsSure verseift und 
das hierbei antstehende Gemisoh in heisser. 25%iger Schwe- 
felsfture gelBst. Beim Erkalten fSllt das 5-Ritro-2~amino- 
anisol aus• 
Fp; 139-1400. 
Ausbeute ; 38%* 
2) 5-Ritro-2-chloranisol: 
1) wird in salz©surer LOsung diazotiert und enschliessend 
mit Cu-Bronz© behandelt* Das 2-Chlorprodukt fSllt aus und 
wird mit Wasserdampf abgetrieben* 
Fp: 83°; gelblich'-weisse Nadeln* 
Ausbeute: 71%. 
3) 2-Chlor-5-aminoenisol: 
Reduction von 2) mit Sn und HC1, alkalisiseren, rusgthern, 
Aether verdampfen 
Fp: 77°. 
Ausbeute; 90%* 4) S-N-PlithylaalnoUthyl-amlno-^-chlpraplsoX: 
- 3) wlrd mit 1 Mol ChlorUthyldllthylamin 6 Stdn. auf 100° 
orhitat. Aufbeitung wie ttblich. 
Kp: 186-189°Amm; gelbes Oel. 
Ausbeute: 27%. 
XIII . S-M-Bla- (dig.thylaminoH.thvl) -amino-2-chloranlsol: (Dr .ZIRFASl 
(XTI) wlrd mit 3-4 Mol Chlortthyldiftthylamin 8 Stdn, auf 
130° erhitzt. Aufarbeitung wlc ublich. 
Kp:203-206o/3mm; gelbee Oel. 
Ausbeutes 33%. 
XIV. 2-M-DiathylamlnottthyX-smlno-A-chloranlaol8 (Dr. ZIKFAS) 
1) p-ChloranlsolI (Ar.233,31) 
Chloriervmg von Anlsol mit bel 70-100°i fraktlonlerte 
Destination. 
Kps195-196°, 
Ausbeute: 62% 
2) 4-Chlor-2-nitroanisols (Ber.29.2599) 
1) wlrd mit SalpetersHure (dsl,4) nitriert, die Nitro- 
verbindung scheldet sich kristallin ab. Umktistallisieren 
aus Alkohol. 
Fp: 98,5°: gelbliche Nadeln. 
Ausbeute: 57%. 
3) 4-0hlor-2-aminoanlsol; 
Reduktion von 2) mit Sn und SalzsHure, Alkalisleren und 
Abtreiben des Amins mit Wasserdampf. 
Fp; 82° 
Ausbeute: 90%. 
4.) 2-N-DiHthylamlnoHthyl-amino-4-chloranisol: 
3) wird mit 1 Mol ChlorttthyldiHthylamin 6 Stdn. auf 130° 
orhitzt. Aufarbeitung wie ttblich. 
Kpsl69-173°/2mniM schwach gelbliches Oel. 
Ausbeute: 4-7%. 
XV. 2rN-pi g (diatbyjLaminoathyll-amli .o-4-ctg.oEflpj gel j (&»., 
(XIV) wird mit 3-4 Mol Chlor&thyldlHthylamln 6 Stdn, suf 
130°eri1itzt* Aufarbeitung wie ftblich. 
Kps lB3-187c/2mr., gelbee Oel, 
Ausbeute: 43% * XVI• 2-N-Di&thyl&mino&thyI-amlno-£-methylanl3olr (Dr. ZIRFAS) 
1) 3-Nitro-A-oxytoluols(Ber.2A>1960) 
p-Toluidln wird in der WErme in etwa 25%ig«r HNO3 nitrlert, 
die NitrierlBsung auf 0° abgekEhlt und durch Zulaufenlassen 
Vo# diazotlert. Man lEbt einJge Zeit stchen 
und erwErmt dann zur vElligen Zersetzung yersichtig. Das 
entstandene 3-Nltro-A-oxytoluol wird mit Wasserdampf abgo- 
trieben. 
Fp:32° 
Ausbeute: 58%• 
2) 3-Nitro-A-metho*ytoluol1 (P,28,287) 
Methylierung ronl) in wEsseriger NaOH mit Dimethylsulfat, 
• ausEthcrn, Destination im Vakuum, 
Kps 155-157°/l3mm 
Ausbeute: 59%. 
3) 3-Amino-A-methoxytoluol1(P•28,288) 
Reduktion yon 2) mit Eisen und 20%lger EaslgsEure* Alka- 
liasieren und Wasserdampfdestillation. Umkristallisieren aus 
Alkohol• 
Fp: 51 >5° •, wel£e BlEttchen. 
Ausbeute: 87,5%. 
A) 2-N-DiEthyl&minoEthyl-amlno-4-methylanlsol: 
3) wird mit 1 Mol ChlorEthylamin 8 Stdn. auf 100° 
erwErmt. Aufarbeitung wie ttblich. 
Kps X39-H3°Amm 
Ausbeute: 51%. 
Mil. 2-N-Bla(dlathylamlno>t.hTlI-ain4nn-A-methylanlsol: (Dr. ZIRFAS) 
(XVI) wird mit 3-A Mol OhlorEthyldlEthylamin 2J+ Stdn* auf 
100° erhltzt* Auferbeitung wie ttblich. 
Kpj 15^-157° Amm 
Ausbeute: 
gez.x Dr* S* Seure. APPENDIX II 
Schulemann* s Modified Glemsa Staining Technique 
1* Tissue is fixed in Susa solution, embedded in paraffin, and cut in 
5m sections. Excess HgClg is removed with dilute KL, and the section 
passed through dilute Na thiosulfite and into water buffered according 
to the method of Professor Weise of Hamburg. 
2. Staining is accomplished by soaking for 24 hours (12 hours for 
spleen and bone-marrow} in a solution freshly prepared as follows; 
a. Hake up Solution A Azure I 2.0 
Methylene 
Blue 1•0 
V'ater to 250.0 
b. Hake up Solution 3 Eos in W.G. 1»0 
Water 100.0 
c. Mix 0.6 cc of Solution A with 50 cc of Weise buffered water. 
d. Mix 0.6 cc of Solution B with 50 cc of Weise buffered water. 
e. Mix these two dilute solutions together and use fresh. In 
the staining bowl the slides are placed obliquely with the 
section side downwards to avoid precipitation. 
3. Decolorizing is accomplished by dipping; 
a. For 30 seconds Into a mixture of saturated solution of HgClg 
25 cc and water 75 cc. 
b. Then into distilled water (at least 72 hours old so that some 
CCg is present) till clear. 
4. The slide is then passed fairly rapidly through the following 
solutions; 
e. Acetone 70 cc and Xylol 30 cc. 
b. Acetone 30 cc and Xylol 70 cc. 
c. Acetone 5 cc and Xylol 95 cc. 
d. Pure Xylol. 
e. Pure Xylol. 
and finally embedded in Gaedax, a synthetic resin of 
I. G. manufacture (a polychlornaphthalene) that has 
no traces of acid. 
I APPENDIX III 
tests in malaria infection by mosquito and 
blood transmission* - F. Sloli* 1936-1937. 
¥> 
Diapromin was first administered to patient No. 62/111* She 
had been infected by means of 10 anopheles. Diapromin was adminis- 
tered from the 8th to the 12th day after the infection, 0.1 gm 
daily, i.e., a total of 0.5 gm. The first febrile attack occurred 
on the 15th day after the infection, i.e., 4 days after the last dose 
of Diapromin; plasmodia were found already 2 days before. The 
period if incubation and the development of the plasmodia were not 
influenced by Diapromin. 
After a discussion with Dr. Kikuth, the author applied a 
dosage of 3 times 0.1 gm Diapromin on the day before the infection, 3 
times 0.1 gm on the day of infection, and 3 times 0.1 gm on the foll- 
owing 4 successive days. This treatment was administered to patients 
3/IY after mosquito infection and 4/IV after blood infection. 
For a control, patient 2/IV was inoculated on the seme day 
with the same anopheles, and patient 5/IV with the same blood. The 
time of incubation and the development' of the plasmodia were not 
influenced by the Diapromin medication, neither in the case of the 
mosquito infection nor in the case of blood infection. The devel- 
opment of the mosquito infection and of the blood infection went 
through an exactly parallel course in those treated with Diapromin 
and in the untreated patients. 
Individual enumeration; 
Case 2/IV without Diapromin infected on 8 June with 18 anopheles. 
1st febrile attack 21 June. 
Case 3/IV with Diapromin infected on 8 June with 15 anopheles. 1st 
febrile attack 21 June. 
Abundant plasmodia findings in both cases on 21 June. 
Case 5/lV blood inoculation on 10 June without Diapromin, 1st febrile 
attack 17 June. 
Case 4/IV blood inoculation on 10 June with Diapccomin, 1st febrile 
attack 23 June. 
In both cases sufficient plasmodia findings on 21 June. 
The somewhat delayed incubation of the Diapromin-treated case lies 
within the customary limits of incubation and is not to be considered 
as an effect of Diapromin. 
Summary: The Diapromin tests performed by the author so far have nc 
'shown any efficacy of the substance* 
A4775 Wt. 19195 175 7/45 Gp.959 Fo»h & Cross Ltd.. London.