Note: Descriptions are shown in the official language in which they were submitted.
:~0~7~99
The present invention relates to N-(6-acyloxy-
benzothiazol-2-yl)-N'-phenyl (or substituted phenyl)ureas
which are use~ul as immune regulants.
2-Substituted benzimidazoles, benzothiazoles and
benzoxazoles have recently been proposecl for a variety of
uses, mainly in the agricultural ~ield. For examplej 2-
trifluoromethylbenzimidazoles are reported to be extremely
active her~icides according to Great Britain patent 1,097,561.
The compounds therein disclosed are also reported to have
molluscicidal, insecticidal and fungicidal properties.
Other 2-substituted benzimidazoles have been found to be
active coccidiostats. In particular, 2-(4-thiazolyl) ben-
zimidazole (thiabendazole) is presently being marketed as an
anthelmintic. In addition, certain 2-hydroxybenzylbenzimi-
dazoles have been revealed as having anti-viral properties
- (see U.S. patent 3,331,739). While the use of benzoxazoles
and benzothiazoles ln the above areas has not been quite
as thoroughly explored as that of benzimidazoles, there is,
nevertheless, considerable interest in compounds of this
structure, particularly as coccidiostats.
Urea derivatives of the àbove classes of compounds
are sparingIy described in the art. N-(benzothiazol-
2-yl~)-N'-phenyl urea lS described In Chem. Abs., 29, 2660;
551 8389; 57, 801; the corresponding 4-methyl compound is
described in Chem. Abs., 25, 104; 50, 1776-1777 and the
corresponding 5-methoxy derivative is described in Chem.
Abs., 52, 20673. ~-~Benzimida ol-2-yl)-N'-phenyl urea is
described in Beilstein, 24 (II), 62 and in Chem. Abs., 15,
3077. In;addition, U.S. Patent 3,299,085 discloses N-(ben-
X-4360A -2- - ~
.- , ~ ,,
67~39
zothiazol-2-yl~ or N-(benzoxazol-2-yl)-N'-Cl-C5 aliphatic
ureas as intermediates in the preparation of certain her-
bicides, and U.S. patent 3,162,644 describecl benæoxazol-
2-yl ureas, useful as plant growth regulators and muscle
relaxants. U.S. patents 3,399,212; 3,336,191; and 3r401,171
disclose benzimidazolyl ureas said to be anthelmintics.
Finally, South African patent 68/4748 (Derwent Pharmdoc
basic number 36565) discloses benzothiazolyl ureas as
antiseptics in detergent compositions.
Recently, immune suppressant and immune regulant
agents have come into prominence because of their use during
transplants of organs from one human to another such as
heart transplants, and in particular, kidney transplants.
It is part of the defense mechanism of humans to attempt to
remove foreign antigens (in this case, the transplated
organ) by the immune reaction. Thus, in all of the organ
transplant operations, it has been necessary to give large
doses of an immune suppressant prior to the operation and
continuing thereafter in order to prevent the host from
rejecting the donor organ. The immune suppressant of choice
is azathioprine, IMURA ~ (U.S. patent 3,056,785).
Belgian patent 744,970 granted July 27, 1970 (see
also United Kingdom patent 1,296,561 published November 15,
1972) described the use of a number of 6-substituted-benzo-
thiazolyl phenyl ureas including N-(6-methoxybenzothia-
zol-2-yl)-N'-phenyl urea. The compounds are said to be
useful as immune suppressants and immune regulants. N-(6-
acyloxybenzothiazol-2-yl)-N'-phenyl ureas were not pre-
viously known.
1067~99
The immune response is composed of a sequence of
cellular transformations and biochemical events leading to a
bimodal response to foreign substances (ant:igens). Cells
which are to participate in the response evolve from stem
cells which originate in the bone marrow and are seeded out
to the peripheral lymphoid organs. From these latter sites,
following antigenic stimulus, the body's response is mounted
in the form of plasma cells ~which produce antibody) and
specific immune lymphocytes. Antibody is released into the
circulatory system and thus may act at a distance from the
producing cell (humoral immunity). Specific immune lympho-
cytes also enter the circulatory system and act at the site
of injury (cellular immunity). The reaction of antibody
with antigen triggers the release of histamine from baso-
philic leucocytes; histamine, in turn, alters the perme-
ability of blood vessels, speeding the influx of both anti-
body and specific immune lymphocytes into the sites of
injury. Thus, the immune response is composed of a series
of biochemical events in a sequence of cells at various
sites in the body. It can be altered--suppressed, in the
case of the compounds herein discussed-~at a number of
biochemical or cellular developmental sites.
Antihistamines only affect a secondary reaction in
the immune response, having no direct effect on antibody-
producing cells or specific immune lymphocytes. A number of
agents, currently in use as immuno-suppressive drugs, act
further back in the chain of events called herein the immune
response. Certain antiinflammatory steroids, e.g. corti-
sone, suppress production of antibody and specific immune
~ ~067499
`` : : :
lymphocytes, but also radically deplete normal lymphoid
tissue and have other undesirabIe side effects. Several
antineoplastic drugs, e.g., azathioprine, cyclophosphamide,
.
and methotrexate, are employed as immunosuppressi~es, but
they also deplete normal lymphoid tissue and radically
depress other bone-marrow-derivedlcells.~ The general;cyto-
toxicity~of the latter drugs is to be expected in view of
their having been selected on the basis of toxicity against~
a spectrum of cell types.
It is an object of this invention to provide N~
(6-àcyloxybenzothiazol-2-yl)-N'-phenyl urea compounds which~
are useful in altering the immune response and exhib'it ~ ~
specificity of action against cells functioning in the ~ ~'
immune response. ` ' ~ '
; This invention provldes N-(6-acyloxybenzothiazoL~
2-yl)-W'-phenyl ureas represented by Formula I;~
/ S
~' 20
wherein R is hydrogen, halo, (Cl-C3~)alkyl or (Cl-C3) alkoxy
and R' is (Cl-C3)alkyl or phenyl.
The present invention also provides a process
for preparing N-(6-acyloxybenzothiazol-2-yl)-N'-phenyl~
:
~' ureas of Formula I wherein R and R' are as defined above, ~
:
which comprises reacting a N-(6-hydroxybenzothiazol-2-yl~-
N'-phenyl urea of Formula II
`: : :
:
X-4360A -s-
~ ~ .
~: ` : :
~06~499
C-~IH-C-NH~
wherein R is as defined above,
with the anhydride:of acetic, propionic, isopropionic, buty-
: ric, isobutyric or benzoic acid in the presence of pyridine.
In the above formula the term (Cl-C3)alkyl in-
cludes methyl, ethyl, n-propyl and isopropyl. Thus, the
term (Cl-C3)alkoxy includes methoxy, ethoxy, n-propoxy and
isopropoxy. The term "haloi' includes fluoro, chloro, bromo
and iodo.
Compounds illustrative of the sco~e of the above
formula include:
: N-(6-acetoxybenzothiazol-2-yl)-N'-(3-methoxyphenyl)- .
~ urea,
; N-(6-propionyloxybenzothiazol-2-yl)-N'-(2-ethylphenyl)-
urea,
N-(6-isopropionyIoxybenzothiazol-2-yl)-N'-(4-n-propoxy- ~ :
phenyl)urea,
N-(6-butyryloxybenzothiazol-2-yl)-N'-(2-chlorophenyl)-
urea,
N-(6-isobutyryloxybenzothiazol-2-yl)-N'-(4-bromophenyl)-
urea,
N-16-benzoyloxybenzothiazol-2-yl)-N'-t3-fluorophenyl)-
urea,
N-(6-acetoxybenzothiazol-2-yl)-N'-(4-iodophenyl)urea,
N-(6-propionyloxybenæothiazol-2-yl)-N'-(2-ethoxy-
phenyl)urea,
~6--
lQ67499
N-(6-isopropionyloxybenzothiazol-2-yl)-N'-(4-iso-
propoxyphenyl)urea,
N-(6-butyryloxybenzothiazol-2-yl)~N'-~4-isopropyl-
pnenyl)urea,
N-(6-isobutyryloxybenzothiazol-2-yl)-N'-(3-tolyl)-
urea, and
N-(6-benzoyloxybenzothiazol-2-yl)-N'-(4-tolyl)urea.
The compounds represented by Formula I are high-
melting, white, crystalline solids, which can be prepared by
acylating the hydroxyl group of the corresponding N-(6-
hydroxybenzothiazol-2-yl)-N'-phenyl (or substituted phenyl)-
urea (II) with the anhydride of acetic, propionic, isopro-
pionic, butyric, isobutyric or benzoic acid in the i~resence
of pyridine as illustrated below:
C-NH-~Ni --/ ~ II
(R'CO) O/pyridine
O ~ ~C-NH-C-NH -~
It will be recognized by those skilled in the art
that the compounds of Formula I wherein R' is phenyl can
have the phenyl ester moiety substituted by inert groups
such as (Cl-C3) alkyl or alkoxy, halo, nitro or trifluoro-
methyl. Such compounds have immune regulant properties
~367499
similar to those of the parent phenyl ester compounds, and
are included within the scope of this invention.
The required reactants represented by FormuIa II
can be prepared by either of the two following synthetic
procedures. In both procedures, the starting matertal is
2-amino-6-hydroxybenzothiazole prepared by condensing
quinone a~d thiourea according to the procedure of J. Org.
Che~. 35~ 4103 (i970) or by demethylating 2-amlno-6~
methoxybenzothiazole by the procedure of J. Hetero. Chem.,
10 10, 769 (1973). In the first synthesis, a carbamate group
is formed on the 2-amino group of the 2-amino-6-hydroxy-
benzothiazole with a phenyl chloroformate, for example,
p-nitrophenylchloroformate. The carbamate is then reacted
with trimethylsilyl chloride in accordance with the pro-
cedure of Greber and Kricheldorf, Angew. Chem. Internat.
, :
Edit., 7, 941 (1968). The trlmethy~lsilyl group has a double
function in this process. In the flrst place, it transforms
the _-nitrophenyl carbamate group to an isocyanate group.
Secondly, the trimethylsllyl group acts as a protecting
group on the free hydroxyl of the benzothiazole moiety, thus
preventing a reaction between the free hydroxyl and the
isocyanate simultaneously formed. The 6-tr~imethylsilyloxy-
benzothiazolyl-2-isocyanate thus formed can then react
readily with aniline or a suitably substituted aniline to
form a urea. Addition of water to the reaction mixture
serves to hydrolyze the trimethylsilyl protecting group and
thus produce the required reactant having the structure of
Formula II above.
X-4360A -8-
499
The second synthetic procedure available for the
preparation of the reactants of Formula II above involves
the reaction of the 2-amino-6-hydroxybenzothiazole with a
stoichiometric excess (up to two moles) of a phenyliso-
cyanate. The isocyanate reacts predomlnately and preferen-
tially with the carbamate group to form~the urea moiety.
However, the competing reaction~to form a 6-carbamoyloxy
derivative proceeds at a measurable rate. The larger the
excess of isocyanate employed, the greater the yield of
urea, but also the greater the amount of 6-carbamoyloxy
derivative. Conversion of the 6-carbamoyloxy derivative to
the desired 6-hydroxy derivative is readily acco~plishe~d,
however, by preferential hydrolysis ln base.
The compounds of Formula I are useful in altering
the immune reaction in mammals. Thus, the compounds can be
classed as "immune regulating agents" by which is meant an
agent which can decrease the formation of antibodies to -
foreign protein. This activity can thus also be charac-
teriæed as anti-allergic in that the allergic reaction is
part of the defense mechanism of the body (the immune
mechanism) against foreign antigens. (This activity is
quite different from an antihistamine activity which affects
only the effects of histamine released by an antibody-
antigen reaction.) Although immune regulating activity was
determined in mice using sheep erythrocytes as the antigen,
it should be understood that the same types of activity
would be shown against any foreign protein (antigen) in any
species of mammal.
X-4360A -9-
~06~4~9
The abili~y of the compounds of Formula I to alter
immune mechanisms in a host animal was measured by their
activity according to the ~ollowing test.
Groups of five 20-gram, male, random-bred, Swiss
mice received intravenous injections of 5 x 107 sheep red
blood cells. The cells for these injections were prepared
from lamb's blood (collected in Alsever's solution) by
washing three times with 0.85 percent saline and resus-
pending in 0.85 percent saline. Ten daily doses of the
compounds, suspended in saline containing 0-125 percent
"Metkocel"* and 0.2 percent "Emulphor"**, were a~kist~red orally
in O.1 ml doses, commencing ~hree days prior to red blood
cell injection. Several dose levels of each drug were
employed, at 2-fold increments. A control group of mice,
receiving a red blood cell ln~ection and ten daily doses of
vehicle instead of drug, was lnc1uded.~ Six days after the
antigen injections, the mice were bled by cardiac puncture
and the sera from each 5-mouse group pooled. The serum
" ,
pools, following complement inactivation, were assayed for
hemagglutinin content by standard procedures, utilizing a
mixture of serial 2-fold saline dilutions of the test sera
with 0.5 percent sheep red blood cell suspens1ons in plastic
depression trays. Following incubation of the trays for 3
~hours at 37C., the hemagglutination patterns were graded.
A 4-fold ~75 percent) or greater antibody reduction (in the
test serum as compared w1th the control serum) was con-
sidered significant. The results were expressed as the
lowest drug dose producing 75 percent or greater antibody
reduction.
.. ..
*Trademark of the Dow Chemical Company for methyl cellulose.
**Trademark for a nonionic emulsifying agent.
--10--
- .
~6~67~9
The compounds were tested further by a modified
serum assay procedure as described hereinbelow. In these
tests, the procedure described above was modified by the use
of 10-mouse groups, rather than 5-mouse groups. The mice
were bled as before, but the sera were titered indivldually
rather than as a pool. Mean hemagglutinin values (log2) +
; S.E. were calculated for each 10-mouse group~and~p values
; (by Student's T Test), in comparison with the control group,
were determined. The lowest drug dose significantly (p <0.01)
lowering antibody titer defined the endpoint. Drugs were
administered in 10 daily doses; in these instances, the
mice were bled on the 7th, rather than the 6th, post-
antigen day. Typical results obtained 1n the individual
serum assay test with representative compounds of Formula I
; are summarized in Table ~.
In Table I the first column~gives the substituent
varient R' of the compounds of Formula I wherein R is hydro-
gen and the second column the immunosuppressive endpoint as
the lowest drug dose in milligrams per kilogram which signi-
ficantly lowers the antibody titer.
Table I. Immunosuppressive Activity of N-(6-
Acyloxybenzothiazol-2-yl)-N'-Phenylureas (Individual Serum
Assay Procedure)
Endpoint Dose
R'(Substituent) (mg/Kg)(p<0.01)
methyl 12.5
ethyl 3.1
propyl 3.1
isopropyl 12.5
phenyl ~12.5
X-4360A -11-
1g~6~99
The compounds of Formula I are useful in organ
transplant operations where they can be used to prevent the
host from rejecting the donor organ. In addition to their
use in organ transplant operations, immune regulating
agents are also useful in various diseases of little-under- -
stood etiology, denominated generically as "auto-immune"
diseases. These diseases include: auto-immune hemolytic
anemia, iodiopathic thrombocytopenic purpura, lupus erythe-
matosus, lupoid hepatitis, lupus nephritis, glomerulone-
phritis, the nephrotic syndrome, Goodpasture's syndrome,
Wegener's granulomatosis, schleroderma, Sezary's disease,
psoriasis, uveitis, rheumatoid arthritis, ulcerative colitis,
thyroiditis and mumps orchitis. Immune suppressant agents
may be more or less useful in the treatment of the above
diseases depending upon the degree to which the disease is
dependent upon an auto-immune mechanism.
Routes of administration include oral, intra-
peritoneal, topical and subcutaneous routes. For oral
administration, the immune regulant can be dissolved or
suspended in polyethylene glycol and mixed with corn oil~ at
a rate of 1-200 mg./ml. A particularly useful medium for
oral administration contains 50 percent polyethylene glycol
200, 40 percent corn oil and 10 percent polyoxyethylene
sorbitol monostearate. Aqueous vehlcles, to which may be
added surface-active agents, are also useful. For topical
application, the compound is preferably administered in
ethanoL or in the above polyethylene glycol-corn oil-surfac-
tant composition whereas for subcutaneous injection an
isotonic solution is used. The immune-regulant is present
in the particular vehicle at the rate of from 1 to 200 mg./ml.
-12-
1~:96~4~9
The heterocyclic ureas o~ Formula I use~ul in
altering the immune response, as can be seen, differ from a
majority of the known immune regulants and immunosuppres-
sants in the mechanism of their action on the mammalian
host. They do not act by directly antagonizing the action
of histamine as do the anti-histamine dxugs. ~On the other
hand, they do not depress bone-marrow function as do the
antineoplastic drugs frequently used in connection with
tissue transplants. The heterocyclic ureas of Formula I
more closely resemble the corticoids in their e~fects on the
immune response, but even here there is a fundamental dif-
ference in that the corticoids deplete Iymphoid tissue and the
heterocyclic ureas of Formula I do not. Thus, it is appar-
ent that these agents function through a mechanism wh~ich
neither depletes normal lymphoid~mass nor depre~aes bone
marrow, thus avoiding the major drawbacks of the currently
.
used immunosuppressive drugs--the corticosteroids and anti-
neoplastic drugs.
This invention is further illustrated by the
following specific examples: (All pKa's cited were deter-~
mined in a 66~percent dimethylformamide/water system).~ ;
PREPARATION OF STARTING MATEhrALs
Preparation l
PREPARATION OF N-(6-HYDROXYBENZO-
THIAZOL-2-YL)-N ? -PHENYLUREA
A slurry was prepared contai~ning~16.7 g. of 2-
amino-6-hydroxybenzothiazole hydrochloride, prepared by the
~method of J. ~. Chem., 35, 4103 (1970), in 300 ml. of
acetone and ll g. of potassium bicarbonate. The slurry was
X-4360A -13-
1al67499
stirred under anhydrous conditions while 22.4 g. of p-nitro-
phenylchloroformate in 300 ml. oE acetone were added thereto
in dropwise fashion. The reaction mixture was stirred for
about 18 hours and then poured into three liters of water.
The reaction mixture was filtered,; and the filter cake, com-
prising 2-amino-6-hydroxybenzothiazolyl-p-nitrophenyl car-
bamate formed in the above reaction, was washed with ether.
The compound crystallized as the hemihydrate.
Analysis calculated for C14H1gN3O4S; 1/2 H2O
Calc.: C, 51.85; H, 2.88; N, 13.33;
Found: C, 51.74; H, 3.40; N, 12.74
A slurry was prepared containing 600 mg. of the
above carbamate in 25 ml. of acetone. About 0.5 ml. of
aniline was added in dropwise fashion. The reaction mixture
was stirred at ambient temperature while 0.3 ml. of tri-
methylsilyl chloride were added in dropwise fashion via a
syringe. The resulting mixture was refluxed for about 18
hours yielding a yellow solution. The reaction mixture was
cooled, poured into water with stirring, and then filtered.
The filter cake was washed with ether and dried. The filter
cake comprised N-(6-hydroxybenzothiazol-2-yl)-NI-phenylurea
formed in the above reaction. m.p. above 250C. Yield=60
percent. Characteristic Mass spectral fragments at 285,212,
192, and 166; pKa=10.9.
Analysis calculated for C14HllH3O2S
Calc.: C, 58.93; H, 3.89; N, 14.73;
Found: C~ 58.34; H, 3.76; N, 13.76
The following compounds were prepared by the above
procedure: N-(6-hydroxybenzothiazol-2-yl)-N'-(4-methoxy-
-14-
674gg
phenyl)urea; pKa=ll.l; Characteristic mass spectral frag-
ments at 315, 192, and 166. m.p. above 250C.
AnalySiS calculated for C15H13N3O2S- 3/4 H2O
Calc~: C, 57.88; H, 4~82; N, 13.50;
Found: C, 57.42; H, 4.27; W, 13.18.
N-(6-hydroxybenzothiazol-2-yl)-N'-(2-fluorophenyl)-
urea. Melting point above 250C. One spot material by thin
. .
layer chromatography. pKa=10.3; Characteristic mass spec-
tral fragments at 303, 192~ and 166.
Analysis calculated for C14HloFN3O2S
Calc.: C, 55.44; H,~ 3.32; N, 13.85
Found: C, 55.28; H, 3.47; N~, 13.31
N-(6-hydroxybenzothiazol-2-yl)-N'-(2-tolyl)urea.
Melting point above 250C. One spot material by thin layer
chromatography; pKa=10.6
:
Analysis oalculated for C15H13N3O
Calc.: C, 57.13; H, 4.16; N, 13.33;
Found: C, 56.90; fl, 4.40; N, 13.37
Preparation 2
ALTERNATE PREPARATION OF N-(6-HYDROXY-
BENZOTHIAZOL-2-YL)-N'-PHENYLUREA
A slurry of 152 g. of 2-amino-6-hydroxybenzoth1a-
zole was prepared in 3 liters of acetone. A solution of
109 g. of phenylisocyanate and 150 ml. of acetone was added
thereto in dropwise fashion. After the addition had been
completed, the reaction mixture was heated at refluxing
temperature overnight. The reaction mixture was cooled to
about 50C. and decolorizing charcoal added. The mixture
was filtered, and a second batch of 109 g. of phenyliso-
.
X-4360A -lS-
~L067499
cyanate in acetone added to the filtrate. The reaction
mixture was again heated to refluxing temperature for about
2 hours. The reaction mixture was cooled, and a white solid
comprising N-(6-phenylcarbamoyloxybenzothiazol-2-yl)-
N'-phenylurea precipitated. The precipitate was separated
by filtration, and the filter cake washed with acetone~
Yield=73 percent.
Analysis calculated for C21H15N4O3S
Calc.: C, 62.52; H, 3.75; N, 13.89; S, 7.95
Found: C, 62.30; H, 3.97; N, 13.69; S, 7.76.
Melting point above 250C.
Four grams of the above carbamoyloxybenzothiazolyl
phenyl urea were dissolved in 150 ml. of anhydrous methanol.
A 10 percent slurry of 0.5 g. of sodium methylate in methanol
was added with stirring. The reaction mixture was stirred
at room temperature overnight. Thin layer chromatography
showed about 50 percent of the carbamoyloxy group had been
removed by hydrolysis. The reaction mixture was then slowly
heated and the progress of the reaction continually checked
by thin layer chromatography. After two hours of heating at
about 45C., the hydrolysis was substantially 100 percent
complete. The reaction mixture was then cooled and care-
fully acidified to pH=about 4 with 10 percent aqueous
hydrochloric acid. N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl-
urea formed in the above reaction was separated by filtra-
tion. The filter cake was washed with methanol and then
ether. Examination of the NMR spectra indlcated that the
phenyl carbamoyl group was no longer present in the mole-
cule; thls fact was further substantiated by the UV shifts
in acid and base.
~ 16-
~67499
PREPARATION OF FINAL PRODUCTS
Examples 1-4
PREPARATION OF N-(6-ACYLOXYBENZOTHIAZOL-2-YL)-
N'-PHENYLUREAS tGBNERAL PROCEDURE)
One hundredth of a mole of the appropriate N-(6-
hydroxybenzothiazol-2-yl)-N'-phenyl(or zubztituted phenyl)~-
; urea is dissolved in 25 ml. of pyridine.~ One equivalent
- ~ :
(0.01 mole) of acetic, propionic, butyric or isobuty~ic
anhydride is added and the reaction mixture is stirred for ~
12 hours. The mixture is poured over ice. The precip1tated
1 0~
product is filtered, washed with water a;nd ethyl ether, and
dried.
The following compounds wère prepared by the
method described above.
~ N-(6-Acetoxybenzothiazo1-2-ylj-N'-pheny1urea, m.p.
;~ 210-213C, y1e1d 2.3 g. (70 percent).
Analysis C16H13N303S MW 327 ~
Calcd:~ C, 58.70; H,~ 4.00, N, 12.84.
Found: C, 58.98; H, 4.22; N, 12.86.
N-(6-Pxoplonyloxybenzoth1azol-2-yl)-N'-phenylurea,
m.p. 212-215C., yield 2.8 g. (81.6 percent).
Analysis C17H15N33S MW 341
Calcd: C, 59.81; H, 4.43; N, 12.31.
Found: C, S9.50; H, 4.69; N, 11.~99.
N-(6-Butyryloxybenzothiazol-2-yl)-N'-phenylurea,
m.p.~?O7-211C., yield 2.3 g. (65 percent).
Analysis C18H17N33S MW 354
Calcd: C, 60.49; H, 5.36; N, 11.76
Found: C, 60.11; H, 5.30; N, 11.39
X-436QA -17~
1~7~9
:
N-(6-Isobutyryloxyben~othlazol-2-yl)-N'-phenyl-
urea, m.p. 212-215~C., yield 3.4 g. (96 percent).
Analysis C18H17N33S MW 354
Calcd: C, 60.49; H, 5.36; N, 11.76.
Found: C, 60.59; H, 5.24; N, 11.50.
Example 5
N-(6-BENZOYLOXYBENZOTHIAZOL-2-YL)-N'-PHENYLUREA
Two and eight tenths grams (0.01 molei of N-(6-
hydroxybenzothiazol-2-yl)-N'-phenyIurea were dissolved in 25
ml. of pyridine. Two and three-tenths grams (0.01 mole) of
benzoic anhydride were added and the mixture was st1rred for
12 hours. The mixture was poured over ice. The precipi-
tated product was filtered,~ washed wlth~water and ethyl
ether and~dried. The yield was 2.3 g. (59 percent) of
.
N-~6-benzoyloxybenzothiazol-2-yl~)-N'-phenylurea, m~.p. 245-
2 4 9 c: .
:
Analysis C21H15N33S MW 389
Calod: C, 64.77; H, 3.88; N, 10.79
Found: C, 64.36; H, i.l9; N, 10.60.
,
: : :
:
:
~:
:~ :
:
X-4360A 18-
