CA1067499A - N-(6-acyloxybenzothiazol-2-yl)-n'-phenyl (or substituted phenyl) ureas - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention relates to N-(6-acyloxybenzothiazol-2-yl)-N'-phenyl urea compounds of the formula I
wherein R is hydrogen, halo, (C1-C3) alkyl or (C1-C3) alkoxy and R' is (C1-C3).alkyl or phenyl, which are useful as immune regulants. Also provided by this invention is 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

II
wherein R is as defined above, with the anhydride of acetic, propionic, isopropionic, butyric, isobutyric or benzoic acid in the presence of pyridine.

Description

:~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.

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.

~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.

- .

~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 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.

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 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-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.

, : : :
:
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~:

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Claims (12)

The embodiments of the invention for which an exclusive property or privilege is claimed are as follows:

1. A process for preparing N-(6-acyloxybenzo-thiazol-2-yl)-N'-phenyl urea compounds of the formula I
wherein R is hydrogen, halo, (C1-C3)alkyl or (C1-C3) alkoxy and R' is (C1-C3)alkyl or phenyl, which comprises reacting a N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl urea of Formula II

II
wherein R is as defined above, with an anhydride of acetic, propionic, isopropionic, butyric, isobutyric or benzoic acid in the presence of pyridine.

2. N-(6-Acyloxybenzothiazol-2-yl)-N'-phenyl urea compounds of the formula I wherein R and R' are as defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process for preparing N-(6-acetoxybenzo-thiazol-2-yl)-N'-phenyl urea which comprises reacting N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl urea with acetic anhydride.

4. N-(6-Acetoxybenzothiazol-2-yl)-N'-phenylurea when prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process for preparing N-(6-propionyloxy-benzothiazol-2-yl)-N'-phenyl urea which comprises reacting N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl urea with propionic anhydride.

6. N-(6-Propionyloxybenzothiazol-2-yl)-N'-phenyl-urea when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

7. A process for preparing N-(6-butyryloxybenzo-thiazol-2-yl)-N'-phenyl urea which comprises reacting N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl urea with butyric anhydride.

8. N-(6-Butyryloxybenzothiazol-2-yl)-N'-phenyl-urea when prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process for preparing N-(6-isobutyryloxy-benzothiazol-2-yl)-N'-phenyl urea which comprises reacting N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl urea with iso-butyric anhydride.

10. N-(6-Isobutyryloxybenzothiazol-2-yl)-N'-phenyl-urea when prepared by the process of claim 9 or by an obvious chemical equivalent thereof.

11. A process for preparing N-(6-benzoyloxybenzo-thiazol-2-yl)-N'-phenyl urea which comprises reacting N-(6-hydroxybenzothiazol-2-yl)-N'-phenyl urea with benzoic anhydride.

12. N-(6-benzoyloxybenzothiazol-2-yl)-N'-phenyl-urea when prepared by the process of claim 11 or by an obvious chemical equivalent thereof.