IE43213B1 - N-(6-acyloxybenzothiazol-2-yl)-n'-phenyl (or substituted phenyl) ureas - Google Patents

Abstract

Novel phenylurea derivatives of the formula I are prepared by reacting an N-(6-hydroxybenzothiazol-2-yl)-N'-phenylurea of the formula II with an anhydride of acetic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid or benzoic acid in the presence of pyridine. In the formulae I and II, R is a hydrogen atom, a halogen atom, an alkyl group having 1-3 carbon atoms or an alkoxy group, and R' represents an alkyl radical having 1-3 carbon atoms or the phenyl radical. The novel phenylurea derivatives of the formula I are suitable for modifying the immune response, and they have a specific action against those cells which are active in the immune response.

Description

The present invention relates to N-(6-acyloxybenzothiazol-2-yl)-N!-phenyl (or substituted phenyl)ureas which are useful as immune regulants.

Similar compounds are described and claimed in Patent Specification Mo. 41459. 2-Substituted benzimidazoles, benzothiazoles and benzoxazoles have recently been proposed for a variety of uses, mainly in the agricultural £ield. For example, 2trifluoromethylbenzimidazoles are reported to be extremely active herbicides according to British Patent Specification No. 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) benzimidazole (thiabendazole) is presently being marketed as an anthelmintic. In addition, certain 2-hydroxybenzylbenzimidazoles have been revealed as having anti-viral properties (see U.S. patent 3,331,739). While the use of benzoxazoles and benzothiazoles in 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 above classes of compounds are sparingly described in the art. W-(benzothiazol2- yl)-Ν'-phenyl urea is described in Chem. Abs., 29, 2660; 55, 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. N-(Benzimidazol-2-yl)-Ν'-phenyl urea is described in Beilstein, 24 (II), 62 and in Chem. Abs., 15, 3(77. In addition, U.S. Patent 3,299,085 discloses N-(ben-243313 zothiazol-2-yl) or N-(benzoxazol-2-yl)-N'-C3-C5 aliphatic areas as intermediates in the preparation of certain herbicides, and U.S. patent 3,162,644 describes benzoxazol2-yl ureas, useful as plant growth regulators and muscle relaxants. U.S. Patent Specifications Nos.3,399,212; 3,336,1915 and 3,401,171 disclose benzimidazolyl-ureas said to be anthelmintics, finally. South African patent 68/4748 (Derwent Farmdoc 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 transplanted organ) by the immune reaction. Thus, in ail 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, IMURAN (U.S. Patent Specification No. 3,056,785)· The word Imuran is a registered trade mark).

Belgian Patent Specification No. 744,970 granted July 27, 1970 (see also British Patent Specification No. 1,296,561 published November 15, 1972) describes the use of a number of 6-substitutedbenzo-thiazolyl-phenyl-ureas including N-(6-methoxybenzothiazo l.-2-yl)-N’-phenyl urea. The compounds arc said ho be useful as immune suppressants and immune rcgulants. N-(6acyloxybenzothiazol-2-yi>-N1-phenyl-ureas were not previously known.

The immune response is composed of a sequence of cellular transformations and biochemical events leadinq to a bimodal response to foreign substances (antigens). 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 antigens 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 lymphocytes 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 basophilic leucocytes; histamine, in turn, alters the permeability of blood vessels, speeding the influx of both antibody 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 antibodyproducing 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., cortisone, suppress production of and specific immune -443213 lymphocytes, but also radically deplete normal lymphoid tissue and have other undesirable side effects. Several antineoplastic drugs, e.g., azathioprine, cyclophosphamide, and methotrexate, are employed as immunosuppressives, but they also deplete normal lymphoid tissue and radically depress other bone-marrow-derivedicells. The general cytotoxicity 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-acyloxybenzothiazol-2-yl)-Ν'-phenyl-urea compounds which are useful in altering the immune response and exhibit specificity of action against cells functioning in the immune response.

This invention provides N-(6-acyloxybenzothiazol2-yl)-N'-phenyl ureas represented by Formula I wherein R is hydrogen, halo, (C^-C^)alkyl or (C^-Cj) alkoxy and R' is (C^-C^)alkyl or optionally substituted 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)Ν'-phenyl urea-of Formula II 43313 HO wherein R is as defined above, with the anhydride of acetic, propionic, butyric, isobutyric or optionally substituted benzoic acid in the presence of pyridine.

In the above formulae the term (C^-C^)alkyl” indicates methyl, ethyl, n-propyl and isopropyl. Thus, the term (Cj-C^Jalkoxy indicates methoxy, ethoxy, n-propoxy and isopropoxy. The term halo” indicates fluoro, chloro, bromo and iodo.

The invention further includes a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier therefor, and a method of making such a composition comprising mixing a compound of formula I with a pharmaceutically acceptable carrier.

Further in accordance with the invention there is provided a method of treating non-human mammals to alter the immune reaction thereof, comprising administering to a nonhuman mammal a compound of Formula I.

Compounds illustrative of the scope of the above formula include: N-(6-aeetoxybenzothiazoi-2-yl)-N!-(3-methoxyphenyl)urea, N-(6-propionyloxybenzothiazol-2-yl)-N!-(2-ethylphenyl)urea, N-(6-butyrjloxybenzothiazol-2-yl) -N! - ( 2-chlorophenyl) ti rea, N-(6-isobutyryloxybcnzothiazol-2-yl)-N’-(4-bromophenyl)· urea, N-(6-benzoyloxybenzothiazol-2-yl)-JJ1-(3-fluorophenyl )urea, N-(6-acetoxybenzothiazol-2-yl)~'\T,-(4-iodophenyl)urea, N-(6~propionyloxybenzothiazol-2~yl)-N’-(2-ethoxyphenyl)urea, N-(6-butyryloxybenzothiazol-2-yl) -N * - (4-isopropyljihenyljurea, 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 highmelting, white, crystalline solids, which can be prepared by acylating the hydroxyl group of the corresponding N-(6hydroxybenzothiazol-2-yl)-N1-phenyl (or substituted phenyl)urea (II) with the anhydride of acetic, propionic, butyric, isobutyric or optionally substituted benzoic acid in the presence of pyridine as illustrated below; HQ‘ r Ml · (J ·~:ι· ' .· ,/ II (R'CO) O/pyridi ne .1 (J 1! It will be recognized by those skilled in the art compounds of Formula I wherein R’ is optionally substituted that the phenyl can have the phenyl ester moiety substituted by groups such as (C^-C^) alkyl or alkoxy, halo, nitro or trifluoromethyl. Such compounds have inmino regulant properties -743213 similar to those of the parent phenyl ester compounds, and are included within the scope of this invention.

The required reactants represented by Formula II can be prepared by either of the two following synthetic procedures. In both procedures, the starting material is 2-amino-6-hydroxybenzothiazole prepared by condensing quinone and thiourea according to the procedure of J. Org.· Chem. 35, 4103 (1970) or by demethylating 2-amino-6methoxybenzothiazole by the procedure of J. Hetero. Chem., .0 10, 769 (1973). In the first synthesis, a carbamate group is formed by reaction of the 2-amino-6-hydroxybenzothiazole with a phenyl chloroformate, for example, g-nitrophenyl chloroformate. The carbamate is then reacted with trimethylsilyl chloride in accordance with the pro15 oedure of Greber and Kricheldorf, Angew. Chem. Iiil.ern.it.

KdiL., 7, 941 (1968). The trimethylsilyl group has a double function in this process. In the first place, it transforms the p-nitrophenyl oxycarbonylamino group to an isocyanate group. Secondly, the trimethylsilyl group acts as a protecting group for the free hydroxyl of the benzothiazole moiety, thus preventing a reaction between the free hydroxyl and the isocyanate formed. The 6-trimethylsilyloxybenzothiazolyl-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. -843313 The second synthetic procedure available for the preparation of the reactants of Formula 11 above involves the reaction of the 2-amino-6-hydroxybenzothiazole with a stoichiometric excess (up to two moles) of a phenyl isocyanate. The isocyanate reacts predominately and preferentially with the amino 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 accomplished, however, by preferential hydrolysis in base.

The compounds of Formula I are useful in altering the immune reaction in mammals. Titus, the compounds can be classed as immune regulating agents by which is meant agents which can decrease the formation of antibodies to foreign protein. This activity can thus also be characterized 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 antibodyantigen reaction.) Although immune regulating activity was determined in mice using sheep erythrocytes as the antigen, i t should be understood that the same types of activity would be shown against any foreign protein (antigen) in any species of mammal. -943213 The ability of the compounds of Formula X to alter immune mechanisms in a host animal was measured by their activity according to the' following test.

Groups of five 20-gram, male, random-bred, Swiss , 7 ; mice received intravenous injections of 5 x 10 sheep red blood cells. The cells for these injections were prepared Jrom lamb's blood (collected in Alsever's solution) by washing three times with 0.85 percent saline and resuspending in 0.85 percent saline. Ten daily doses of the compounds, suspended in saline containing 0-125 percent Methocel (Methocel” is a registered Trade Mark) and 0.2 percent Emulphor, (Emulphor” is a registered Trade Mark) were administered orally in 0.1 ml doses, commencing three 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 injection and ten daily doses of vehicle instead of drug, was included. 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-foltl saline dilutions of the test sera with 0.5 percent sheep ied blood cell suspensions in plastic depression trays. Following incubation of the trays for 3 j hours at 37°C., the hemagglutination patterns were graded.

A 4-fold (75 percent) or greater antibody reduction (in the test serum as compared with the control serum) was considered significant. The results were expressed as the lowest drug dose producing 75 percent or greater antibody reduction. -1043313 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 individually rather than as a pool. Mean hemagglutinin values (log^) + S.B. 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, postantigen day. Typical results obtained in the individual serum assay test with representative compounds of Formula I are summarized in Table I.

In Table I the first column gives the substituent varient R' of the compounds of Formula I wherein R is hydrogen and the second column the immunosuppressive endpoint as the lowest drug dose in milligrams per kilogram which significantly lowers the antibody titer.

Table I. Immunosuppressive Activity of N-(6Acyloxybenzothiazol-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 -1143213 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-understood etiology, denominated generically as “auto-immune diseases. These diseases include: auto-immune hemolytic anemia, iodiopathic thrombocytopenic purpura, lupus erythematosus, lupoid hepatitis, lupus nephritis, glomerulonephritis, 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, intraperitoneal , 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 2(<0, 40 percent corn oil and 10· percent polyoxyethylene s· rbitol monostearate. Aqueous vehicles, to which may be a< ded surface-active agents, are also useful. For topical application, the compound is preferably administered in ethanol or in the above polyethylene glycol-corn oily-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. -1243213 The heterocyclic ureas of Formula I, useful in altering the immune response, as can be seen, differ from a majority of the known immune regulants and immunosuppressants 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 drugs. 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 effects on the immune response, but even here there is a fundamental difference in that the corticoids deplete lymphoid tissue and the heterocyclic ureas of Formula I do not. Thus, it is apparent that these agents function through a mechanism which neither depletes normal lymphoid mass nor depresses bond marrow, thus avoiding the major drawbacks of the currently used immunosuppressive drugs—the corticosteroids and antineoplastic drugs.

This invention is further illustrated by the following specific examples: (All pKa's cited were determined in a 66 percent dimethylformamide/water system).

PREPARATION OF STARTING MATER IALS Preparation 1 PREPARATION OF N-(6-HYDROXYBENZOTHIAZOL-2-YL)-N'-PHENYLUREA A slurry was prepared containing 16.7 g. of 2amino-6-hydroxybenzothiazole hydrochloride, prepared by the. method of J. Org. Chem., 35, 4103 (1970), in 300 ml. of acetone and 11 g. of potassium bicarbonate. The slurry was -133 213 stirred under anhydrous conditions while 22.4 g. of p-nitrophenylchloroformate in 300 ml. of acetone were added thereto in dropwise fashion. The reaction mixture was stirred for about 18 hours and then poured into throe liters of water.

The reaction mixture was filtered, and the filter cake, comprising ja-nitrOphenyl-N-i6-hydroxybenzofchiazolyl-2- carbamate formed in the above reaction, was washed with ether. The compound crystallized as the hemihydrate.

Analysis calculated for ci4HigN3°4S/ 1/2 H.,0 LO 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 500 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 trimethylsilyl chloride was 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)~N'-phenylurea formed in the above reaction, m.p. above 250°C. Yield=60 percent. Characteristic Mass spectral fragments at 285,212, J 92, and 166; pKa=10.9.

) Analysis calculated for 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)-N1 -(4-methoxy-1443213 phenyl)urea; pKa=ll.l; Characteristic mass spectral fragments at 315, 192, and 166. m.p. above 250°C.

Analysis calculated for ci5Hi3N3°2S· H2° Calc.: C, 57.88; H, 4.82; N, 13.50; Found: C, 57.42; H, 4.27; N, 13.18.

N-(6-hydroxybenzothiazol-2-yl)-Ν'-(2-tolyl)urea. Melting point above 250°C. One spot material by thin layer chromatography. pKa=10.3; Characteristic mass spectral fragments at 303, 192, and 166.

Analysis calculated for C^^H^gFN^OgS 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)-N1 -(2-tolyl)urea.

Melting point above 250°C. One spot material by thin layer chromatography; pKa=10.6 Analysis calculated for σ^Η^Ν^Ο^ε Calc.: C, 57.13; H, 4.16; N, 13.33; Found: C, 56.90; II, 4.40; N, 13.37 Preparation 2 ALTERNATE PREPARATION OF N-(6-HYDROXYBENZOTHIAZOL-2-YL)-N'-PHENYLUREA A slurry of 152 g. of 2-amino-6-hydroxybenzothiazole 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 50°C. and decolorizing charcoal added. The mixture was filtered, and a second batch of 109 g. of phenyl iso-1543213 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 C2iHX5N4°3S 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 250°C.

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 45°C., the hydrolysis was substantially 100 percent complete.. The reaction mixture was then cooled and carefully acidified to pH=about 4 with 10 percent aqueous hydrochloric acid. N-(6-hydroxybenzothiazol-2-yl)-N'-phenylurea formed in the above reaction was separated by filtration. The filter cake was washed with methanol and then ether. Examination of the NMR spectra indicated that the phenyl carbamoyl group was no longer present in the molecule; this fact was further substantiated by the UV shifts in acid and base. -1643213 PREPARATION OF FINAL PRODUCTS Examples 1-4 PREPARATION OF N-(6-ACYLOXYBENZOTHIAZOL-2-YL)N'-PHENYLUREAS (GENERAL PROCEDURE) One hundredth of a mole of the appropriate N-(6hydroxybenzothiazol-2-yl)-Ν'-phenyl(or substituted phenyl)urea is dissolved in 25 ml. of pyridine. One equivalent (0.01 mole) of acetic, propionic, butyric or isobutyric anhydride is added and the reaction mixture is stirred for 12 hours. The mixture is poured over ice. The precipitated product is filtered, washed with water and ethyl ether, and dried.

The following compounds were prepared by the method described above.

N-(6-Acetoxybenzothiazol-2-yl)-N'-phenylurea, m.p. 210-213°C, yield 2.3 g. (70 percent).

Analysis C16H13N3O3S MW 327 Calcd: C, 58.70; H, 4.00; N, 12.84.

Found: C, 58.98; H, 4.22; N, 12.86.

N-(6-Propionyloxybenzothiazol-2-yl)-Ν'-phenylurea, m.p. 212-215°C., yield 2.8 g. (81.6 percent).

Analysis C^H^N^S MW 341 Calcd: C, 59.81; H, 4.43; N, 12.31.

Found: C, 59.50; H, 4.69; N, 11.99.

N-(6-Butyryloxybenzothia zol-2-yl)-N'-phenylurea, m.p. 207-211°C., yield 2.3 g. (65 percent).

Analysis C^H-^N^S MW 354 Calcd: C, 60.49; H, 5.36; N, 11.76 Found: C, 60.11; n, 5.30; N, 11.39 -173213 N-(6-Isobutyryloxybenzothiazol-2-yl)-Ν'-phenylurea, m.p. 212-215°C., yield 3.4 g. (96 percent). i Analysis ClgH17N3O3S 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 2.8 grams (0.01 mole) of N-(6hydroxybenzothiazol-2-yl)-N1-phenylurea were dissolved in 25 I ml. of pyridine. 2.3 grams (0.01 mole) of benzoic anhydride were added and the mixture was stirred for 12 hours. The mixture was poured over ice. The precipiiated product was filtered off, washed with water and ethyl ether and dried. The yield was 2.3 g. (59 percent) of N-(6-benzoyloxybenzothiazol—2—yl)-Ν'-phenylurea, m.p. 245249°C.

Analysis C21H15N3°3S 389 Calcd: C, 64.77; H, 3.88; N, 10.79 Found: C, 64.36; H, 4.19; N, 10.60.

Claims (14)

1. CLAIMS:1. N-(6-Aeyloxybenzothiazol-2-yl)-N'-phenyl urea compounds of the formula 0 / \ z \ 11 /' II T Π T-NH-C-NH—< 5 wherein R is hydrogen, halo, (C^-C 3 )alkyl or (©-C 3 ) alkoxy and R' is (C^-C 3 )alkyl or optionally substituted phenyl.

2. A compound of claim 1 wherein R is hydrogen and R' is C^) alkyl.

3. N-(6-acetoxybenzothiazol-2-yl)-N'-phenylurea Ιθ

4. · N-(6-propionyloxybenzothiazol-2-yl)-Ν'-phenylurea

5. N-(6-butyryloxybenzothiazol-2-yl)-N'-phenylurea

6. N-(6-isobutyryloxybenzothiazol-2-yl)-Ν'-phenylurea.

7. A compound of claim 1 wherein R is hydrogen and R' is optionally substituted phenyl.

8. · N-(6-benzoyloxybenzothiazol-2-yl)-N’phenylurea.

9. A process for preparing N-(6-acyloxybenzothiazol-2-yl)-Ν'-phenyl-urea compounds as defined in claim 1, which comprises reacting a K-(6-hydroxybenzothiazol-2-yl)-N’20 phenyl-urea of formula TI -IS4 3 213 wherein R is as defined in claim 1, with the anhydride of acetic, propionic, butyric, isobutyric or optionally substituted benzoic acid in the presence of pyridine.

10. A process for preparing a N-(6-acyloxybenzothiazol2-yl)-N’-phenyl-urea compound as defined in claim 1, substantially as hereinbefore described with reference to any one <>Γ Examples 1 to 5·

11. A N-(6-acyloxybenzothiazol-2-yl)-N*-phenyl-urea compound as defined in claim 1, substantially as hereinbefore described with reference to any one of Examples 1 to 5·

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or claim 11 and a pharmaceutically acceptable carrier therefor.

13. · A method of making a pharmaceutical composition according to claim 12 comprising mixing a compound according to any one of claims 1 to 8 or claim 11 with a pharmaceutically acceptable carrier.

14. A method of treating non-human mammals to alter the immune reaction thereof, comprising administering to a non-human mammal a compound according to any one of claims 1 to 8 or claim 11.