AU427296B2 - Azido-isothiazoles - Google Patents

Description

/rsn T. resntinvenzion a Is concerned with new azido- isothiazoles an ihthe preparation thereof and is als8o concerned with compositions conann these new azido- isothiazoles. The new azido-isothiazoles according to the present invention are compounds of the general formula:-

R CR N N

wherein R is a halogen atom or an SR, 3SJR 1 Or S radical and .R Is a straight or branched-chain alkyl radical containing up to 12 carbon atoms or a benzyl or phenyleth2yl radical, the benzene nucleus of which may be substituted by nitro groups and/or halogen atoms'. Wle-have found that the new azido-isothiazoles according to the present invention are outstanding Insect repellents and, in addition, possess good anti-bacterial and anti-mycetic properties. When, in the compounds of general formula the substituent R is a mercapto, sulphinyl or sulphonyl group substituted by R ,then the radical Rlis preferably a methyl, ethyl,.n-propyl, Isopropyl, I- or 2-n--butyl, isobutyl "tert.-butyl, n-amyl, isoamyl, hexyl, heptyl or octyl radical or an Isomer of these radicals and their higher honlologues containing up to 12 carbon atoms. Wlhen the radical R is' radicatl, then it is preferably a benzyl, I- or 2-phenyl-ethyl, 4-nitrobenzyl, 2 ,l-dinitroenzyl, 4-fluorobenzy., 3- or 4-chlorobenzyl, 2. 427296

10,336 2-(4-chlorophenyl)-ethyl, 3,4- or 2,6-dichlorobenzyl or 4-bromobenzyl radical. Of the compounds of general formula in which the substituent R is a halogen atom, the 3-chloro- and the are preferred. Furthermore, the R can also be iodine or fluorine. The azido-isothiazoles according to the present invention can be prepared in a simple manner, for example, by the reaction of the corresponding 3-R-5-Y-4-cyano-isothiazoles with a metal azide, especially with sodium or potassium azide. Y hereby signifies a halogen atom, preferably a chlorine or bromine atom, or a diazonium cation. The reaction conditions for such nucleo-7 philic substitutions on heteorocyclic compounds are known. For this reaction, it has proved to be especially expedient to use polar solvents, for example, water, aliphatic alcohols contain- ing up to 4 carbon atoms, especially methanol and ethanol, dinethyl formamide, dinethyl sulphoxide, ketones, such as acetone, cyclic ethers, such as dioxan and tetrahydrofuran, or mixtures of these solvents. The reaction temperature should preferably not exceed 500C.; it is expedient to work in the temperature range of between 0 and 35 0 C. The starting materials of general formula in which, however, a diazonium cation is present in the instead of an azido group, can be obtained in known manner from the corresponding 5-amino compounds by reaction with nitrous acid. In the case of the subsequent reaction of the diazonium salts, preferably of the sulphates or chlorides, with

3 427296

10,336 170 the metal azide, the azide group is formed in known manner

together with the elimination of nitrogen.

Purthernore, 3-R-5-azido-cyano-isothiazoles can be prepar

from the corresponding 3-R-5-hydrazino-4-cyano-isothiazoles by

diazotisation in the usual way in acidic solution. By diazoti- sation, there is to be understood the reaction of amino com-

pounds with nitrous acid in acidic solution. As is known, asides are thereby formed from hydrazines. The reaction condi- tions to be used are well known from the literature.

The 3-R-5-hydrazino-4-cyano-isothiazoles to be used as

starting materials can be prepared especially easily when

corresponding compounds, in which, in the 5-position, instead

of the hydrazino group, there is present a group which can be

replaced by the hydrazine radical, are reacted with hydrazine.

Examples of groups which can be replaced by a hydrazine radical

include halogen atoms, nitro, amino, SR SOR SO2R 1 OS02H, OS0 2 R1 -OSO2.C 6 H 4 .CH3 p-OS0 2 .CH 4 B3r and OCOR1 groups, wherein R has the same neaning as above. In the case of this reaction, in which the hydrazine is preferably used in the form

of 80% hydrazine hydrate, the substituent present in the

position of the isothiazole ring is exchanged for the hydrazino

group almost exclusively and in a surprisingly smooth reaction.

Such reactions are hitherto unknown.for isothiazole

derivatives.

The diazotisation is expediently carried out at tempera-

tures which do not increase substantially above ambient temp-

erature.

As acids for the diazotisation, there can be used mineral

1 0,336/(70 acids, such as hydrochloric acid, as wvell as aliphatic carbo- xylic acids containing up *to 4 carbon atoms, such as acetic acid

The insect-repellent action of the new compounds according to the present invention was tested against the yellow fever mosquito (Aedes ~yi in vitro and also in vivo.

In the case of the first test, the compounds to be investigated were.dissolved in acetone in a series of concentrations and filter papers (9 cm. diameter) were imprelgnated with these solutions and then dried. The filter papers thus treated were suspended on 15 cm. long strings in the middle of 30 litre glass bell jars. Untreated filter papers of the same size were suspended in two control vessels. Into each glass bell jar were then released 150 yellow fever mosquitoes. In the control vessels with the untreated filter papers, 40 50 of the mosquitoes (about 30%) came to rest on the filter papers.* In the case of the filter papers which had been impregnated with active material, these were partially or completely avoided by the mosquitoes, depending upon the concentration of active material therein. By counting the number of mosquitoes on the filter papers, there was then determined the RD80 i.e. the dosage, expressed in mg./100 cm2 at which 80% of the mosquitoes which would otherwise land on the filter paper, avoid it. As comparative substance, there was used the known insect repellent N,N-diethyl-m-toluamide. The results obtained are summarised in-the-following Tfgbl----

6 4272 96

10,3 6 170 TABLE I Insect-repellent activity of azido-isothiazoles

active material RD80 (in mg./ 100 cm2

0.07

0.1" thiazole-4-ea41borlo 4-1o.

so- 0.38 thiazole 4-ee:et t.l1:

s0.4 thiazole th zea§4 .itrilo

0.13 thiazol- 6a F~t:Littil N,N-diethyl-m-toluamide 0.57

From the results summarised above, it can be clearly seen that the effectiveness of the compounds according to ttht off the present invention are 1.5 to 8 times better tha Vt eo N, -diethyl-m-toluamide used as comparison substance and which is at present the leading commercial preparation. For the in vivo testing, there were applied solutions of the active materials of the same concentrations on cm2 of the skin of the underarm of test subjects, one arm of the subject being treated with a solution of a compound according to the present invention and the other arm of the same subject with the solution of the comparison substance, i.e. N,N-diethyl-m-toluamide. The arms, on which the treated surface were bounded by armbands, were separately introduced into cages, each of which contained about 1000 hungry feml'e mosquitoes and then the time Vas

determined until the subject had received three bites.

The protection times provided by the new compounds according

7 4.27 296

10, 33 6 170 to the present invention were compared with that of l,N1-diethyl-m-toluamide obtained on the same subject. The average protection time ratios are summarised in the following Table II.

TABLE II

active compound protective time ratio 3-chloro-5azido5iso s 2 thiazole-4- abenit!il-e lt- Z14tf1o iso- thiazole--ea4eeni4e1- 4r- yfc- so- thiazolIGrUa4avbea-tple

oso thiazole I n i lI

1.4 thiazole h4. fazbpritrilz

1- diethyl-m-toluaiide i

This Table also clearly demonstrates the superiority of the new compounds according to the present invention as insect repellents. PFurthermore, the new compounds also possess out- standing anti-microbial properties. Besides a wide anti- bacterial spectrum, which includes gram-positive and gram- negative bacteria, they also exhibit an anti-mycetic effect and thus act against mycobacteria and fungi. Due to this property, the new compounds are outstandingly suitable, for example, for the treatment of skin infections. The extremely broad spectrum of activity thereby includes a wide field of application. The anti-bacterial action was examined in a test tube test and in an agar dilution test., using standard

8 427296 methods. 10,33670 There was thereby determined the minimum inhibiting concentration against characteristic represent- atives f the most important groups of micro-organisms. In the case of the agar dilution test, the test substances were added in graduated concentrations to agar media inoculated with the test micro-organisms, followed by incubation at 37°C. and assessment after 24 hours. In the case of the test tube dilution test, the incubation also took place at 37°C. but the assessment was made after 18 hours. There were also used micro-organisms which are difficult to influence, such as Pyocyaneus and Proteus bacteria, as well as Klebsiellae,/f and. penicillin-resistant Sjtaphylococci.

The anti-mycetic testing was carried out by the agar dilution,test against various dermatophytes, yeasts and fungi. Here, too, the test substances were added to the agar media in graduated concentrations. The incubation was carried out at 25°C., and the evaluation of the results after 15 days. The minimum inhibiting concentration was again determined.

The new compounds according to the present Invention can be worked up together with most of the conventional solid or liquid carriers and/or adjuvants used for the desired application. In the selection of the additives, it is only necessary to bear in mind that the new active materials are organic azides so that, for example,, strongly acidic or strongly basic additives should be weakened by the addition of buffer substances. If possible, elevated temperatures should also be avoided during the formulation. For use as insect repellents, the new compounds 9 427296

Sto P acording to the present 10,336/170 inventin can be worked up not Only into cosmetic compositions but also Into technical compositions. The active material content of such compo- sitions is generally between 0.2 and 70j, preferably between 0.5 and 40%. Of course, if necessary, the new active materials can also be combined with known insect repellents. As cosmetic Preparations, there can be con- sidered, in particular, emulsions, salves, sprays or insect-repellent pencils. In this case, as additives there are used those normally employed in the production of cosmetics. As solvents, there can be used, for example, water, ethanol, ispropanol, propylene glycol, glycerol, dichloromethane or acetone. As carrier and/or filler materials, there can be used, for example, paraffin hydro- carbons, such as viscous paraffin oil, petroleum jelly and hard paraffin; fatty alcohols, such as ce.tyl alcohol, stearyl alcoholand cetyl stearyl alcohol; fatty oils; glycerol mono-, di- and tri-fatty acid esters which, depending on the constitution and degree of.substitution are solid, salve-like or liquid; other fatty acid esters, such as propylene glycol monostearate; natural and semi- synthetic materials, such as stearin, ceresin, bees' wax and spermaceti; coolants, such as aluminium stearate; and thickening agents, such as cellulose ethers and. collodium wool.

As emulslfiers, there can be used anion-active substances, for example, 6odi~1 cetyl stearyl sulphate, sodium lauryl sulphate and alkali metal soaps of higher fatty acids, as well as non-ionic substances, such as cholesterol, cholestanol, wool wax alcohol and fatty acid ethers and eters, as well as polyoxyethylated products.

4 272 96

1 0,33 6 0 For technical purposes, the new compounds can be incorporated into paints, into polishing, cleaning and detergent agents, as well as into impregnation agents

for textiles fibres, foils or packing materials. For this purpose, but bearing in mind the azide character of the new compounds, there can be used all the conven- tional substrat.; filling and additive materials. In the case of the use of the new compounds in

.anti-microbial agents, in the first place there are to be considered topical preparations, for example, creams, salves, powders, lotions and emulsions. Here, too, the conventional carrier and'adjuvant materials can be used which must, in particular, have a sufficient skin compat- ibility., As examples, there may be mentioned vegetable oils, benzyl alcohol, polyethylene glycols, gelatine, lactose, starch, magnesium stearate, talc and petroleum jelly. The compositions can be sterilised and mixed with adjuvants, such as lubricating, preservation, stabilis- ation or wetting agents, emulsifiers, salts for influencing the osmotic pressure and buffer substances, as well as colouring and/oa @omataes substances. The new agents, which contain the active materials in concentrations of 0.05 to 5% by weight, are usein the usual manner in the case of all indications in which bacterial and/or mycetic affections are present or are to be expected,-for example.,- polydermias, folliculitides, infected wounds and burns, inflammatory and allergeric. dermatoses. The compositions are preferably applied thinly several times a day on the diseased skin area. The frequency of use depends upon the nature and severity of the-affecti-on. -1 f~l _74-Z79~

10,33 6 The following Examples are given for the purpose of

illustrating the present invention:-

A. Preparation of the azido-isothiazoles.

Example 1.

A solution of 26.0 g. sodium azide in 80 ml. water is

added dropwise. 7ith stirring and cooling, to a solution of

71.6 g. 3,5-dichloro-4-cyano-isothiazole in 400 ml.dimethyl

formamide in such a manner that the temperature of the reacti

mixture does not rise above 400 C. The reaction mixture is tt

cooled to further stirred for half an hour, poured intc

400 ml. ice water and the product which thereby precipitates

out is filtered off with suction. There is thus obtained

3-chloro-5-azido-4-cyano-isothiazole which, after recrystall-

isation from ethanol, melts at 86 88 0 with decompositior

In an analogous manner, there is prepared

4-cyano-isothiazole which is in the form of bright yellow

crystals decomposing above 62 0 C.

Example 2.

a) 404 g. 3,5-di-(methylthio)-4-cyano-isothiazole are

boiled under reflux in 3.5 litres ethanol with 260 g.

hydrazine hydrate for 6 hours and subsequently left to stand

overnight. Unreacted starting material which crystallises ou

is filtered off with suction and the filtrate stirred into 2C

litres water. The precipitated crystalline product is filter

off with suction, dried, suspended in 500 ml. benzene and

again filtered off with suction. There remains behind pure

3-methylthio-5-hydrazino-4-cyano-isothiazole, which melts at 0 171 173 C.

12 4272 9

10,336/7 61 g. 3--tVlho5hdai-o4caoio.izl are suspended in 500 ml. glacial acetic acid. A solution of 27.2 g. sodium nitrate in 120 ml. water is added dropwise, with stirring and cooling in ice water, in such a manner- that the +te.erature

remains between 20 and 23 0 C. The reaction mixture is subse- quently stirred for 15 minutes, poured into 500 ml. ice vwater and the precipitated material filtered off '7ith suction. The 3-e'1~lho5aid--yn-s~izl thus obtained is re- crystallised fr~m isopropanol; it has a melting point of 98 100

The follo.7ing compounds are prepared in an analogous manner: 3-ehyslbnl5aio4eaoiohaoe rn.D. 128 130 C.; 3-eblupi.15aio4eaoistiaoe m.pD. 13 1140 3-tVti--zd-4caoiohaoe m.p. 54 5601.; 3-etbylslponl-azido-4..cyanO-i3Othiazole; decomposes abov 0 3 -n-propylthio-5azido-4-cyano-.isothiazole; n.p. 28 300. 3 -n-propylsulphcnyl-5.azido-4.ya-lo-isothiazole; decomposes above 91 0 3 -iso.-ropylthio-5azido4cyano-.isothiazole; D. 60 620 C.; 3 -isopropyl1suloionyl5azido4cyanoisothiazole; decomposes above 102 0 C.; 3 -n-amylthio.5-azido-.4-.cano-.isothiazole; yellow, non-distill- able oil; 3-1hxyti--zd-4 ,aoiohaoe yellow, non-distill- able oil; 3 -n-octylthio5azido.4-..yano-.isothiazole; yellow, non-distill- able oil; 13 427296

10,.336/70 3-n-dodecylthio-5-azido-4-cyano-isothiazole; yellow, non- distillable oil; 3-benzylthio-5-azido-4-cyano-isothiazole; m.p. 94 950 3-(2-phenyl-ethylthio)-5-azido-4-cyano-isothiazole; 3-(2-chlorobenzylthio)-5-azido-4-cyano-isothiazole; m.p. 94 9500.;

3-(4-chlorobenzylthio)-5-azido-4-cyano-isothiazole; m.p. 64 6700.;

3-(3,4-dichlorobenzylthio)-5-azido-4-cyano-isothiazole; m.p. 84 860 and

3-(4-nitrobenzylthio)-5-azido-4-cyano-isothiazole; decomp. 0 97 104 C. b) 32 g. 5-amino-3-chloro-4-cyano-isothiazole are stirred. into a mixture of 200 ml. glacial acetic acid and 20 ml. concentrated sulphuric acid and diazotised with a solution of 14 g. sodium nitrite in 40 ml. water. After 15 minutes, a solution of 14 g. sodium azide in 30 ml. water is added to the ice-cold solution. After stirring for several hours, evolution of nitrogen has ceased. The reaction mixture is extracted several times with ether. The ether phase is washed with a solution of sodium bicarbonate and water. After dryihg over anhydrous sodium sulphate, the ether is evaporated off in a vacuum and the -residue recrystallised- from isopropanol. There is obtained 3-chloro-5-azido-4-cyano-isothiazole; which melts, with decomposition, at 870 C. B. Formulations for insect-repellent agents. In these Examples the percentages are percentages by weight.

14 427296

1 0,33 6/70 Z~ample 3. Spray liquid. 3 -chloro-5-azi-do-4.cyano..isothiazole isopropanol 2xann~le 4. Insect zrotective salve. 4% 71% aqueous metbyl-cellulose solution alkyl-carboxylic acid polyethylene glycol ester.

Insect Drotection spray. 3 -etbvltbio-5azido4-cYaoisothiazole 0.5'4 highbly viscous collodium wool odoriferous ma'terial 94.0% dichlorometbane. This solution is filled into an aerosol spray can with the same amount of a propellant gas consisting of 50.0% dicblo- rodifluor.ometbane, 25.0% trichloroflC1uorometh ane an3 25.0% technical propane-butane mixtuire (liquid gas). 3xamnle 6. Insect-rep)ellent Ircoer. 35.0%; alkyl-phenol-formal .Iebyde resin 14.0% linseed oil 14.0% .7ood oil I1.27' siccative 2.0-,4 3-(3,4-dichlorobenzylthio5-azido4cyafo-iothazo

33.8% wvhite spirit.

.4 272 96

1 0,33 6 Example 7. Insect-repellent wall-paint. 20.0% polyvinyl acetate dispersion plasticiser-free) polyvinyl acetate dispersion plasticiser- containing) 3 -chloro-5-azido-4-cyano-isothiazole ethanol 35.0% chalk titanium dioxide aqueous methyl cellulose solution 22.0% water. C. Formulations for anti-microbial agents. Examole 8. Powder. Sterilised lactose is mixed with very finely-divided 3 -chloro-5-azido-4-cyano-isothiazole to give a 0.25% composition. Example 9. Cream. 0.3% 3 -chloro-5-azido-4-cyano-isothiazole cetyl alcohol very viscous paraffin oil glycerol monostearate propylene glycol monostearate glycerol 0.1% very finely divided silicic acid petroleum jelly 30.0% polyoxyethylene sorbitan monopalmitate

0.07% 2-hydroxybenzoic acid methyl ester 16 427296

1 0,33 6,/70 0.03/' j2-hydroxybenzoic acid propyl ester- 3.054 propylene glycol 39.0% water Example Salve. 0.25% 3 -cbloro-5'azdo4cyano-.isothiazole cetyl alcohol 1.01,1 anhydrous w~ool fat 15.0% -Qvery viscous paraffin oil 81.0% white petroleum jelly Example 11. Cream. 3-nethylthio-5-a zid 0-4-cyano-is othiazol e mixture of cetyl and octadecyl alcohol 32.0% rhite petroleum jelly very viscous paraffin oil neutral, viscous oil of vegetable origin (triglyceride mixture) Polyoxyethylene sorbitan monopalmitate glycerol monostearate 0.2% sor'oic acid 0.01% perfume oil 0.25% very finely divided silicic acid glycerol 39.0% water Example 12. Lotion. 0.3% 3 -chloro-5..azido-4cyano-.isothiazole vey 1O.3 iscus10,33 6/70 ver visou.paraffin oil ethanol glycerol Propylene glycol 0.15% sorbic acid

1 0,33-67 fatty alcohol polyglycol ether

mixture of cetyl-stearyl alcohol, sodium cetyl-stearyl sulphonate and non-ionic emulsifier

0.01% perfume oil

82.0% water.

r i. I

i I 1.

'i-

i

19 4 272 -96

Claims (1)

10,33 6 17D The claims defining the invention are as follows:-

1. Azido-isothjazoles of the general formula:-

R C

S 3

wherei-n R is a halogen atom or an SR ,SORI or SO 2R Ia radical and R is a straight or branched-cha-in alkyl radical containing up to 12 jcarbon atoms or a benzyl or phenyl-ethyj. radical, the benzene nucleus of which may be substituted by nitro groups and/or halo~gen atoms. 2. 3-Chloro-5-azido.. 4 -cyano-isothiazole. 3. 3 -Bromo-5-azido..4-.cyano...isothiazole. 4. 3 -N-ethylthio-5-.azido-4-.cyano-.isothiazole. 3-Methyl suiphinyl- S-azido-4-cyano-isoJhjazole. 6. 3-Methyl suiphonyl- S-azido-4-cyano..isothiazole. 7. 3-Ethylthio- S-azido-4-cyano-4sothiazole. 8. 3-Ethylsulphonyl.. 5 -azido-4-cyano-isothiazole. 9. 3 -n-Propylthio-5-.azido.4-.cyano...isothiazole4 3 -n-Propylsulphony-5-azido-4.cyano..isothiazole. 11. 3 -Isopropyl thio- S-azido-4-cyano...isothiazole. 12. 3-spoyslhnl5aio4caoiohaoe 13. 3-n-Amyl.thio- S-azido-4-cyano...isothiazole. 14. 3-n-Hexyl thio- S-azido-4-cyano-.isotbiazole. 3-n-Octyl thio-5-azido-4-.cyanoisothiazole. 3 16. -n-Dodecylthio5-azido..4-.cyano.isothiazole.

17. 3-Benzyl thio-5-azido-4..cyano...isothiazole. 18.* 3-C 2-Phenyl-ethyl.thio )-S-azido-4-cyano-isothiazojle. 19. 3-c 2-Chlorobenzyl thia S-azido-4-cyano-Isothiazole.

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1 0,33 6 3-(4-0hlorobenzylthio)-5-azido-4-cyano-isothiazole 21. 3-(3,4-Dichlorobenzylthio)-5-azido-4-cyano-isothiazole.

22. 3-(4-iitrobenzylthio)-5-azido-4-cyano-isothiazole.

23. Process for the preparation of azido-isothiazoles of the

general formula given in claim 1, wherein a compound of the general formula:-

R ON

in which.Y is a halogen atom or a diazonium cation and R has

the same meaning as'in claim 1, is reacted with a metal azide

in a polar solvent.

24. Process according to claim 23, wherein Y in the starting material is a chlorine or bromine atom.

Process according to claim 23 or 24, wherein the metal

azide used is sodium or potassium azide.

26. Process according to any of claims 23 25,.wherein the reaction is carried out at a temperature which does not exceed

500C.

27. Process according to claim 26, wherein the reaction is

carried out at a temperature between 0 and 350C.

28. Process according to claim 23 27, wherein the polar solvent used is water, an aliphatic alcohol containing up to 4

carbon atoms, dimethyl formamide, dimethyl sulphoxide, a ketone

or a

10,336770 cyclic ether or a mixture of such solvents.

29. Process for the preparation of azido-isothiazoles of the generpl formula given in claim 1, wherein a compound of the general formula given in claim 23, in which Y is a hydrazino group, is diazotised in acidic solution.

Process for the preparation of azido-isothiazoles of the general formula given in claim 1, substantially as hereinbefore described and exemplified.

31. Azido-isothiazoles of the general formula given in claim 1, whenever prepared by the process according to any of claims 23

52. Insect-repellent, anti-microbial and antl-mycetic compositions, comprising at least one compound of the general formula given in claim 1, in admixture with an appropriate solid or liquid diluent or carrier. 3355.Compsitions according to claim 52, wherein the active material of the general formula given in claim I is any one of those hereinbefore specifically exemplified. A 34. Compositions according to claim 32 or 33, wherein the content of active material is between 0.2 and 70% by weight. Compositions according to claim 34, wherein the content of active material is between U.5 and 40% by weight. 36. Compositions according to claim 32 or 33 for topical application, wherein the content of active material is between 0.05 and 5% by weight.

37. Compositions according to any of claims 32 56, substantially as hereinbefore described and exemplified.

DATED this 14th day of January, 1970.

E. N13RCK AKTIENGESELLSCHAFT By its Patent Attorneys

ARTHUR S. CAVE CO. Per: 4